Biologically active quinoline and quinazoline alkaloids part I

Abstract

Quinoline and quinazoline alkaloids, two important classes of N-based heterocyclic compounds, have attracted tremendous attention from researchers worldwide since the 19th century. Over the past 200 years, many compounds from these two classes were isolated from natural sources, and most of them and their modified analogs possess significant bioactivities. Quinine and camptothecin are two of the most famous and important quinoline alkaloids, and their discoveries opened new areas in antimalarial and anticancer drug development, respectively. In this review, we survey the literature on bioactive alkaloids from these two classes and highlight research achievements prior to the year 2008 (Part I). Over 200 molecules with a broad range of bioactivities, including antitumor, antimalarial, antibacterial and antifungal, antiparasitic and insecticidal, antiviral, antiplatelet, anti-inflammatory, herbicidal, antioxidant and other activities, were reviewed. This survey should provide new clues or possibilities for the discovery of new and better drugs from the original naturally occurring quinoline and quinazoline alkaloids.

1 |. INTRODUCTION

Quinoline alkaloids are important N-based heterocyclic aromatic compounds with a broad range of bioactivities. They have attracted significant attention from researchers over the past 200 years.¹ After the quinoline alkaloid quinine (1) (Fig. 1) was isolated from the bark of the Cinchona tree in 1820, it replaced the crude bark in the treatment of malaria.^2,3 Although 1 has relatively low efficacy and tolerability, it played a historical role in the development of quinoline alkaloids, and still plays an important role in the treatment of multi-resistant malaria.^2,4 Camptothecin (CPT, 2) (Fig. 1), isolated from the Chinese tree Camptotheca acuminata in the early 1960s, is the most important and famous quinoline alkaloid from an anticancer aspect.^5,6 Ever since mechanistic studies determined that CPT specifically targets DNA topoisomerase (topo) I, modified CPT analogs have been at the frontline of anticancer drug development. In addition, numerous quinoline alkaloids have been isolated and identified from natural sources, and many studies have documented their antitumor, antimalarial, antibacterial, antifungal, antiparasitic and insecticidal, antiviral, antiinflammatory, antiplatelet and other activities (Table 1).^1,7 Now, quinoline alkaloids and their derivatives have extensive medical and agricultural applications.

FIGURE 1:

Chemical structures of historically important quinoline and quinazoline alkaloids 1–4

Table 1.

The active quinolone and quinazoline alkaloids^a

No.	Compound	Activity	Reference
1	Quinine	Anti-tumor activity	93
		Antimalarial activity	2,3,166,167
		Trypanocidal activity	108
2	Camptothecin	Anti-tumor activity	6,60–64
3	Vasicine	Antifeedant activity	215
		Cardiovascular protective activity	281
		Bronchodilator activity	332
		Oxytocic activity	340
4	Febrifugine	Antimalarial activity	176–186
		Trypanocidal activity	219
28	Quinidine	Anti-tumor activity	91,92
		Antiarrhythmic activity	256–266
		Effect on CYP3A4	323
29	Zanthosimuline	Anti-tumor activity	94
30	Huajiaosimuline	Anti-tumor activity	94,95
		Antiplatelet activity	95
31	Flindersine	Anti-tumor activity	96,97
		Anti-bacterial activity	228
		Anti-fungal activity	244
		SRS-A antagonist	333
32	Haplamine	Anti-tumor activity	97
		Anti-fungal activity	244
33	γ-Fagarine	Anti-tumor activity	100,121
		Antiplatelet activity	95
		Cardiovascular protective activity	275
		Anti-HIV activity	284
		Mutagenicity	336
		Estrogenic activity	341
34	Skimmianine	Anti-tumor activity	98,100
		Antimalarial activity	173
		Anti-leishmania activity	199
		Trypanocidal activity	200
		Anti-bacterial activity	228
		Anti-fungal activity	245
		Antiplatelet activity	95,269–272
		Cardiovascular protective activity	273,275
		Antagonists at the 5-HT2 receptor site	307
		Mutagenicity	335
		Estrogenic activity	341
35	Haplopine	Anti-tumor activity	97
		Antimalarial activity	173
		Anti-bacterial activity	228
		Antiplatelet activity	95
		Cardiovascular protective activity	275
		Anti-HIV activity	284
		Estrogenic activity	341
36	Evolitrine	Anti-tumor activity	98
		Antifeedant activity	201
		Antiplatelet activity	269–272
		Cardiovascular protective activity	275
		Antiviral activity	292
		Anti-inflammatory activity	293
37	Kokusaginine	Anti-tumor activity	98
		Antimalarial activity	173
		Trypanocidal activity	200
		Insecticidal activity	203,204
		Anti-bacterial activity	228
		Anti-fungal activity	245
		Antiplatelet activity	269–272
		Cardiovascular protective activity	275
		Antagonists at the 5-HT2 receptor site	307
38	Maculosidine	Anti-tumor activity	98
39	2,3-Methylenedioxy-4,7-dimethoxyquinoline	Anti-tumor activity	98
40	Dictamnine	Anti-tumor activity	99,100
		Antifeedant activity	201,202
		Anti-fungal activity	245,246
		Antiplatelet activity	267,269–272
		Cardiovascular protective activity	275
		Antiviral activity	292
		Mutagenicity	335
41	Graveoline	Anti-tumor activity	99
		Herbicidal activity	314
42	Maculine	Anti-tumor activity	101
		Anti-fungal activity	245
43	5-Methoxymaculine	Anti-tumor activity	101
44	5,8-Dimethoxymaculine	Anti-tumor activity	101
45	4,5,6,7,8-Pentamethoxyfuroquinoline	Anti-tumor activity	101
46	Flindersiamine	Anti-tumor activity	101
		Anti-bacterial activity	227
		Anti-fungal activity	245
47	7-(2′-Hydroxy-3′chloroprenyloxy)-4-methoxy-furoquinoline	Anti-tumor activity	102
48	7-(2′,3′-Epoxyprenyloxy)-4-methoxyfuroquinoline	Anti-tumor activity	102
49	Pteleine	Anti-tumor activity	103
		Antiplatelet activity	269–272
50	(+)-7,8-Dimethoxymyrtopsine	Anti-tumor activity	102,103
51	Medicosmine	Anti-tumor activity	104
52	Jineol	Anti-tumor activity	105
		Anti-oxidant activity	329
53	3,8-Dimethoxyquinoline	Anti-tumor activity	105
54	3,8-Diacetoxyquinoline	Anti-tumor activity	105
55	Senepodine A	Anti-tumor activity	106
56	7-Hydroxy-4-[5′-hydroxymethylfuran-2′-yl]-2-quinolone	Anti-tumor activity	107
57	Acetylcupreine	Anti-tumor activity	108
		Insecticidal activity	108
58	3,3-Diisopentenyl-N-methyl2,4-quinoldione	Anti-tumor activity	109
59	Cuspareine	Anti-tumor activity	110
		Antimalarial activity	110
60	Galipeine	Anti-tumor activity	110
		Antimalarial activity	110
61	Galipinine	Anti-tumor activity	110
		Antimalarial activity	110
62	Angustureine	Anti-tumor activity	110
		Antimalarial activity	110
63	Asimicilone	Anti-tumor activity	111
64	Lepadin A	Anti-tumor activity	112,113
65	Lepadin B	Anti-tumor activity	112,113
66	Lepadin C	Anti-tumor activity	112,113
67	Lepadin D	Antimalarial activity	112,113
		Trypanocidal activity	112,113
		Anti-fungal activity	112,113
68	Lepadin E	Anti-tumor activity	112,113
		Antimalarial activity	112,113
		Trypanocidal activity	112,113
		Anti-fungal activity	112,113
69	Lepadin F	Anti-tumor activity	112,113
		Antimalarial activity	112,113
		Trypanocidal activity	112,113
		Anti-fungal activity	112,113
70	Lepadin G	Anti-tumor activity	112,113
71	Benzastatin C	Neuroprotective activity	114,115
		Anti-oxidant activity	114,115
72	Benzastatin D	Neuroprotective activity	114,115
		Anti-oxidant activity	114,115
73	(−)-SW-163C	Anti-tumor activity	116,117
74	(−)-SW-163E	Anti-tumor activity	116,117
75	3S*,4R*-Dihydroxy-4-(4′methoxyphenyl)-3,4-dihydro-2(1H)-quinolinone	Anti-tumor activity	118
76	3R*,4R*-Dihydroxy-4-(4′methoxyphenyl)-3,4-dihydro-2(1H)-quinolinone	Anti-tumor activity	118
77	Peniprequinolone	Anti-tumor activity	118
		Nematicidal activity	210
78	Aspernigerin	Anti-tumor activity	119
79	(+)-Quinocitrinine A	Anti-tumor activity	120
		Anti-bacterial activity	120
80	(−)-Quinocitrinine B	Anti-tumor activity	120
		Anti-bacterial activity	120
81	Isodictamnine	Anti-tumor activity	121
82	Iso-γ-fagarine	Anti-tumor activity	121
83	Luzopeptin A	Anti-tumor activity	121–126
		Anti-HIV activity	286
84	Luzopeptin B	Anti-tumor activity	121–126
		Anti-HIV activity	286
85	Luzopeptin C	Anti-tumor activity	121–126
		Anti-HIV activity	286
86	Streptonigrin	Anti-tumor activity	127
87	7-(1-Methyl-2-oxopropyl)streptonigrin	Anti-tumor activity	127
88	BE-22179	Anti-tumor activity	128,129,132,133
89	Thiocoraline	Anti-tumor activity	130–133
		Anti-bacterial activity	240
90	Confusadine	Anti-tumor activity	134
		Antiplatelet activity	274
91	Furomegistine I	Anti-tumor activity	135
92	Furomegistine II	Anti-tumor activity	135
93	Megistosarconine	Anti-tumor activity	136
94	Cyclomegistine	Anti-tumor activity	137
95	4-Carbomethoxy-6-hydroxy2-quinolone	Anti-tumor activity	138
		Anti-oxidant activity	330
96	Viridicatin	Anti-tumor activity	139
97	Viridicatol	Anti-tumor activity	139,140
98	Fumiquinazoline A	Anti-tumor activity	141,142
99	Fumiquinazoline B	Anti-tumor activity	141,142
100	Fumiquinazoline C	Anti-tumor activity	141,142
101	Fumiquinazoline D	Anti-tumor activity	141,142
102	Fumiquinazoline E	Anti-tumor activity	141,142
103	Fumiquinazoline F	Anti-tumor activity	141,142
104	Fumiquinazoline G	Anti-tumor activity	141,142
105	(−)-Spiroquinazoline	Anti-tumor activity	143
106	Luotonin A	Anti-tumor activity	144–146
107	Luotonin B	Anti-tumor activity	144–146
108	Luotonin E	Anti-tumor activity	144–146
109	Luotonin F	Anti-tumor activity	144–146
110	Deoxyvasicine	Anti-tumor activity	148
		Anticholinesterase activity	309
111	Tryptanthrin	Anti-tumor activity	152–155
		Antimalarial activity	187,188
		Trypanocidal activity	217
		Antifeedant activity	216
		Anti-bacterial activity	253,254
		Anti-inflammatory activity	298,299
112	Qingdainone	Anti-tumor activity	152
113	3-(2-Carboxyphenyl)-4(3H)-quinazolinone	Anti-tumor activity	156
114	1-Methoxy-7,8-dehydrorutaecarpine	Anti-tumor activity	157
115	Rutaecarpine	Anti-tumor activity	157
		Antiplatelet activity	277
		Anti-inflammatory activity	306
		Effect on CYP1A1, CYP1A2 and CYP1B1	318–322
116	1-Hydroxyrutaecarpine	Anti-tumor activity	157
		Antiplatelet activity	277
117	Samoquasine A	Anti-tumor activity	158–161
118	2-Acetyl-4(3H)-quinazolinone	Anti-tumor activity	162,163
		Anti-HIV activity	162,163
119	2-n-Propylquinoline	Antimalarial activity	172
		Anti-leishmania activity	192–196
		Trypanocidal activity	197
		Molluscicidal activity	198
		Antiviral activity	289–291
120	2-Pentylquinoline	Antimalarial activity	172
		Anti-leishmania activity	192–196
		Trypanocidal activity	197
		Molluscicidal activity	198
		Antiviral activity	289–291
121	Chimanine B	Antimalarial activity	172
		Anti-leishmania activity	192–195
122	Chimanine D	Antimalarial activity	172
		Anti-leishmania activity	192–195
		Antiviral activity	289–291
123	4-Methoxy-2phenylquinoline	Antimalarial activity	172
124	2-(3,4- Methylenedioxyphenylethyl)quinoline	Antimalarial activity	172
		Anti-leishmania activity	192–195
		Molluscicidal activity	198
		Antiviral activity	289–291
125	Acronycidine	Antimalarial activity	173
126	Acronydine	Antimalarial activity	173
127	Veprisine	Antimalarial activity	174
		SRS-A antagonists	333
128	N-Methylpreskimmianine	Antimalarial activity	174
129	2-Nonyl-4-(1H)-quinolone	Antimalarial activity	175
		Immunomodulatory activity	297
130	2-Undecyl-4-(1H)-quinolone	Antimalarial activity	175
		Immunomodulatory activity	297
131	2-(Undec-1-enyl)quinolin4-(1H)-one	Antimalarial activity	175
132	Isofebrifugine	Antimalarial activity	176–186
133	Quinazolin-4-(3H)-one	Antimalarial activity	181
		Bronchodilator activity	331,332
134	2-Methoxyrutaecarpine	Effect on CYP1A1, CYP1A2 and CYP1B1	318
136	5,8,13,14-Tetrahydro-2methoxy-14-methyl-5oxo-7H-indolo[2′,3′:3,4]-pyrido[2,1b] quinazolin-6-ium chloride	Antimalarial activity	174
137	(−)-Janoxepin	Antimalarial activity	189
138	Cusparine	Anti-leishmania activity	199
140	rel-(7R,8R)-8-[(E)-3-hydroxy3-methyl-1-butenyl]-4,8-dimethoxy-5,6,7,8-tetrahydrofuro[2,3-b]quinoline-7-yl acetate	Trypanocidal activity	200
141	Evocarpine	Insecticidal activity	204
		Anti-bacterial activity	222,223,225
		Cardiovascular protective activity	276
		Immunomodulatory activity	297
		Hypolipidaemic activity	328
142	Dihydroevocarpine	Insecticidal activity	204
		Anti-bacterial activity	222
		Immunomodulatory activity	297
		Hypolipidaemic activity	328
143	Antidesmone	Trypanocidal activity	205
144	N-Methyl-2-nonylquinolin-4(1H)-one	Trypanocidal activity	206
145	N-Methyl-2-hexylquinolin-4(1H)-on	Trypanocidal activity	206
146	Atanine	Antiparasitic and anthelmintic activity	207
147	Quinolactacide	Insecticidal activity	208,209
148	Penigequinolone A	Nematicidal activity	210
		Herbicidal activity	315
149	Penigequinolone B	Nematicidal activity	210
		Herbicidal activity	315
150	3-Methoxy-4-hydroxy-4-(4′-methoxyphenyl)quinolinone	Nematicidal activity	210
151	3-Methoxy-4,6-dihydroxy-4- (4′-methoxyphenyl)quinolinone	Nematicidal activity	210
152	Leiokinine A	Antifeedant activity	211
153	Leiokinine A	Antifeedant activity	211
154	3,4-Dihydroxyquinoline-2-carboxylic acid	Antifeedant activity	212
155	(−)-Yaequinolone J1	Insecticidal activity	213
156	(−)-Yaequinolone J2	Insecticidal activity	213
157	3-Methoxy-4,5-dihydroxy-4- (4′-methoxyphenyl)quinolinone	Insecticidal activity	214
158	Vasicinone	Antifeedant activity	215
		Bronchodilator activity	331
159	Vasicinol	Antifeedant activity	215
160	(+)-Nα-Quinaldyl-L-arginine	Antifeedant activity	218
161	1,3-Dimethylquinazoline2,4-dione	Insecticidal activity	220,221
162	1-Methyl-2-pentadecyl4(1H)-quinolone	Anti-bacterial activity	222
		Immunomodulatory activity	297
163	1-Methyl-2-[(4Z,7Z)-4,7-tridecadienyl]-4(1H)-quinolone	Anti-bacterial activity	222,225
		Cardiovascular protective activity	276
		Immunomodulatory activity	297
		Hypolipidaemic activity	328
164	1-Methyl-2-[(6Z,9Z)-6,9-pentadecadienyl]-4(1H)-quinolone	Anti-bacterial activity	222,225
		Cardiovascular protective activity	276
		Immunomodulatory activity	297
		Hypolipidaemic activity	328
165	1-Methyl-2-undecyl-4(1H)-quinoline	Anti-bacterial activity	222,225
		Immunomodulatory activity	297
166	1-Methyl-2-[(Z)-7tridecadienyl]-4(1H)-quinolone	Anti-bacterial activity	223
167	1-Methyl-2-(6Z)-6undecenyl-quinolone	Anti-bacterial activity	225
168	2,3-Dimethyl-4-quinolone	Anti-bacterial activity	226
169	Megistoquinone I	Anti-bacterial activity	230
170	Megistoquinone II	Anti-bacterial activity	230
172	3-(2,3-Dihydroxy-3-methylbutyl)-4,7-dimethoxy-1-methyl-1H-quinolin-2-one	Anti-bacterial activity	231
173	Quinoline-4-carbaldehyde	Anti-bacterial activity	232,233
		Anti-fungal activity	249
174	3-Methyl-2-(non-2enyl)quinolin-4(1H)-one	Anti-bacterial activity	234,235
175	2-(2-Heptenyl)-3-methyl-4(lH)-quinolone	Anti-bacterial activity	234,235
		Anti-fungal activity	249
176	YM-30059	Anti-bacterial activity	236
177	Aurachin A	Anti-bacterial activity	237
		Effect on cytochrome	316,317
178	Aurachin B	Anti-bacterial activity	237
		Effect on cytochrome	316,317
179	Aurachin C	Anti-bacterial activity	237
		Effect on cytochrome	316,317
180	Aurachin D	Anti-bacterial activity	237
		Effect on cytochrome	316,317
181	Helquinoline	Anti-bacterial activity	238
182	CJ-13136	Anti-bacterial activity	239
183	CJ-13217	Anti-bacterial activity	239
184	CJ-13536	Anti-bacterial activity	239
185	(−)-CJ-13564	Anti-bacterial activity	239
186	CJ-13565	Anti-bacterial activity	239
187	CJ-13566	Anti-bacterial activity	239
188	(+)-CJ-13567	Anti-bacterial activity	239
189	(−)-CJ-13568	Anti-bacterial activity	239
190	Sch 40832	Anti-bacterial activity	241
191	2-Heptylquinolin-4-ol	Anti-bacterial activity	242
192	2-Pentylquinolin-4-ol	Anti-bacterial activity	242
193	trans-Decahydroquinoline 243A	Anti-bacterial activity	243
194	Anhydroevoxine	Anti-fungal activity	244
195	Platydesmine	Anti-fungal activity	245
		Anti-HIV activity	284
196	1-Methyl-2-[6′-(3′′,4′′-methylenedioxyphenyl)hexyl]-4-quinolone	Anti-fungal activity	247
197	Distomadine B	Anti-fungal activity	248
198	Distomadine A	Anti-fungal activity	248
199	4-Hydroxymethylquinoline	Anti-fungal activity	249
200	Quinoline-4-carbaldoxime	Anti-fungal activity	249
201	Quinoline-4-carboxylic acid	Anti-fungal activity	249
202	N-Mercapto-4-formylcarbostyril	Anti-fungal activity	250
203	Virantmycin	Anti-fungal activity	251,252
		Antiviral activity	251,252
204	Fumiquinazoline H	Anti-bacterial activity	255
205	Fumiquinazoline I	Anti-bacterial activity	255
206	Simulenoline	Antiplatelet activity	95
207	Benzosimuline	Antiplatelet activity	95
208	Zanthobungeanine	Antiplatelet activity	95
209	Robustine	Antiplatelet activity	95
		Cardiovascular protective activity	275
210	Edulitine	Antiplatelet activity	95
211	4-Methoxy-1-methylquinolin-2-one	Antiplatelet activity	268
		Anti-HIV activity	284
212	Confusameline	Antiplatelet activity	269–272
		Cardiovascular protective activity	275
		Antagonists at the 5-HT2 receptor site	307
213	1-Methoxyrutaecarpine	Antiplatelet activity	277
214	Acrophyllidine	Cardiovascular protective activity	278
215	Evodiamine	Anti-inflammatory activity	297
		Vasodilatory effect	279
216	Dehydroevodiamine	Vasodilatory effect	279
217	Uranidine	Anti-HIV activity	282
218	Buchapine	Anti-HIV activity	283
219	3-Prenyl-4-prenyloxyquinolin-2-one	Anti-HIV activity	283
220	Sandramycin	Anti-HIV activity	285
221	Orixalone A	Anti-inflammatory activity	294
222	Quinolactacin A1	Anti-inflammatory activity	295,296
		Anticholinesterase activity	310
223	Quinolactacin A1	Anti-inflammatory activity	295,296
		Anticholinesterase activity	310
224	Quinolactacin B	Anti-inflammatory activity	295,296
225	Quinolactacin C	Anti-inflammatory activity	295,296
226	Isaindigotone	Anti-inflammatory activity	304
227	Quinazoline-2,4-dione	Anti-inflammatory activity	305
		Antihypertensive activity	305
228	Goshuyuamide II	Anti-inflammatory activity	306
229	Pteleprenine	Agonist of nicotinic acetylcholine receptors	308
230	Dictyoquinazol A	Cortical neurons protective activity	312
231	Dictyoquinazol B	Cortical neurons protective activity	312
232	Dictyoquinazol C	Cortical neurons protective activity	312
233	Fiscalin A	Inhibition of the binding of substance P	313
234	Fiscalin B	Inhibition of the binding of substance P	313
235	Fiscalin C	Inhibition of the binding of substance P	313
236	Circumdatin H	Effect on the respiratory chain	324
237	Circumdatin E	Effect on the respiratory chain	324
238	FR225659	Hypoglycemic activity	325–327
239	239	Hypoglycemic activity	325–327
240	240	Hypoglycemic activity	325–327
241	241	Hypoglycemic activity	325–327
242	242	Hypoglycemic activity	325–327
243	2,8-Dihydroxy-3,4-dimethoxyquinoline	Anti-oxidant activity	329
244	N-Methylflindersine	SRS-A antagonists	333
245	2-Methyl-4(3H)-quinazolinone	Inhibitor of poly(ADP-ribose) synthetase	338
246	Eduline	Effect on muscle	339
247	Japonine	Effect on muscle	339

^aCompounds 5–27 are CPT analogs and are not specifically listed in this table.

Quinazoline alkaloids are another class of N-based heterocyclic compounds. To date, approximately 150 naturally occurring quinazoline alkaloids have been isolated from several families of the plant kingdom, as well as from animals and microorganisms; many are derived biogenetically from anthranilic acid.^8,9 In 1888, the first quinazoline alkaloid, vasicine (3) (Fig. 1), was isolated from Adhatoda vasica and later from other species.^10,11 Our group optimized the extraction technology of this compound from Peganum harmala and recently reported its acaricidal activity.¹² In the 1950s, more comprehensive study of quinazoline alkaloids began after a new quinzolinone alkaloid, 3-[β-keto-γ-(3-hydroxy-2-piperidyl)-propyl]-4-quinazolone [febrifugine,² 4] (Fig. 1), with antimalarial effects was isolated from the Asian plant Dichroa febrifuga.¹³ Since then, many more quinazoline alkaloids and their derivatives were isolated, synthesized, and found to exhibit diverse pharmacological activities with broad agricultural and medical uses (Table 1).^14–21

Several thousands of publications (journal articles, books, and patents) on quinoline and quinazoline alkaloids have been recorded through 2016. The topics include the extraction, synthesis, pharmacology, and other aspects of these compounds. The increasing numbers of publications reflect the importance and research intensity in this field, as well as the bright prospect for drug development of these compounds. Furthermore, some excellent reviews on quinoline and quinazoline alkaloids from a historical point of view are available.^{1,6,8,9,12,22–57} These publications focused mainly on the chemical structures of isolated compounds, the synthetic methods and approaches to new derivatives, and the derivatives’ biological properties. They have contributed significantly to the general scientific understanding of quinoline and quinazoline alkaloids. However, from 2008 to date, additional significant studies have been published, and a more comprehensive and up-to-date review is merited. Therefore, this review combines newer literature reports with the authors’ research as well as presents the developments in this field more from the perspective of biological activities. It covers quinoline and quinazoline alkaloids related not only to anticancer and antimalarial effects, but also other biological activities. We hope that this review will provide new clues or possibilities for the development of these compounds. Due to the vast amount of literature, we will split the material into two review papers. This review will cover the literature up to 2008 (Part I, all active quinoline and quinazoline alkaloids isolated are listed in Table 1), and the forthcoming review (Part II) will summarize the literature from 2009 to 2016.

2 |. BIOACTIVITIES OF QUINOLINE AND QUINAZOLINE ALKALOIDS

2.1 |. Antitumor activity

2.1.1 |. Quinoline alkaloids

Cancer is known medically as a malignant neoplasm, which includes over 200 human diseases, all involving unregulated cell growth.⁵⁸ Many new natural products with anticancer activities have been isolated and could possibly The active quinoline and quinazoline alkaloids^a be used in the treatment of cancer. Among such potential anticancer compounds or agents, some quinoline and quinazoline alkaloids fused with various heterocycles have displayed potent anticancer activity. CPT (2) is one of the most important and famous.⁵⁹ It is a specific and strong inhibitor of the DNA-replicating enzyme topo I.^59,60 In the presence of CPT, cells either undergo cell cycle arrest in S-phase or continue progression with subsequent accumulation of DNA damage, ultimately resulting in cell death.^61–63 Because of this distinct cytotoxic mechanism, CPT exhibits significant activity against established cell lines from leukemias and various solid cancers, such as colon, lung, breast, ovarian, and melanoma, in experimental systems. However, CPT is water insoluble and results in severe and unpredictable side effects. These shortcomings hampered the development of CPT in the 1970s. Meanwhile, these problems also stimulated interest in the synthesis of CPT analogs to find active and clinically useful anticancer drugs with the same mechanism of action.⁶ More than 5000 publications on CPT were recorded between 1966 and 2012. This dramatic number of publications not only reflects the research intensity, but also the importance and bright prospect of CPT derivatives in cancer treatment.

To date, five non-water-soluble CPT analogs, rubitecan (5),^64,65 9-aminocamptothecin (6),⁶⁶ gimatecan (7),⁶⁷ karenitecin (8),⁶⁸ DB-67 (9),⁶⁹ and three water-soluble analogs, exatecan (10)^70–72, lurtotecan (11),^73,74 and sinotecan (12)^75,76 (Fig. 2), are in preclinical and clinical studies. Newly emerging homocamptothecin (hCPT) derivatives, BN80915 (13) and BN-80927 (14)^77,78 (Fig. 2) with a stabilized seven membered hydroxylactone ring, the CPT prodrug afeletecan (15),^79,80 and different delivery systems (16–18)^81–84 (Fig. 3) are also currently undergoing clinical trials. More importantly, three CPT analogs, topotecan (19),⁸⁵ irinotecan (20),⁸⁶ and belotecan (approved only in South Korea) (21),⁸⁷ have received governmental approval for the clinical treatment of ovarian, small-cell lung, and refractory colorectal cancers.

FIGURE 2:

The chemical structures of camptothecin analogs 5–14

FIGURE 3:

The chemical structures of camptothecin analogs 15–18

In recent years, the authors’ laboratories designed and synthesized several series of CPT derivatives. In 2008, a nitroxylradicalmoiety(1-oxyl-2,2,5,5-tetramethylpyrroline-3-carboxylicacid)waslinkedatthe20-hydroxylofCPTvia different hydrophilic amino acid spacers to generate a series of novel spin-labeled CPT derivatives (23–27) (Fig. 5).⁸⁸ The new compounds showed similar or better in vitro cytotoxic activity than the parent drug CPT and the clinically available drug 20 against human bladder cancer T-24. In 2012, a series of 7-acyl CPT derivatives showed significant inhibition of A-549, DU-145, KB, and KBvin cell growth with IC₅₀ values ranging from 0.0154 to 13.3 μM.⁸⁹ In continued efforts, 20-sulfonylamidine CPT derivatives with potent antitumor activity were also synthesized.⁹⁰ Among them, compound 22 (Fig. 4) showed the best potency against the growth of A549, DU-145, KB, and KBvin with IC₅₀ values of 0.031, 0.050, 0.14, and 0.026 μM, respectively. It induced significant DNA damage by selectively inhibiting topo I and activating the ATM/Chk-related DNA damage-response pathway. Furthermore, compound 22 at 300 mg/kg (i.p.) showed no overt acute toxicity in contrast to CPT in vivo (LD₅₀ 56.2 mg/kg, i.p.). Thus, 22 is attractive as a potential candidate for anticancer chemotherapy, and the modification with sulfonylamidine-substituted side chains may overcome some limitations of CPT.

FIGURE 5:

The chemical structures of camptothecin analogs 23–27

FIGURE 4:

The chemical structures of camptothecin analogs 19–22

The antitumor activity of quinidine (28) (Fig. 6), another major quinoline alkaloid from the Cinchona tree, was observed in 1989.⁹¹ This compound effectively modulates resistance, increasing the sensitivity of the multidrug resistant breast cancer cell line MCF-7 to adriamycin by eight-fold. In other studies, a combination of 28 and epirubicin was not more toxic than epirubicin alone and, at a dose of 250 mg b.d., levels of 28 equivalent to those active in vitro were achieved in patients.⁹² Thus, the treatment of advanced breast cancer with a combination of 28 and epirubicin appears feasible. In addition, quinine (1) (Fig. 1) increased the cellular accumulation of anthracycline in resistant cells and enhanced the in vitro cytotoxic activity of epidoxorubicin in resistant DHD/K12 rat colon cancer cells, and also circumvented anthracycine resistance in clinical practice.⁹³

FIGURE 6:

Chemical structures of compounds 28–51

Subsequently, more quinoline alkaloids were isolated and evaluated for cytotoxic activity. In 1994, Chen and coworkers isolated two pyranoquinoline alkaloids, zanthosimuline (29) and huajiaosimuline (30) (Fig. 6), from the root bark of Zanthoxylum simulans.⁹⁴ In cytotoxicity testing, 29 exhibited a general cytotoxic response to various cultured human cancer cell lines, especially P-388 cells (EC₅₀ 5.20 μM). However, 30 produced a more selective cytotoxic activity profile and was especially effective against estrogen receptor-positive breast cancer ZR-75–1 (EC₅₀ 11.1 μM) and P-388 (EC₅₀ 9.80 μM) cells. The two compounds also induced the expression of cellular markers associated with cell differentiation in cultured HL-60 cells.⁹⁴ In later studies, the same authors again verified the cytotoxic activity of 30.⁹⁵

Two additional pyranoquinoline alkaloids, flindersine (31), and haplamine (32), as well as three furoquinoline alkaloids, γ-fagarine (33), skimmianine (34), and haplopine (35), (Fig. 6) from the genus Haplophyllum,^96,97 showed cytotoxic activity against the HeLa cell line (IC₅₀ < 50.0 μM), while only 32 was active against the HCT 116 cell line (IC₅₀ 64.5 μM). A structure–activity relationship (SAR) analysis showed that the aliphatic side chains at the 2^′-position of the pyrano group of the pyranoquinoline alkaloids may increase the cytotoxic activity against human cancer cell lines. However, colchicine (positive drug) was much more potent with IC₅₀ values of 1.10 and 1.30 μM against HeLa and HCT 116 cell lines, respectively.⁹⁷

As indicated above, furoquinoline alkaloids, which are derived biogenetically from 2-substituted oxygenated 4-quinolones after a prenylation at C-3, can exhibit cytotoxic activity. In 1999, several furoquinoline alkaloids, including γ-fagarine (33), skimmianine (34), evolitrine (36), kokusaginine (37), and maculosidine (38), along with 2,3-methylenedioxy-4,7-dimethoxyquinoline (39) (Fig. 6), were isolated from the root bark of Acronychia laurifolia.⁹⁸ Compounds 34 and 36–38 exhibited varying potencies of cytotoxic activity against specific human cancer cell lines, BC1 (EC₅₀ 15.4, 25.3, > 70, and > 70 μM, respectively), KB-V1⁺ (17.0, 12.7, 17.0, and 17.4 μM, respectively) and KB-V1⁻ cell line (10.8, 16.6, 55.6, and 39.4 μM, respectively), but were inactive against Lu1, Col2, KB, and LNCaP cells.⁹⁸

The furoquinoline dictamnine (40) and the 2-phenylquinolinone graveoline (41) from Ruta graveolens demonstrated greater cytotoxic activity against HeLa (EC₅₀ 12.6, 14 μM) compared with KB (EC₅₀ 103, 26.8 μM) cancer cell lines.⁹⁹ In another study, 40, 33, and 34 were identified as moderate cytotoxic constituents from Z. pistaciiflorum against murine leukemia P-388, A549, and HT-29 cell lines.¹⁰⁰

Five additional furoquinoline alkaloids, maculine (42); 5-methoxymaculine (43); 5,8-dimethoxymaculine (44); 4,5,6,7,8-pentamethoxyfuroquinoline (45); and flindersiamine (46) (Fig. 6), from Vepris punctate, showed modest cytotoxic activity toward the A2780 cell line (IC₅₀ < 20 μM).¹⁰¹ In 2005 and 2006, 7-(2^′-hydroxy-3^′-chloroprenyloxy)4-methoxyfuroquinoline (47), 7-(2^′,3^′-epoxyprenyloxy)-4-methoxyfuroquinoline (48), pteleine (49), and (+)-7,8-dimethoxymyrtopsine (50) (Fig. 6) were isolated from two Melicope species, the former two compounds from M. bonwickii and the latter two from M. semecarpifolia.^102,103 Compounds 47 and 48 showed cytotoxic activity when tested against the HeLa cell line (IC₅₀ 34 and 20.1 μM, respectively).¹⁰² Compound 49 showed similar potency toward the P-388 cell line (EC₅₀ 39.0 μM), but both 49 and 50 were less potent against the HT-29 cell line (EC₅₀ 66.4 and 124 μM, respectively).¹⁰³ The rare furanoquinoline alkaloid medicosmine (51) (Fig. 6) has a fused 2,2-dimethyl2H-pyran ring rather than the simple methoxy group found in 49. It was isolated from the aerial parts of Boronella koniambiensis and was slightly cytotoxic against the murine L1210 leukemia cell line (IC₅₀ 48.0 μM).¹⁰⁴

Jineol (52), a simple quinoline alkaloid from an animal rather than plant source, was isolated from the centipede Scolopendra subspinipes mutilans in 1996, together with 3,8-dimethoxyquinoline (53) and 3,8-diacetoxyquinoline (54) (Fig. 7).¹⁰⁵ Compared with 53 and 54, compound 52 exhibited greater cytotoxic activity in vitro against five human tumor cell lines, A-549 (EC₅₀ 36.0 μM), SKOV-3 (EC₅₀ 27.9 μM), SK-Mel-2 (EC₅₀ 34.7 μM), XF-498 (EC₅₀ 62.1 μM) and HCT-15 (EC₅₀ 11.8 μM). It was less effective than cisplatin, but more effective than carboplatin.¹⁰⁵ Senepodine A (55) (Fig. 7), a novel C₂₂N₂ alkaloid isolated from Lycopodium chinense, was significantly cytotoxic toward murine lymphoma L1210 cells (IC₅₀ 0.290 μM).¹⁰⁶ 7-Hydroxy-4-[5^′-hydroxymethylfuran-2^′-yl]-2-quinolone (56) (Fig. 7) from Aquilegia ecalcarata was moderately cytotoxic toward GLC-82 and HCT cells (IC₅₀ 8.80–10.1 μM) in vitro.¹⁰⁷

FIGURE 7:

Chemical structures of compounds 52–63

Other studies found cytotoxic activity with acetylcupreine¹⁰⁸ (57) (Fig. 7) from Remijia peruviana against mammalian CHO cells (ED₅₀ 43.8 μM) and with 3,3-diisopentenyl-N-methyl-2,4-quinoldione¹⁰⁹ (58) (Fig. 7) from Esenbeckia almawillia against HL-60, CEM, B-16, HCT-8, and MCF-7 cancer cells (IC₅₀ 29.5– > 80.3 μM). The simple tetrahydroquinoline alkaloids cuspareine (59), galipeine (60), galipinine (61), and angustureine (62) (Fig. 7) were cytotoxic toward HeLa cells (IC₅₀ 18.6–161 μM), with 59 showing the highest potency (IC₅₀ 18.6 μM).¹¹⁰

In 1992, the new 2-quinolone alkaloid asimicilone (63) (Fig. 7) was isolated from Asimina parviflora.¹¹¹ It showed cytotoxic activity against A-549, HT-29, and MCF-7 (IC₅₀ 7.47, 11.4, and 25.3 μM, respectively). The IC₅₀ values of adriamycin (positive control) against the same three human tumor cell lines were 0.001, 0.008, and 0.425 μM respectively.

Then, in 1995 and 2002, seven novel decahydroquinoline alkaloids, lepadins A–G (64–70) (Fig. 8), were isolated.^112,113 Compounds 65 and 66 showed significant in vitro cytotoxic activity toward various murine and human cancer cell lines, 69 and 70 showed mild activity, and 67 was inactive.^112,113 The biological activity was postulated to be dependent on the configuration at C-2 and the nature of the functionality at C-3 in the decahydroquinoline.

FIGURE 8:

Chemical structures of compounds 64–70

In 1996, two tetrahydroquinoline alkaloids, benzastatins C (71) and D (72) (Fig. 9) were isolated by Kim et al. from the bacterium Streptomyces nitrosporeus 30643.^114,115 The former chlorinated compound was cytotoxic against N18RE-105 cells with an IC₅₀ value of 38.1 μM, but its hydroxylated congener 72 was inactive even at 100 μM.^114,115 In addition, two new quinoline-containing octadepsipeptides, (−)-SW-163C (73) and E (74) (Fig. 9) were isolated from culture broth of the Streptomyces strain SNA15896.^116,117 SW-163E (74) demonstrated better antitumor activity than SW-163C (73) in in vitro tests against various murine and human tumor cell lines (IC₅₀ 0.200–1.60 vs. 17.0–140 nM, respectively). When in vivo activity was assessed in mice implanted with P388 leukemia, 74 prolonged life span at a dose of 0.010 mg/kg, but was acutely toxic at higher doses (LD₅₀ 0.600 mg/kg for 74 vs. > 100 mg/kg for 73).

FIGURE 9 :

Chemical structures of compounds 71–82

In 2006, two new diastereomeric alkaloids 3S*,4R*-dihydroxy-4-(4^′- methoxyphenyl)-3,4-dihydro-2(1H)-quinolinone (75) and 3R*,4R*-dihydroxy-4-(4^′- methoxyphenyl)-3,4-dihydro-2(1H)-quinolinone (76), together with the prenyl-substituted peniprequinolone (77) (Fig. 9), were isolated from cultures of the marine fungus Penicillium janczewskii strain H-TW5/869.¹¹⁸ They showed moderate cytotoxic activity toward eight human tumor cell lines (MDA-MB 231, DU-145, SKOV-3, HT-29, A549, CAKI-1, SK-MEL 2, K562 cells). Among these compounds, 76 was markedly active against the SKOV-3 cell line. Furthermore, a novel cytotoxic alkaloid aspernigerin (78) (Fig. 9) from a culture of Aspergillus niger strain IFBE003 showed cytotoxic activity when tested against KB, HeLa, and SW1116 cell lines with IC₅₀ values of 22.0, 46.0, and 35.0 μM, respectively.¹¹⁹ (+)-Quinocitrinine A (79) and (−)-quinocitrinine B (80) (Fig. 9) with a rare pyrrolo[3,4-b]quinoline ring system were isolated from cultures of P. citrinum Thom 1910 in 2003.¹²⁰ Both compounds showed antiproliferative activity toward L-929, K-562, and HeLa cells.

Two naturally occurring isoalkaloids, isodictamnine (81), and iso-γ-fagarine (82) (Fig. 9), as well as γ-fagarine (33), were found in Glycosmis arborea.¹²¹ They showed inhibitory effects toward the tumor promoter 12-Otetradecanoylphorbol 13-acetate induced Epstein-Barr virus early antigen.

Luzopeptins A–C (83–85) (Fig. 10), quinoline-substituted cyclic decadepsipeptides from Actinomadura luzonensis, showed potent cytotoxic and antitumor activity.^122–126 Compound 83, with two acetylated sites in its peptide ring, was active against several experimental animal tumor systems. Compound 84 (one acetylated site) was less active, and compound 85 (no acetylation) was inactive. However, compound 85 was slightly more effective than 83 and 84 in assays to evaluate bifunctional DNA intercalation and drug-induced DNA-DNA intermolecular cross-linking. The peptidic cyclic structure of luzopeptins is essential for the bifunctional intercalation of the twin chromophores, probably by providing proper conformational orientations of the chromophores.^122–126

FIGURE 10:

Chemical structures of compounds 83–89

In 2002, streptonigrin (86) and its N-(1-methyl-2-oxopropyl) derivative, 7-(1-methyl-2-oxopropyl)-streptonigrin (87) (Fig. 10), were isolated from the fermentation broth of the actinomycete strain Micromonospora sp. IM 2670.¹²⁷ They induced apoptosis through a p53-dependent pathway in human neuroblastoma SH-SY5Y cells. Compound 86 also caused nuclear accumulation of p53 and induced DNA ladders in SH-SY5Y cells as well as mediated p53-dependent apoptosis. Compound 86 was more cytotoxic than 87 (IC₅₀ 0.050 vs. 0.900 μM) toward SH-SY5Y cells.¹²⁷

Furthermore, two quinoline-containing octadepsipeptides, BE-22179 (88) and thiocoraline (89) (Fig. 10), were isolated from the culture broths of Streptomyces strain A22179^128,129 and Micromonospora sp. L-13-ACM2–092,^130,131 respectively. BE-22179 (88) exhibited potent inhibition of topo П and significant in vitro cytotoxic activity against various murine leukemia and human stomach adenocarcinoma cell lines, as well as in vivo activity in mice transplanted with L1210 leukemic cells.^128,129 More specifically, it inhibited the DNA-relaxing activity of L1210 topo П and prevented both DNA and RNA synthesis as well as the growth of L1210 mouse leukemic cells.^128,129 Compound 89 also displayed significant cytotoxic effects against P-388, A-549, and MEL-28 cell lines (IC₅₀ 0.002 μM). It also inhibited RNA synthesis more specifically than DNA synthesis, bound to supercoiled DNA, but, unlike 88, did not inhibit topo II.^130,131 Boger and co-workers reported the first total syntheses of both macrocyclic compounds and noted the exceptional IC₅₀ values of 88 and 89 (200 and 400 pM, respectively) against the L1210 cell line.^132,133

Of course, some isolated natural alkaloids exhibit weak or no cytotoxic activity in various studies against specific tumor cell lines. Confusadine (90) (Fig. 11) from the plant Melicope semecarpifolia showed poor cytotoxic activity toward P-388, A549, and HT-29 human cancer cell lines, and was substantially less potent than the related confusameline with a simple hydroxyl group and dutadrupine with a fused 2,2-dimethyl-2H-pyran ring rather than the 2-hydroxy-3-methylbut-3-enyloxy side chain.¹³⁴ Furomegistines I (91) and II (92) (Fig. 11) were isolated from bark extracts of Sarcomelicope megistophylla;¹³⁵ both alkaloids showed weak to no cytotoxic activity toward A549 and HT29 cells (IC₅₀ 90 and 100 μM, respectively). Megistosarconine (93, IC₅₀ 70 μM)¹³⁶ and cyclomegistine (94, IC₅₀ 80 μM)¹³⁷ (Fig. 11) from S. megistophylla also exhibited poor cytotoxic activity towards L1210 leukemia cells. 4-Carbomethoxy-6-hydroxy2-quinolone (95) (Fig. 11), a new alkaloid isolated from Oryza sativa cv. Mihyangbyo, did not exhibit antiproliferative activity toward the U937 cell line (IC₅₀ 539 μM).¹³⁸

FIGURE 11:

Chemical structures of compounds 90–97

The fungal metabolites viridicatin (96) and viridicatol (97) (Fig. 11) were isolated from cultures of P. crustosum and P. discolor, respectively, grown on cheese agar.¹³⁹ The compounds exhibited weak to no cytotoxic activity in an MTT assay; the IC₅₀ values of 97 toward KB, KBv200, A549, HepG2, MCF7, K562, SMMC7221, and SGC 7901 tumor cell lines were 98.8, 65.2, 237, 336, 178, 98.8, 317, and 316 μM, respectively.¹⁴⁰

2.1.2 |. Quinazoline alkaloids

In 1992 and 1995, fumiquinazolines A–C (98–100) and D–G (101–104) (Fig. 12) were isolated from the fungus A. fumigatus.^141,142 All seven fumiquinazolines were moderately cytotoxic in a P388 lymphocytic leukemia test system. Meanwhile, (−)-spiroquinazoline (105) (Fig. 12) from cultures of the fungus A. flavipe inhibited the binding of substance P to human astrocytoma cells.¹⁴³

FIGURE 12:

Chemical structures of compounds 98–110

Four important quinazoline alkaloids, luotonins A, B, E, and F (106–109) (Fig. 12), from the aerial parts of P. nigellastrum have two major skeleton types, pyrroloquinazolinoquinoline (106–108) and 4(3H)-quinazolinone (109).^144,145 All four compounds exhibited promising cytotoxic activity toward P388 murine leukemia as well as potent topo II inhibition, but 106 was the most cytotoxic (IC₅₀ 6.32 μM)¹⁴⁶ with the added ability to stimulate topo I-mediated cleavage of DNA.¹⁴⁷ It stabilized the covalent binary complex formed between DNA and human topo I during DNA relaxation and mediated topo I-dependent activity in yeast Saccharomyces cerevisiae lacking the yeast topo but containing a plasmid with the human topo I gene. Due to its outstanding cytotoxic activity toward murine leukemia P-388 cells at low concentrations and the ability to inhibit topos I and II, 106 has been studied extensively.¹⁴⁸ Alkaloid 106 and its derivatives were cytotoxic against a human lung large cell carcinoma cell line H460, but were less potent than a CPT-related control.¹⁴⁹ To improve the biological as well as pharmacokinetic properties of 106 as an anticancer drug lead compound, systematic syntheses of derivatives have been performed.^149–151 Another metabolite of this plant, deoxyvasicine (110) (Fig. 12), exhibited good cytotoxic activity toward mouse leukemia P-388 cells.¹⁴⁸

Tryptanthrin (111, indolo[2,1-b]quinazolin-6,12-dione) and qingdainone (112) (Fig. 13) were first isolated from the traditional Chinese medicine Qingdai in 1985, and both compounds showed cytotoxic activity against melanoma B₁₆ cells in vitro.¹⁵² Compound 111 also affected cell differentiation and apoptosis of U-937 and HL-60 leukemia cells.¹⁵³ Low concentrations of 111 induced differentiation of leukemia cells but higher concentrations killed leukemia cells through apoptosis, possibly through a caspase-3/Fas antigen pathway. Meanwhile, 111 suppressed the growth of azoxymethane-induced intestinal tumors in F344 rats,¹⁵⁴ and strongly inhibited the induction of hepatocyte growth factor in human dermal fibroblasts.¹⁵⁵ 3-(2-Carboxyphenyl)-4(3H)-quinazolinone (113) (Fig. 13) from Isatis indigotica, an open-ring analog of 111, showed endotoxic activity in vitro in the limulus amoebocyte lysate test.¹⁵⁶

FIGURE 13:

Chemical structures of compounds 111–118

In 2005, Chen and co-workers isolated three new quinazoline alkaloids, 1-methoxy-7,8-dehydrorutaecarpine (114), rutaecarpine (115), and 1-hydroxyrutaecarpine (116) (Fig. 13), from the root bark of Z. integrifoliolum.¹⁵⁷ In in vitro tests, all three alkaloids were cytotoxic toward murine P-388 (EC₅₀ 12.3, 36.8, and 12.4 μM, respectively) and human HT-29 (EC₅₀ 27.1, 118, and 24.7 μM, respectively) cells. Samoquasine A (117) (Fig. 13) with a benzo[h]quinazoline ring system was isolated from seeds of the custard apple Annona squamosa.^158–161 It showed significant cytotoxic activity against murine lymphoma L1210 cells (IC₅₀ 1.94 μM).¹⁵⁸ However, the original published structure was reinvestigated and revised.^159–161 The simple quinazoline alkaloid 2-acetyl-4(3H)-quinazolinone (118) (Fig. 13) showed cytotoxic activity only at high concentrations.^162,163

2.2 |. Antimalarial activity

2.2.1 |. Quinoline alkaloids

Malaria is the most lethal human parasitic infection. According to the WHO World Malaria Report 2015, an estimated 292,000 African children under five died from malaria, and the disease caused an estimated 306,000 deaths worldwide in the same age group.¹⁶⁴ Malaria is caused by five species of protozoan parasites of the genus Plasmodium, including P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi. Of these, P. falciparum and P. vivax account for more than 95% of malaria cases in the world.¹⁶⁵ The bark of the Cinchona tree was utilized in early clinical history to treat human malaria. With the development of natural product technology, quinine (1), a quinoline alkaloid, was isolated from the bark of the Cinchona tree in 1820. Due to its low price, parenteral administration, and high efficacy against P. falciparum, it was widely used to treat malaria worldwide.^166,167 To meet the needs of this compound in southeast Asia during World War II, the synthesis of 1 was promoted and completed, and some derivatives were developed with better potency and lower toxicity.^168–171 In 2006, WHO stopped recommending 1 as a first-line treatment for malaria, because of its high toxicity and the developing resistance of Plasmodium sp. However, it has still been used when artemisinins are not available.¹⁷¹ To date, 1 and its analogs have saved thousands of people^’s lives worldwide and made an enormous contribution to human health.

In 1996, Gantier and co-workers isolated six quinoline alkaloids, 2-n-propylquinoline (119), 2-pentylquinoline (120), chimanines B (121) and D (122), 4-methoxy-2-phenylquinoline (123), and 2-(3,4-methylenedioxyphenylethyl)quinoline (124) (Fig. 14) from the bark of Galipea longiflora, which is used to treat recurrent fevers, such as malaria, in Bolivia.¹⁷² All six compounds showed the same approximate level of activity as the well-known antimalarial compound chloroquine against P. vinckei petteri infected mice. Four G. officinalis tetrahydroquinolines, cuspareine (59), galipeine (60), galipinine (61), and angustureine (62) (Fig. 7) exhibited antimalarial activity against one chloroquine-sensitive and two chloroquine-resistant strains of the malaria parasite P. falciparum; 61 was the most active compound (IC₅₀ 0.276–2.76 μM for the resistant strains at 24 and 72 h).¹¹⁰ Three novel decahydroquinoline alkaloids lepadins D–F (67–69) (Fig. 8) from the genus Didemnum also showed significant antiplasmodial activity; the most potent compound was 69.112,113

FIGURE 14:

Chemical structures of compounds 119–131

Certain furoquinoline alkaloids also demonstrated antimalarial activity. In in vitro tests, kokusaginine (37), skim-mianine (34), haplopine (35) (Fig. 6), acronycidine (125), and acronydine (126) (Fig. 14) were active against HB3 (chloroquine-sensitive) and W2 (chloroquine-resistant) clones of P. falciparum.¹⁷³ The most active compound, 126, was at least fourfold more potent against the resistant clone (IC₅₀ 22.6 and 4.63 μM, respectively), although it was less potent than chloroquine (IC₅₀ 0.032 and 0.466 μM, respectively). The pyranoquinolone veprisine (127) and its prenylated congener N-methylpreskimmianine (128) (Fig. 14) also exhibited antimalarial activity against P. falciparum D6 (IC₅₀ 6.65 and > 14.8 μM, respectively) and W2 (IC₅₀ 6.98 and 5.68 μM, respectively) clones.¹⁷⁴

In 1999, three quinolone alkaloids were isolated from a new gram-negative marine bacterial strain of Pseudomonas sp.¹⁷⁵ Compounds 129–131 (Fig. 14) showed activity against the malaria parasite P. falciparum (ID₅₀ 3.51–16.8 μM).

2.2.2 |. Quinazoline alkaloids

Febrifugine (4) (Fig. 1) and isofebrifugine (132) (Fig. 15) were first isolated as active components of the traditional Chinese medicine Chan Shan (roots of D. febrifuga Lour.), which has marked antimalarial effects. Both compounds were named by Koepfli and co-workers in the 1940s.^176–178 They found that 4 was 100 times more active against P. lophurae in ducks than quinine (1), while 132 possessed only modest activity against the same malaria strain.^176–178

FIGURE 15:

Chemical structures of compounds 132–137

Additional antimalarial testing showed that 4 (EC₅₀ 0.910 nM) was almost 100 times more potent toward P. falciparum compared with chloroquine (EC₅₀ 18.0 nM), twice as potent as its hydrochloride salt (EC₅₀ 1.8 nM) and about ten times as potent as 132 (EC₅₀ 9.00 nM).¹⁷⁹ Takaya and co-workers verified that compounds 4 and 132 exert powerful antimalarial activity in vitro, with similar potencies against chloroquine-sensitive P. falciparum FCR-3 (EC₅₀ 0.700 and 3.40 nM, respectively), as well as against chloroquine-resistant P. falciparum K1 (EC₅₀ 1.20 and 1.80 nM, respectively).¹⁸⁰ In in vivo assays, the acetone adduct of 4 displayed better activity than the acetone adduct of 132 against mouse malaria P. berghei. In 2003, Murata et al. investigated the mechanisms of 4, 132, and quinazolin-4(3H)-one (133) (Fig. 15).¹⁸¹ The results indicated that 4 may act differently from other antimalarial drugs, and could be used as a novel lead compound for antiplasmodial chemotherapy. The basicity of both the 1- and the 1^′′-nitrogen atoms of 4 is crucial in conferring powerful antimalarial activity.

To possibly decrease unacceptable emetic properties and other side effects, a combination of 4 and 132 was studied against a blood-induced infection with chloroquine-resistant P. berghei NK65 in ICR mice.^180,182 A four-day dosage of 1 mg/kg of the 4/132 mixture alone showed slight antimalarial activity, but all mice died during days 19 to 27 with increasing parasitemia. However, mice treated with chloroquine (20 mg/kg) plus the two alkaloids survived the entire experiment. In addition, malaria parasites in the mice given chloroquine plus alkaloids decreased on day 6 and then were undetectable by microscopic examination during the remaining observation period. Several analogs, including halofuginone, a chloro-bromo substituted derivative of 4, were also synthesized to produce better efficacy and lower toxicity.^183–186

Three new quinazoline alkaloids, 2-methoxyrutaecarpine (134), 2-methoxy-13-methylrutaecarpine (135), and the cationic variant 5,8,13,14-tetrahydro-2-methoxy-14-methyl-5-oxo-7H-indolo[2^′,3^′:3,4]pyrido[2,1-b]quinazolin-6-ium chloride (136) (Fig. 15), were isolated from stem bark of Araliopsis tabouensis.¹⁷⁴ The two latter compounds showed promising antimalarial activity against P. falciparum D6 (IC₅₀ 5.44 and 5.99 μM, respectively) and W2 (IC₅₀ > 14.2 μM) clones, but were less potent than the positive drug artemisinin (IC₅₀ < 0.92 μM against both clones).

Furthermore, the indoloquinazolinedione tryptanthrin (111) (Fig. 13) showed significant in vitro antimalarial activity against P. falciparum, both sensitive and multidrug-resistant strains,^187,188 and exhibited remarkable in vitro activity (below 100 ng/mL) against sensitive and multidrug-resistant P. falciparum malaria. The pharmacophore containing two hydrogen bond acceptors (lipid) and two hydrophobic (aromatic) features mapped well onto many well-known antimalarial drug classes, including quinolines, chalcones, rhodamine dyes, Pfmrk cyclin dependent kinase inhibitors, malarial FabH inhibitors, and plasmepsin inhibitors. Compound 111 and its analogs are also highly potent against strains of P. falciparum that are up to 5000-fold resistant to atovoquone, 50-fold resistant to chloroquine, and 20-fold resistant to mefloquine. This novel class of compounds has opened a new chapter for study in the chemotherapy of malaria (−)-Janoxepin (137) (Fig. 15), an interesting oxepine-pyrimidinone natural product, was isolated from a culture of the fungus A. janus.¹⁸⁹ However, it did not⋅show antiplasmodial activity against P. falciparum.

2.3 |. Antiparasitic and insecticidal activities

2.3.1 |. Quinoline alkaloids

Leishmaniasis (kala-azar) is a major public health problem in Africa, Asia, and Latin America,¹⁹⁰ causing significant morbidity and mortality. To date, more than 70 isolated natural alkaloids have been used to treat this disease. Some of these alkaloids are quinoline or quinazoline type.¹⁹¹ In the 1990s, Fournet et al. studied the antiprotozoal activity of several 2-substituted quinoline alkaloids isolated from G. longiflora.^192–195 After administrating chimanine D (122) subcutaneously and 2-n-propylquinoline (119) orally (0.540 mmol/kg per day) to mice for 10 days, the liver parasites were suppressed by 86.6% and 99.9%, respectively. The reference drug resulted in 97.4% parasite suppression in the liver. The alkaloids did not cause any apparent toxicity during the experiment. Additional studies indicated that chimanine B (121) reduced lesion weight and parasite loads substantially after oral administration or intralesion injection, and showed improved performance compared with the positive drug glucantime in BALB/c mice infected with Leishmania amazonensis and L. venezuelensis. Compound 121 may be chosen as a lead molecule in the development of oral therapy against leishmaniasis. Compounds 119 and 122 were also more potent than glucantime against L. amazonensis PH8. After a single treatment with proximate injection, 119 reduced the lesion severity; however, it was less active than glucantime.

2-Propyl- and 2-pentyl-quinoline (119 and 120) were again investigated by Belliard and co-workers in 2003.¹⁹⁶ The compounds exhibited significant activity against the virulent strain L. venezuelensis, and 119 decreased intestinal P-glycoprotein activity in mice infected with L. donovani. Based on the P-gp inhibition, 119 could be valuable as an oral drug to restrict leishmanial multi-drug-resistance in humans with kala-azar.

Besides its antiprotozoal activity, 119 was as clinically effective as the known trypanocidal agent benznidazole in mice chronically infected with Trypanosoma cruzi, the pathogenic parasite of Chagas disease.¹⁹⁷ Benznidazole and 119 were administered orally at 25 mg/kg for 30 days starting at 60 days post-infection. At day 35 post-treatment, the 119-treated mice had a significantly different serological value from those of the control and the benznidazole-treated mice; however, at day 85 post-treatment, the difference was not statistically different. These results indicate that 119 and its analogs should be further investigated for potent trypanocidal activity and control of chronic Chagas’ disease. In addition, compounds 119 and 120, as well as 2-(3,4-methylenedioxyphenylethyl)quinoline (124), exhibited molluscicidal activity against the freshwater snail Biomphalaria glabrata.¹⁹⁸

Four quinoline alkaloids 121, 124, cusparine (138) (Fig. 16), and 2-(3,4-dimethoxyphenylethyl)quinoline (139) (Fig. 16) as well as the furanoquinoline alkaloid skimmianine (34) were as effective as the positive control drug against the Leishmania parasite.¹⁹⁹ In addition, 34 inhibited the parasite enzyme adenine phosphoribosyltransferase. Other furoquinoline alkaloids also exhibit antiparasitic and insecticidal activities. Kokusaginine (37) (IC₅₀ 0.560 mM), 34 (IC₅₀ 1.46 mM), and rel-(7R,8R)-8-[(E)-3-hydroxy-3-methyl-1-butenyl]-4,8-dimethoxy-5,6,7,8-tetrahydrofuro [2,3-b]quinolin-7-yl acetate (140) (Fig. 16) (IC₅₀ 0.977 mM) from Almeidea rubra exhibited moderate in vitro trypanocidal activity against the trypomastigote forms of T. cruzi.²⁰⁰ Dictamnine (40) and evolitrine (36, 8-methoxydictamnine) exhibited antifeedant activity against fourth instar larvae of the tobacco caterpillar Spodoptera litura.²⁰¹ Compound 40 was also deterrent against two insect pests [Sitophilus zeamays (maize weevil) and Trilobium castaneum (red flour beetle)] responsible for spoilage of stored products.²⁰² However, the furoquinoline alkaloid 37 (LC₅₀ 1420 μM) was extremely less potent than the quinolinone alkaloids evocarpine (141) and dihydroevocarpine (142) (Fig. 16) in a brine shrimp toxicity assay (LC₅₀ 2.27 and 62.6 μM, respectively).^203,204

FIGURE 16:

Chemical structures of compounds 138–161

The Cinchona alkaloid quinine (1)¹⁰⁸ and lepadins D–F (67–69) showed significant antitrypanosomal activity; the most potent compound was 69.^112,113 Antidesmone (143) (Fig. 16), a tetrahydroquinolinedione alkaloid from Antidesma membranaceum, also displayed potent and selective antitrypanosomal activity (IC₅₀ 0.066 μM) against T. cruzi, but only weak antimalarial activity against P. falciparum K1 and NF254 and anti-leishmanial activity against L. donovani.²⁰⁵ In contrast, 2-nonylquinolin-4(1H)-one (129), N-methyl-2-nonylquinolin-4-one (144), and N-methyl-2-phenylquinolin-4-one (145) (Fig. 16) from Raulinoa echinata did not show activity against the trypomastigote forms of T. cruzi (IC₅₀ > 300 μM), but compound 129 was weakly fungicidal toward Leucoagaricus gongylophorus.²⁰⁶

In 1995, Perrett and Whitfield reported that atanine (146) (Fig. 16), a quinolin-2-one alkaloid from Evodia rutaecarpa, showed antiparasitic and anthelmintic activity against larvae of the human parasite Schistosoma mansoni and the soil nematode Caenorhabditis elegans.²⁰⁷ The novel tetracyclic quinolin-4-one quinolactacide (147) (Fig. 16) from the fermentation broth of P. citrinum Thom F 1539 also showed excellent insecticidal activity against green peach aphids (Myzus persicae) (88% and 100% mortality at 250 and 500 ppm, respectively) and diamondback moth (Plutella xylostella) (42% at 500 ppm).^208,209

Subsequently, peniprequinolone (77), penigequinolones A (148) and B (149), 3-methoxy-4-hydroxy-4-(4^′-methoxyphenyl)quinolinone (150), and 3-methoxy-4,6-dihydroxy-4-(4^′-methoxyphenyl)quinolinone (151) (Fig. 16) were isolated from Penicillium cf. simplicissimum in 2000.²¹⁰ Compounds 148 and 149 showed potent nematicidal activity (LD₅₀ 100 mg/L) toward Pratylenchus penetrans. Thus, the penigequinolones may be useful for controlling parasitic nematodes.

Nakatsu and co-workers studied the anti-feedant activity of two unusual quinolin-4-ones, leiokinines A (152) and B (153) (Fig. 16), from E. leiocarpa.²¹¹ The compounds showed weak effects against the pink bollworm Pectinophora gossypiella. 3,4-Dihydroxyquinoline-2-carboxylic acid (154) (Fig. 16) from the sponge Aplysina cavernicola acted as a powerful feeding deterrent of the fish species Blennius sphynx,²¹² and acetylcupreine (57) affected the feeding behavior of the potato beetle Leptinotarsa decemlineata.¹⁰⁸

(−)-Yaequinolone J1 (155) and (+)-yaequinolone J2 (156) (Fig. 16), two new alkaloids related to the abovementioned penigequinolones, were isolated from a Japanese soil sample of Penicillium sp. FKI-2140 in 2005.²¹³ Both compounds showed activity in a brine shrimp assay with a minimum inhibitory concentration (MIC) of 13.9 μM. 3-Methoxy-4,5-dihydroxy-4-(4^′-methoxyphenyl)-quinolinone (157) (Fig. 16), without the side chain at C-6, was also toxic to brine shrimp with an IC₅₀ value of 63.5 μM.²¹⁴

2.3.2 |. Quinazoline alkaloids

Among vasicine alkaloids found in A. vasica, vasicine (3), vasicinone (158), and vasicinol (159) (Fig. 16) showed feeding deterrence at concentrations of 0.05 and 0.1% against two beetle species Aulacophora foveicollis and Epilachna vigintioctopunctata.²¹⁵ The latter compound blocked oocytes in the oviduct and exhibited severe antifertility effects against T. castaneum and the cotton pest Dysdercus koenigii.

The well-known alkaloid tryptanthrin (111) showed insecticidal activity against larvae of the house longhorn beetle Hylotrupes bajulus and the termite Reticulitermis santonensis. Moreover, the compound also displayed antifeedant activity, as termites avoided the treated pine samples.²¹⁶ In addition, compound 111 showed antitrypanosomal activity against T. brucei with an EC₅₀ value of 23.0 μM.²¹⁷ Furthermore, (+)-N_α-quinaldyl-L-arginine (160) (Fig. 16) found in the exudates of the ladybird beetle Subcoccinella 24-punctata proved to be a highly effective feeding deterrent to the ant species Myrmica rubra.²¹⁸

A mixture of the cis and trans isomers of febrifugine (4) was isolated from Hydrangea macrophylla.²¹⁹ Trans-4 showed anticoccidial activity against Eimeria parasites in chickens, whereas cis-4 was inactive even at much higher dosages.

1,3-Dimethylquinazoline-2,4-dione (161) (Fig. 16) was identified as a sex pheromone of Phyllopertha diversa or chafer beetle.²²⁰ Female beetles release the compound in only picogram quantities. As many as 153 male beetles per trap per hour were successfully lured to field traps baited with 161, while the control captures were extremely low (0.4). The compound was catabolized by an antennal cytochrome P450 system, which was highly specific to male insects.²²¹

2.4 |. Antibacterial and antifungal activities

2.4.1 |. Quinoline alkaloids

E. rutaecarpa extracts display antibacterial activity against Helicobacter pylori, which is implicated in the pathogenesis of chronic gastritis, peptic ulcers, and gastric cancers. Consequently, many compounds have been isolated and identified from this plant. In 1999, Rho and co-workers isolated six quinolone alkaloids, evocarpine (141), dihydroevocarpine (142), 1-methyl-2-pentadecyl-4(1H)-quinolone (162), 1-methyl-2-[(4Z,7Z)-4,7-tridecadienyl]-4(1H)-quinolone (163), 1-methyl-2-[(6Z,9Z)-6,9-pentadecadienyl]-4(1H)-quinolone (164), and 1-methyl-2-undecyl-4(1H)-quinolone (165), (Fig. 17), which showed potent anti-H. pylori activity with MIC values of 10–20 μg/mL.²²²

FIGURE 17:

Chemical structures of compounds 162–176

The following year, Hamasaki et al. explored the in vitro anti-H. pylori activity of an extract from the fruits of E. rutae-carpa (Gosyuyu), one part of the Chinese herbal medicine Gosyuyu-to (Wu-Chu-Yu).²²³ Two 1-methyl-2-tridecenyl-4(1H)-quinolones [141 (8Z) and 166 (7Z)] (Fig. 17) were identified as the strongest antibacterial principles. Their MIC values were less than 0.147 μM against clinically isolated and reference H. pylori strains and similar to the values of the antibiotics amoxicillin and clarithromycin.²²³ Additional studies indicated that these alkaloids were highly selective against H. pylori and almost inactive against other intestinal pathogens. They inhibited the bacterial respiration and reduced the bacterial growth in vivo, but not DNA synthesis.²²⁴ In addition, these compounds significantly decreased the number of viable H. pylori in the stomachs of infected Mongolian gerbils and reduced neutrophil infiltration without causing harmful adverse effects, including animal mortality.²²⁴ The above results indicated that these alkyl methyl quinolone alkaloids have a unique antimicrobial mechanism(s) different from those of other antibiotics such as amoxicillin and clarithromycin. They may be beneficial in the treatment of H. pylori-associated gastroduodenal diseases, whether used alone or together with the above-mentioned antibiotics or proton pump inhibitors.²²³

Five quinolone alkaloids, 141, 163–165, and 1-methyl-2-(6Z)-6-undecenyl-quinolone (167) (Fig. 17), from E. rutaecarpa also displayed promising antimycobacterial activities in in vitro tests with Mycobacterium fortuitum, M. smegmatis, and M. phlei (MICs 12.5–200 μM).²²⁵ Among these compounds, 141 was the most active (MIC 12.5 μM). Quinolone alkaloid 129, its N-methyl congener (144), and 2,3-dimethyl-4-quinolone (168) (Fig. 17) from Boronia bowmanii exhibited moderate antibacterial activity against Bacillus subtilis, Staphylocccus aureus, Sarcina lutea, exterotoxigenic E. coli, Salmonella typhi, and Klebsiella sp.²²⁶

The furoquinoline alkaloid flindersiamine (46) from E. yaaxhokob exhibited moderate antimicrobial activity against S. aureus and S. faecalis.²²⁷ In other studies, the furoquinolines kokusaginine (37), skimmianine (34) and haplopine (35), as well as the pyranoquinoline flindersine (31), exhibited photo-activated antimicrobial activity against S. aureus.²²⁸ Compounds 37, 34, and 35 displayed photo-activated DNA binding activity in the presence of several restriction enzymes and likely target DNA. However, the pyranoquinoline alkaloid 31 did not show photo-activated DNA binding activity and must act on other cellular target components to exert its photo-toxic activity.²²⁸ The furoquinoline pteleine (49) showed moderate antimicrobial activity against M. smegmatis, B. subtilis, S. aureus, and Candida albicans (MIC 4.39– 87.8 μM), while 34 and dictamnine (40) were less potent against the two former microbes and inactive against the latter two microbes.²²⁹

Megistoquinones I (169) and II (170) (Fig. 17), probable oxidation products of a furo[2,3-b]quinoline precursor, were isolated from the bark of S. megistophylla.²³⁰ Both alkaloids showed antibacterial properties against two gram-positive, S. aureus (MIC 9.073, 2.577 mM) and S. epidermidis (MIC 10.7, 2.51 mM), and four gram-negative, Pseudomonas aeruginosa (MIC 12.5, 3.33 mM), E. coli (MIC 18.3, 3.51 mM), Enterobacter cloacae (MIC, 12.0, 3.06 mM), and Klebsiella pneumoniae (MIC 20.3, 4.23 mM), bacteria.

Two new functionalized 3-prenylquinolinones, N-methyl-4-hydroxy-7-methoxy-3-(2,3-epoxy-3-methylbutyl)-1Hquinolin-2-one (171) and 3-(2,3-dihydroxy-3-methylbutyl)-4,7-dimethoxy-1-methyl-1H-quinolin-2-one (172) (Fig. 17) were isolated from Toddalia aculeata.²³¹ Both compounds strongly inhibited the growth of the bacteria E. coli, B. cereus, and Lactobacillus lactis at millimolar concentrations.

A special carbaldehyde substituted compound, quinoline-4-carbaldehyde (173) (Fig. 17), was isolated from the herb R. chalepensis.^232,233 It significantly inhibited the growth of Clostridium perfringens. This result may verify the phytoprotective effects of the herbal remedy. However, the compound^’s effect on E. coli was weak, and effects on the beneficial gastrointestinal bacteria Bifidobacterium bifidum, B. longum, and L. acidophilus were slight or absent.

During a research escalation on the antibacterial activity of microorganism metabolites, two 2-alkyl-4(1H)-quinolinone alkaloids (174, 175) (Fig. 17) were isolated from P. cepacia strain RB425 collected from lettuce root²³⁴ and strain LT4–12-W,²³⁵ respectively. Both alkaloids exhibited antibiotic activity against fungal and bacterial plant pathogens. Meanwhile, YM-30059 (a structurally related N-hydroxyquinolin-4-one) (176) (Fig. 17) was isolated from Arthrobacter sp. YL-02729S as an antibacterial and cytotoxic compound.²³⁶ It displayed moderate activity against gram-positive bacteria, including B. subtilis and multiple-drug resistant S. aureus and S. epidermidis.

Four sesquiterpenoid quinoline antibiotics, aurachins A–D (177–180) (Fig. 18) from the myxobacterium, Stigmatella aurantiaca, were active against gram-positive bacteria and weakly active against some fungi.²³⁷ Against B. subtilis, S. aureus, Arthrobacter aurescens, Brevibacterium ammoniagenes, and Corynebacterium fascians, the four compounds showed the following MIC values, 177: 12.658, 6.329, 0.481, 0.987, 3.949; 178: 6.849, 3.425, 2.137, 3.425, 4.273; 179: 0.396, 1.029, 0.501, 0.132, 2.058; 180: 0.413, 1.074, 0.523, 0.138, 2.149 μM, respectively. Meanwhile, one of the simplest quinolines, helquinoline (181) (Fig. 18), from the fermentation broth of Janibacter limosus strain Hel-1, showed moderate activity toward B. subtilis, S. viridochromogenes Tü57, and S. aureus.²³⁸

FIGURE 18:

Chemical structures of compounds 177–189

In 1998, Dekker and co-workers isolated eight new quinolin-4-ones from the fermentation broth of the actinomycete Pseudonocardia sp. CL38489.²³⁹ These compounds were given the code numbers CJ-13136 (182), CJ-13217 (183), CJ-13536 (184), (–)-CJ-13564 (185), CJ-13565 (186), CJ-13566 (187), (+)-CJ-13567 (188), and (–)-CJ-13568 (189) (Fig. 18). All eight compounds inhibited the growth of H. pylori; the most potent compound was the epoxide CJ13564 (185) with minimum bacterial concentration (MBC) 30.769 nM and MIC 0.308 nM. Moreover, the antibacterial activity of these compounds was highly selective and specific. Thus, because they are less likely to disturb the normal gastro-intestinal microbial flora, they could be used as antiulcer agents.

In addition to promising antitumor activity with potential clinical value,²⁴⁰ the octadepsipeptide (−)-thiocoraline (89) exhibited potent antibiotic activity against S. aureus (MIC 0.05 μg/mL), B. subtilis (MIC 0.05 μg/mL), and Micrococcus luteus (MIC 0.03 μg/mL).^130,131 Sch 40832 (190) (Fig. 19), a minor metabolite from the fermentation broth of M. carbonacea var. africana, also exhibited potent activity less than 0.504 μM against gram-positive bacteria.²⁴¹

FIGURE 19:

Chemical structures of compounds 190–195

Two bacterial alkaloids 2-heptylquinolin-4-ol (191) and 2-pentylquinolin-4-ol (192) (Fig. 19) were isolated from Alteromonas sp.²⁴² The latter compound inhibited respiration in other bacteria at a low concentration (75.0 nM) and DNA and protein synthesis, as well as bacterial motility, at micromolar concentrations. It also inhibited the growth of phytoplankton and diatoms, and altered the composition of bacterial communities growing on particles suspended in sea water.

Quinoline-related animal metabolites also show antibacterial activity. trans-Decahydroquinoline 243A (193) (Fig. 19) was isolated from amphibian (frog) skin in 2005.²⁴³ It inhibited the growth of the gram-positive bacterium B. subtilis, gram-negative bacterium E. coli, and the fungus C. albicans. The two novel pyrrolo[3,4-b]quinoline alkaloids quinocitrinine A (79) and (−)-quinocitrinine B (80) showed moderate antimicrobial activity toward a range of bacteria and fungi.¹²⁰

As indicated above, quinoline alkaloids have also been investigated for antifungal activities. Decahydroquinoline alkaloids lepadins D–F (67–69) showed weak antifungal effects.^112,113 The decahydroquinolone alkaloid anhydroevoxine (194) (Fig. 19), as well as two pyranoquinolone alkaloids flindersine (31), and haplamine (32) from Haplophyllum sieversii showed growth-inhibitory antifungal activity against Colletotrichum fragariae, C. gloeosporioides, C. acutatum, Botrytis cinerea, Fusarium oxysporum, and Phomopsis obscurans in a dose-response manner at 100, 50, and 150 μM.²⁴⁴ Among these compounds, 31 presented the highest antifungal activity. In addition, 32 was selectively more toxic toward freshwater phytoplanktons such as Pseudanabaena sp. LW397 and the odor-producing cyanobacterium Oscillatoria perornata. The furoquinoline alkaloid flindersiamine (46) and its congeners kokusaginine (37), skimmianine (34), dictamnine (40), maculine (42), and platydesmine (195) (Fig. 19) inhibited the growth of the fungus L. gongylophorus, a symbiotic fungus of the insect pest Atta sexdens rubropilosa.²⁴⁵ Dictamnine (40) also was a weak inhibitor of the pathogenic fungus Cladosporium cucumerinum (MIC 125.628 μM), while haplopine (35) exhibited relatively low activity.²⁴⁶

1-Methyl-2-[6^′-(3^′′,4^′′-methylenedioxyphenyl)hexyl]-4-quinolone (196) (Fig. 20) from R. graveolens was highly active against the necrotrophic fungus B. cinerea.²⁴⁷ Distomadine B (197) and its analog (+)-distomadine A (198) (Fig. 20) with furo[3^′,4^′:5,6]pyrano[2,3,4-de]quinoline skeletons were isolated from Pseudodistoma aureum.²⁴⁸ Compound 198 showed moderate antifungal activity toward C. albicans, but was inactive in various antitumor, antiviral, anti-inflammatory, and antimycobacterial assays.

FIGURE 20:

Chemical structures of compounds 196–205

One quinolone [2-(hept-2-enyl)-3-methylquinolin-4-one (175)] and four quinoline [quinoline-4-carbaldehyde (173), 4-hydroxymethylquinoline (199), quinoline-4-carbaldoxime (200), and quinoline-4-carboxylic acid (201) (Fig. 20)] alkaloids were isolated from cultures of the soil myxobacterium Archangium gephyra (strain Ar T205) in 1996.²⁴⁹ Among these five alkaloids, compound 176 proved to be the most active against Phytophthora capsici and other fungal plant pathogens. In 2001, the simple antibiotic N-mercapto-4-formylcarbostyril (202) (Fig. 20) from P. fluorescens (strain G308) showed good activity against a range of plant pathogenic fungi, including F. oxysporum, F. culmorum, C. cucumerinum, and C. lagenarium.²⁵⁰ Moreover, a new antiviral antibiotic, virantmycin (203) (Fig. 20), was isolated from the culture broth of strain AM-2722 in 1980.^251,252 It exhibited weak antifungal activity with MICs from 12.5 to 50 μg/mL against S. sake, Piricularia oryzae, Trichophyton interdigitale, A. niger, Alternaria kikuchiana, Mucor racemosus, and C. albicans.

2.4.2 |. Quinazoline alkaloids

The quinazoline alkaloid tryptanthrin (111) showed exciting potential as an antimycobacterial agent against a multiple drug-resistant strain of M. tuberculosis.²⁵³ It also exhibited good antibacterial activity against H. pylori in both in vitro and in vivo studies.²⁵⁴

Fumiquinazolines H and I (204, 205) (Fig. 19) were isolated from the culture broth and mycelia of an Acremonium sp. in 2000.²⁵⁵ Both compounds showed weak antifungal activity toward C. albicans in a broth microdilution assay, but no activity in antimicrobial assays or toward various cancer cell lines.

2.5 |. Cardiovascular protective and antiplatelet activities

2.5.1 |. Quinoline alkaloids

Although Pasteur first isolated quinidine (28) from the bark of the Cinchona tree in 1853, the compound^’s possible use in arrhythmias was not noted until 1912 after patient observed that quinine, another Cinchona alkaloid and a stereoisomer of quinindine, had a beneficial effect on his own heart arrhythmia. Compound 28 was later noted to be the most effective Cinchona alkaloid on the heart. In 1920, Lewis proposed that 28 restores normal cardiac rhythm by closing the gap between the crest and wake of the circus wave generated in arrhythmia.²⁵⁶ Since then, alkaloid 28 has been widely investigated for its antiarrhythmic activity and was acknowledged as the most potent of the antiarrhythmic compounds in the early 20^th century.²⁵⁷ In studies on the effect of reserpine pretreatment on the action of 28 in isolated cat hearts with complete heart blocks, exogenous catecholamines were demonstrated to antagonize the cardiac actions of 28, and cardiac catecholamines to antagonize the depressant action of 28.^258–261 Alkaloid 28 slows amphibian heart rate with its foremost effects attributed to a rise in the threshold for electrical stimuli and its consequences.²⁶² Further studies indicated that 28 interferes selectively with vasoconstrictor stimuli, which activate alpha adrenergic receptors, and this mechanism as well as a direct vasodilator effect may contribute to vasodilatation and hypotension.²⁶³ Therapeutic doses (10–20 μM) of 28 strongly inhibit fast inward current I_Na in isolated ventricular cells,²⁶⁴ affect the spontaneous contractions of rabbit atria,²⁶⁵ and depress the active transport of serotonin by platelets.²⁶⁶

Other quinoline and quinazoline alkaloids also have cardiovascular effects. At a concentration of 100 μg/mL, the furoquinoline alkaloid dictamnine (40), isolated from Zanthoxylum species in 1994,^267,268 completely inhibited the platelet aggregation induced by arachidonic acid, and was also markedly effective in inhibiting platelet aggregation induced by collagen and PAF. Pyranoquinolone [huajiaosimuline (30), simulenoline (206), benzosimuline (207), zanthobungeanine (208)], furoquinoline [γ-fagarine (33), skimmianine (34), haplopine (35), robustine (209)], and quinolone [edulitine (210)] alkaloids (Fig. 21) also inhibited the aggregation induced by thrombin, arachidonic acid, collagen, and PAF in washed rabbit platelets.⁹⁵ Likewise, 4-methoxy-1-methylquinolin-2-one (211) (Fig. 21) completely inhibited arachidonic acid-induced platelet aggregation in vitro at a concentration of 100 μg/mL.²⁶⁸

FIGURE 21:

Chemical structures of compounds 206–216

In other related studies on furoquinoline alkaloids from Zanthoxylum and Melicope species, confusameline (212) (Fig. 21), skimmianine (34), evolitrine (36), kokusaginine (37), dictamnine (40), and pteleine (49) showed significant antiplatelet aggregation activity.^269–272 Compound 34 affected the cardiovascular function and vasopressor responses in rats,²⁷³ and confusadine (90) inhibited the platelet aggregation triggered by various inducers.²⁷⁴

Moreover, furoquinoline alkaloids also show cardiovascular protective activity. Robustine (209) and confusameline (212) (Fig. 21), as well as γ-fagarine (33), skimmianine (34), haplopine (35), evolitrine (36), kokusaginine (37), dictamnine (40), inhibited human phosphodiesterase 5, which regulates the intracellular levels of cGMP and influences vascular smooth muscle tone.²⁷⁵ Three quinolone alkaloids, evocarpine (141), 1-methyl-2-[(4Z,7Z)-4,7-tridecadienyl]-4(1H)-quinolone (163), and 1-methyl-2-[(6Z,9Z)-6,9-pentadecadienyl]-4(1H)-quinolone (164) from E. rutaecarpa blocked the angiotensin II receptor and inhibited angiotensin II binding to rat liver receptor (IC₅₀ 43.4, 34.1, and 48.2 μM, respectively).²⁷⁶

2.5.2 |. Quinazoline alkaloids

The antiplatelet activity of the quinazoline alkaloids rutaecarpine (115), 1-hydroxyrutaecarpine (116), and 1-methoxyrutaecarpine (213) (Fig. 21) from Z. integrifolium was investigated.²⁷⁷ In in vitro tests, 116 was the strongest inhibitor of arachidonic acid-induced platelet aggregation, with an IC₅₀ values of 3.32–6.65 μM.

In 2000, studies showed that acrophyllidine (214) (Fig. 21) from A. haplophylla has antiarrhythmic activity.²⁷⁸ It suppressed ischemia/reperfusion-induced polymorphic ventricular tachyarrhythmias with an EC₅₀ value of 4.40 μM in isolated rat heart, increased the atrioventricular and His-Purkinje system conduction intervals, ventricular repolarization time, and basic cycle length, and prolonged the refractory periods of the AV node, His-Purkinje system, and ventricle in a perfused whole-heart model. Moreover, this furoquinoline alkaloid prolonged the action potential duration and decreased both the maximal upstroke velocity of depolarization and action potential amplitude in a concentration-dependent manner in isolated rat ventricular myocytes.²⁷⁸ These changes alter the electrophysiological properties of the conduction system and may be responsible for the compound^’s termination of ischaemia/reperfusion induced ventricular arrhythmias.

The quinazoline alkaloids rutaecarpine (115), evodiamine (215), and dehydroevodiamine (216) (Fig. 21) produced a vasodilatory effect on endothelium-intact rat aorta with equal potency in smooth muscle from rat thoracic aortas.²⁷⁹ Compound 115 produced a full nitric oxide (NO)-dependent vasodilation, whereas 216 and 217 exhibited partial endothelium-dependent effects, 50% and 10%, respectively. Another quinazoline alkaloid vasicine (3) also showed hypotensive and cardiac depressant properties.^280,281

2.6 |. Antiviral activity

Uranidine (217) (Fig. 22), a quinolone alkaloid and well-known yellow pigment, inhibits the RNA-directed DNA synthesis of the reverse transcriptases (RTs) of human immunodeficiency viruses HIV-1 and HIV-2, with the 3-hydroxy-4-oxo system likely being a key structural element for the inhibitory activity.²⁸² Furthermore, 2-undecyl-4(1H)-quinolone (130) from the gram-negative marine bacterial strain of Pseudomonas sp. showed activity against HIV-1.¹⁷⁵

FIGURE 22:

Chemical structures of compounds 217–220

Buchapine [218, 3-(1,1-dimethylallyl)-3-(3-methylbut-2-enyl)-1H-quinoline-2,4-dione] and 3-prenyl-4-prenyloxy1H-quinolin-2-one (219) (Fig. 22) from E. roxburghiana also showed anti-HIV-1 activity.²⁸³ Both compounds were active against infectious HIV-1 (EC₅₀ 0.940 and 1.64 μM, respectively) in human lymphoblastoid host cells (cell growth IC₅₀ 29 and 26.9 μM, respectively). They also showed inhibitory activity in an HIV-1 RT assay (IC₅₀ 12 and 8 μM, respectively).

Three furoquinoline alkaloids, γ-fagarine (33), haplopine (35), and (+)-platydesmine (196), as well as 4-methoxy1-methylquinolin-2-one (212) also inhibited HIV-1 replication in H9 lymphocyte cells at low concentrations (EC₅₀ < 5.85 μM) without significantly affecting the growth of uninfected H9 cells.²⁸⁴ Compound 33 showed the best therapeutic index, while 35, 196, and 212 were less effective. 2-Acetyl-4(3H)-quinazolinone (118) also inhibited HIV replication.^162,163

Moreover, quinoline-containing decadepsipeptides can significantly inhibit HIV-1 RT, but also display notable cytotoxicity against tumor cell lines. Various modified derivatives of sandramycin (220) (Fig. 22) (HIV RT IC₅₀ 0.13 nM) retained its HIV potency, but exhibited 150- to 1000-fold less cytotoxic activity.²⁸⁵ Thus, promising candidates could be further developed as HIV-1 chemotherapeutic agents. Three other decadepsipeptides luzopeptins A–C (83–85) were identified as potent inhibitors of the HIV RT responsible for the emerging clinical resistance to recently introduced RT inhibitors.²⁸⁶ Moreover, the rank orders of cytotoxic potency (A > B > > C) and antiviral potency/HIV RT inhibition (C > B > A) were reversed, and 85 suppressed HIV replication in infected MT-4 cells at noncytotoxic concentrations.^{123–126,287}

At very low concentrations, virantmycin (203) inhibited various RNA and DNA viruses, including the Indiana strain of vesicular stomatitis virus, Egypt Ar 339 strain of Sindbis virus, M_CM_ILLAN strain of Western equine encephalitis virus, MIYADERA strain of Newcastle disease virus, DIE strain of vaccinia virus, IHD strain of vaccinia virus, HF strain of herpes simplex virus type 1, and UW strain of herpes simplex virus type 2.^251,252 The compound affected the cell membranes, including specific virus receptor sites, and suppressed viral replication at a very early stage. In addition, compound 203 showed excellent growth inhibition of influenza virus.²⁸⁸

2-(3,4-Methylenedioxyphenethyl)quinoline (124), chimanine D (122), 2-pentylquinoline (120), and 2-nproplyquinoline (119) from G. longiflora inhibited the growth of cells infected with human T-lymphotropic virus type 1 (HLTV-1).^289–291 Certain quinolines also showed antiproliferative activity against HTLV-1 infected HUT-102 cells. Evolitrine (36) and dictamnine (40) inhibited activation of Epstein-Barr virus early antigen in Raji cells.²⁹²

2.7 |. Anti-inflammatory and immunomodulatory activities

2.7.1 |. Quinoline alkaloids

In 2005, Lal and co-workers studied the anti-inflammatory activity of the furoquinoline alkaloid evolitrine (36) and its analogs.²⁹³ The results showed that 36 effectively inhibited the formation of edema resulting from sub-plantar injection of carrageena in rats (57% inhibition at a dosage of 20 mg/kg), but did not produce toxic symptoms, cardiovascular effects, or weight loss.²⁹³ Also, the quinolone alkaloid orixalone A (221) (Fig. 23) from Orixa japonica strongly inhibited NO production in murine macrophage RAW 264.7 cells stimulated with interferon-γ and LPS at micromolar concentrations and, thus, might be used as an anti-inflammatory or cancer-preventive agent to suppress excessive synthesis of NO.²⁹⁴

FIGURE 23:

Chemical structures of compounds 221–228

Quinolactacins A1 and A2 (222, 223), B (224), and C (225) (Fig. 23) were isolated from culture broth of the entomopathogenic fungus Penicillium sp. EPF-6.^295,296 This rare compound class contains an N-methyl quinolone fused to a lactam ring. Only compound 223 inhibited the production of tumor necrosis factor (TNF) induced by LPS in murine peritoneal macrophages (IC₅₀ 12.2 μg/mL) and in macrophage-like J774.1 cells.

In 2003, nine 2-alkyl-4(1H)-quinolone alkaloids, 129, 130, 141, 142, 144, and 162–165 from the fruits of E. rutaecarpa were evaluated for immunomodulatory effects.²⁹⁷ With IC₅₀ values between 0.910 and 15.9 μM, these alkaloids inhibited the activity of nuclear factor of activated T cells (NFAT), without affecting cell viability. Among the N-methylated quinolones, compounds with longer aliphatic side chains on the quinolone ring showed stronger inhibition of NFAT activity and comparable inhibitory effects against NF-κB activity. These results indicated that these quinolones could be used as lead compounds for treating diseases of the immune system.²⁹⁷

2.7.2 |. Quinazoline alkaloids

In 2000, the anti-inflammatory activity of tryptanthrin (111) was first reported.²⁹⁸ This alkaloid significantly inhibited the production of both NO and prostaglandin E₂ (PGE₂) in murine macrophage RAW 264.7 cells activated by interferon-γ and LPS inadose-dependent manner.This potential new anti-inflammatory agent was subsequently investigated for other anti-inflammatory effects and its mechanism of action. In pharmacological studies, 111 ameliorated artificially induced colitis in mice, as well as suppressed weight loss, tissue damage, and subsequent mortality.²⁹⁹ Meanwhile, it showed 100-fold greater selectivity toward COX-2 than COX-1 in the biosynthesis of eicosanoids, as well as inhibition of 5-lipoxygenase.³⁰⁰ Moreover, it inhibited the production of interferon-γ and interleukin-2 by lymphocytes in response to staphylococcal enterotoxin B.³⁰¹ These results indicated that 111 not only has potent dual effects on prostaglandin and leukotriene synthesis for the treatment of inflammatory diseases, but also can potentially be used to control food-borne intestinal diseases. Finally, Oberthür et al.³⁰² and Heinemann et al.³⁰³ postulated that 111 could be more easily absorbed through the skin than other alkaloids, because of its lower bioavailability resulting from ready crystallization from solution.

Subsequently, the natural vasicinone analog isaindigotone (226) (Fig. 23), isolated from I. tinctoria, was found to be a superior scavenger of superoxide generated in the hypoxanthine/xanthine oxidase system (IC₅₀ 42.2 nM).³⁰⁴ The compound inhibited PGE₂ and NO generation in RAW 264.7 macrophages stimulated by LPS. Its free phenolic group wasimportanttotheanti-inflammatoryactivity.Thesimplealkaloidquinazoline-2,4-dione(227)(Fig. 23)alsoexhibited anti-inflammatory and antihypertensive properties.³⁰⁵

In 2006, two indolopyridoquinazolinone alkaloids rutaecarpine (115) and evodiamine (215), as well as the structurally related quinazoline-2,4-dione goshuyuamide II (228) (Fig. 23) were evaluated for anti-inflammatory activity.³⁰⁶ Compounds 115 and 215 strongly inhibited PGE₂ synthesis in LPS-treated RAW 264.7 cells at 1 to 10 μM, and 215 also inhibited COX-2 induction and NF-κB activation. Compound 228 inhibited 5-lipoxygenase from RBL-1 cells (IC₅₀, 6.60 μM), resulting in reduced synthesis of leukotrienes. However, these three compounds did not inhibit inducible NO synthase-mediated NO production.³⁰⁶

2.8 |. Anti-Alzheimer’s disease and other neurological disorders

2.8.1 |. Quinoline alkaloids

The furoquinoline alkaloids skimmianine (34), kokusaginine (37), and confusameline (212) inhibited 5-HT-induced contraction mediated by 5-HT₂ receptors in the presence of methiothepin in rat isolated aorta.³⁰⁷ These three compounds may act on 5-HT receptors in animals, more selectively to the 5-HT₂ subtype, in the rank order of 34 > 37 > 212. The quinoline alkaloids benzastatins C (71) and D (72) inhibited glutamate toxicity in N18-RE-105 cells with EC₅₀ values of 2 and 5.40 μM, respectively.^114,115

The quinolone alkaloid pteleprenine (229) (Fig. 24) from O. japonica significantly inhibited acetylcholine- and nicotine-induced contraction of guinea pig ileum.³⁰⁸ Thus, this natural product might be a novel lead compound as an agonist of nicotinic acetylcholine receptors.

FIGURE 24:

Chemical structures of compounds 229–235

2.8.2 |. Quinazoline alkaloids

In 1996, the anticholinergic natural product deoxyvasicine (110) was identified in a search for a new compound for the treatment of Alzheimer^’s disease, and a 3-chloro derivative of the parent hexahydroazepino[2,1-b]quinazoline structure was found to be about eight-fold more potent as an acetylcholinesterase (AChE) inhibitor than the unsubstituted compound.³⁰⁹ In addition, both quinolactacin A2 (223) and quinolactacin A1 (222) inhibited AChE, but 223 was more potent (IC₅₀ 19.8 vs 280 μM).³¹⁰ 1-Methyl-2-undecylquinolin-4(1H)-one (165), an Evodia alkaloid, acted as an irreversible and selective inhibitor of type B monoamine oxidase.³¹¹

Dictyoquinazols A–C (230–232) (Fig. 24), from the mushroom Dictyophora indusiata, showed protective effects in primary cultured mouse cortical neurons against the excitotoxicity induced by glutamate and N-methyl-D-aspartate in a dose-dependent manner.³¹² These results indicated that the above compounds have potential value in the treatment of neurological disorders or neurodegenerative diseases of the brain, such as Parkinson^’s and Alzheimer^’s diseases and Huntington^’s chorea. Fiscalins A (233), B (234), and C (235) (Fig. 24), from a fungal culture of Neosartorya fischeri, inhibited the binding of substance P, an undecapeptide neurotransmitter, to human neurokinin-I receptors with Ki values of 57, 174, and 68 μM, respectively.³¹³

2.9 |. Herbicidal activity

In 2004, Hale and co-workers found that the 2-phenylquinolinone alkaloid graveoline (41) has marked herbicidal activity and may be useful as a biodegradable, environmentally friendly herbicide. It inhibited the germination of representative monocot and dicot seeds, impeded the growth of aquatic duckweed, and reduced cell division in onion.³¹⁴ A mixture of two highly substituted 4-phenyl 2-quinolone alkaloids penigequinolones A (148) and B (149) inhibited the growth of tea pollen tubes by 40% at 10 mg/L and 100% at 100 mg/L.³¹⁵ Compared with other natural pollen inhibitors, the mixture^’s effects were stronger than those of emeniveol, but weaker than those of hericerin and isofunicone.³¹⁵

2.10 |. Effects on CYP450 family and cytochromes

In 1990, Oettmeier et al. reported that aurachins A–D (177–180) inhibit photosynthetic electron transport.³¹⁶ Aurachin C (179) was an extremely potent inhibitor of the quinol oxidation sites of two different cytochrome enzymes and competed for the binding sites normally occupied by quinones of the electron transport chain. Aurchin D (180) was a highly effective inhibitor of cytochrome bd. Both 179 and 180 were active on the cytochrome b₆/f-complex, the latter showing the most pronounced inhibition to date.³¹⁷

In 2003, Don et al. studied the indolopyridoquinazolinone alkaloid rutaecarpine (115) and its analogs for their effects on CYP450.³¹⁸ 2-Methoxyrutaecarpine (134) and 115 inhibited all three cytochromes (CYP1A1, CYP1A2, and CYP1B1) of the human cytochrome P450 family without particular selectivity. Alkaloid 115 also modulated the effects of CYP1A1 and 1A2 in human or mouse liver and kidney and CYP2B in rat liver.^319–322 and the Cinchona alkaloid quinidine (28) also modified CYP3A4 activity.³²³

Finally, the quinazoline-benzodiazepine alkaloids, (−)-circumdatins H (236) and E (237) (Fig. 25), isolated from fungal sources, inhibited the mitochondrial respiratory chain in submitochondrial particles from beef heart.³²⁴ Their effects were presumably due to interference with NADH oxidase activity (IC₅₀ 1.50 and 2.50 μM, respectively).

FIGURE 25:

Chemical structures of compounds 236–247

2.11 |. Hypolipidemic and anti-hyperglycemic activities

FR225659 (238) and four related compounds (239–242) (Fig. 25) were isolated from the culture broth of Helicomyces sp. No. 19353 as novel gluconeogenesis inhibitors in 2003.^325,326 Despite high hypoglycemic activity in vitro, 241 and 242 exhibited weak or no activity in vivo, while 240 showed weak activity in vitro and in vivo. Compounds 238 and 239 showed significant activity, and furthermore, orally administered 238 suppressed glucagon-induced hyperglycemia in mice. The peripheral blood glucose levels of db/db mice, an animal model of spontaneous type 2 diabetes, were significantly decreased in a dose-dependent manner by the administration of 238. Thus, this compound could be used as a novel lead to develop new hypoglycemic agents.^325–327

Activity-guided fractionation based on inhibition of diacylglycerol acyltransferase led to the isolation of evocarpine (141), dihydroevocarpine (142), 1-methyl-2-[(4Z,7Z)-4,7-decadienyl]-4(1H)-quinolone (163), and 1-methyl-2-[(6Z,9Z)-6,9-pentadecadienyl]-4(1H)-quinolone (164) from the fruits of E. rutaecarpa.³²⁸ The four compounds displayed moderate activity (IC₅₀ 23.8, 69.5, 20.1, and 13.5 μM, respectively) suggesting they could be used in the design of hypolipidemic and antiobesity agents.

2.12 |. Anti-oxidant activity

In 2006, jineol (52) and 2,8-dihydroxy-3,4-dimethoxyquinoline (243) (Fig. 25) were isolated from the centipede S. subspinipes.³²⁹ Both compounds exhibited antioxidant activities on copper-mediated (IC₅₀ 2.60 and 63.0 μM), AAPHmediated oxidation (IC₅₀ 3.90 and 71.8 μM), and SIN-1-mediated oxidation (70% and 29% at 5 μM) in thiobarbituric acid reactive substances (TBARS) assay. Both compounds also showed 1,1-diphenyl-2-picrylhydrasyl radical scavenging activity and 52 exhibited metal chelating activity.³²⁹

Moreover, 4-carbomethoxy-6-hydroxy-2-quinolone (95), from the aleuronic layer of the dark purple anthocyaninpigmented rice cultivar O. sativa cv. Heugjinmi, exhibited moderate anti-oxidative activity in a radical-scavenging assay (IC₅₀ 166 μM).³³⁰ The quinoline alkaloids benzastatins C (71) and D (72) were also identified as free-radical scavengers, inhibiting lipid peroxidation in rat liver microsomes with EC₅₀ values of 3.30 and 4.20 μM, but they were less effective than vitamin E (0.400 μM).^114,115

2.13 |. Bronchodilator activity

In 1959, Amin and Merta identified the effect of quinazolin-4(3H)-one (133) and vasicinone (158) on bronchial musculature.³³¹ In in vitro tests on guinea pig tracheal rings, these two compounds produced relaxation at 495 μM, about 1/2000 the activity of adrenaline, whereas vasicine (3) caused slight relaxation at 53.2 μM, but contraction at higher concentrations.³³²

In 1996, Kamikawa et al. reported that three pyranoquinolone alkaloids flindersine (31), veprisine (127), and N-methylflindersine (244) (Fig. 25) from Fagara chalybea showed good bronchodilator activity on both perfused guinea pig lungs and isolated tracheal preparations.³³³ Compounds 31 and 244 were slightly less potent than 127. Compound 127 also exhibited moderate positive inotropic activity on guinea pig left atria, which was inhibited by propranolol, indicating the presence of a β₂-agonist action. In addition, all three compounds were antagonists of slow reacting substance-A (SRS-A), with 127 active at a concentration as low as 1 μg/mL without showing antihistaminic and anti-serotonin properties.³³³

2.14 |. Mutagenicity

In 1987, the mutagenic activity of extracts of R. graveolens was attributed in part to well-known furoquinoline alkaloids.³³⁴ Schimmer and co-workers reported further study results in 1988 and 1989.^335,336 γ-Fagarine (33), skimmianine (34), and dictamnine (40) exhibited strong mutagenicity in S. typhimurium strains TA98 and TA100, but had comparatively little or no activity in the corresponding non-R-factor strains TA1538 and TA1535.³³⁵ The metabolic capacity of the corresponding liver microsome preparations was increased by pretreatment of rats with phenobarbital (Pb) and to a lesser amount with 3-methylkholanthrene. The results suggested that furoquinolines are activated to mutagenic metabolites by cytochrome P450 and cytochrome P448, and feasibly the flavin-containing monooxygenase.³³⁵ Alkaloid 33 induced sister chromatid exchange in human lymphocyte culture.³³⁶ Akaloid 40 showed photo-induced genotoxicity toward an E. coli lysogen, as determined by prophage induction.³³⁷

2.15 |. Other activities

2-Methyl-4(3H)-quinazolinone (245) (Fig. 25) from the culture broth of the micro-organism B. cereus BMH225-mF1 strongly inhibited poly(ADP-ribose) synthetase (IC₅₀ 1.10 μM) and was competitive with the substrate.³³⁸ It also had low acute toxicity, and the mice tolerated i.p. treatment with 250 mg/kg of compound.

Eduline (246) and japonine (247) (Fig. 25), two well-known 2-phenyl 4-quinolone alkaloids from O. japonica, showed strong relaxant activity on small intestine muscle, with equal potency (relaxative tension 0.17 ± 0.05 g at 10 μM for 245, 0.12 ± 0.03 g at 5 μM for 246) to that of papaverine (10 μM, 0.16 ± 0.03 g).³³⁹ The quinazoline alkaloid vasicine (3) potentiated the effect of oxytocin on rat mammary gland and stimulated muscular contraction in guinea pig ileum and uterus.³⁴⁰

The furoquinoline alkaloids μ-fagarine (33), skimmianine (34), and haplopine (35) showed pronounced estrogenic activity.³⁴¹ When these three compounds (10 mg/kg) were administered to immature rats, the uterine mass increased by 193.9%, 22.6%, and 74.4% without liquid. The compounds differed structurally only in the C-7 substituent (H, OMe, OH, respectively). Results with other compounds also showed that the basicity/electronic state of the N atom influences the level of estrogenic activity.³⁴¹

3 |. CONCLUSIONS AND OUTLOOK

Since the first quinoline alkaloid (quinine) and quinazoline alkaloid (vasicine) were identified in 1820 and 1888, respectively, quinoline and quinazoline alkaloids have attracted significant attention from researchers worldwide, and represent a promising and expanding platform for active natural compounds.

Among these compounds, CPT is the most famous and important as a DNA topo I inhibitor. Its discovery opened a new area for anticancer drug development. Subsequently, many alkaloids containing a quinoline ring, such as luzopeptin C, streptonigrin, BE-22179 and thiocoraline, with significant inhibitory effects on DNA and RNA synthesis and the topo II enzyme have been identified. The molecular structures have provided valuable clues for antitumor drug design. Besides quinine, the discoveries of febrifugine, tryptanthrin, and their analogs with significant antimalarial activity and different mechanism of action have provided additional modalities for treating malarial disease. These novel classes of compounds have opened a new chapter for study in the chemotherapy of malaria. Alkyl methyl quinolone alkaloids have a highly selective and unique antimicrobial mechanism different from that of other antibiotics, and thus, may be beneficial in the treatment of H. pylori-associated gastroduodenal diseases. In addition to the aforementioned activities, quinoline and quinazoline alkaloids exhibit other important bioactivities, such as antifungal, antiparasitic, insecticidal, anti-inflammatory, antiplatelet, and other effects. We hope that such compounds will provide more avenues for the development of new drugs in the future, particularly as improved methods of isolation and identification of quinoline and quinazoline alkaloids open the way to targeted pharmacological modeling and resulting synthetic modification.

Undoubtedly, these two alkaloid classes will attract tremendous continued attention and long-lasting interest from boththeacademiccommunityandthepharmaceuticalindustrytoadvancethediscoveryofnewandbetterdrugsbased on the original effects of the naturally occurring quinoline and quinazoline alkaloids.

Biography

Xiaofei Shang, M.S., received his B.S. in bioscience from Longdong University in 2007 and his M.S. in biochemistry from Lanzhou University in 2010, and he is now a Ph.D. candidate in medicinal chemistry at Lanzhou University. He is currently an Assistant Professor of the Key Laboratory of Veterinary Pharmaceutical Development of Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Science (CAAS). His research interests include the isolation, structural elucidation, and structural modification of bioactive compounds from natural products. He has published about 20 articles, and received several projects.

Susan L. Morris-Natschke, Ph.D., received her B.S. in chemistry from the University of Maryland-College Park in 1975 and her Ph.D. in organic chemistry from the University of North Carolina-Chapel Hill (UNC-CH) in 1982. She is currently a Research Professor in the Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, UNC-CH, where she has been on the faculty since 1983. Her interests include scientific writing/editing, as well as the synthesis and SARs of bioactive natural products.

Ying-Qian Liu, Ph.D., received his B.S. in chemistry from Hebei Normal University in 2002 and his Ph.D. in bioorganic chemistry from Lanzhou University in 2007. He worked as a postdoctoral scholar in the School of Life Sciences at Lanzhou University from 2008 to 2013 and then as a visiting scholar at the University of North Carolina at Chapel Hill from 2011 to 2012. He is currently a Professor in the School of Pharmacy at Lanzhou University. His research interests include the design and synthesis of bioactive compounds as potential anticancer or pesticide agents, development of novel methodologies in organic chemistry, as well as drug mechanism and pharmacokinetics evaluation. He has published more than 50 research articles, applied for more than 28 patents, and directed several projects.

XiaoGuo,M.S., received her B.S. in bioscience from Northwest Normal University in 2010 and her M.S. in plant sciences from Northwest Normal University in 2013, and she now is a Ph.D. candidate in veterinary science from CAAS. Her research interests include the isolation, structural elucidation, and bioactivity of natural products.

Xiao-Shan Xu, B.S., received his B.S. in pharmacy from Chengdu University of Traditional Chinese Medicine in 2015, and he is now a Masters candidate in medicinal chemistry at Lanzhou University. His research interests include the design and synthesis of bioactive compounds as anticancer agents and the development of novel methodologies in medicinal chemistry.

Masuo Goto, Ph.D., received his B.S. degree in pharmacology in 1987, M.S. in pharmaceutical science in 1989, and Ph.D. in molecular biology in 1993 from Kanazawa University. He was a research fellow in cell and developmental biology at the National Institutes of Health from 1999 to 2003, followed by a postdoctoral fellow at the School of Medicine, UNC-CH from 2003–2009. Currently, he is Research Assistant Professor, UNC Eshelman School of Pharmacy, UNCCH. He is interested in elucidating the molecular mechanisms of action of antiproliferative small molecules mainly discovered and developed from natural products. His research goals are to develop novel strategies to prevent and overcome multidrug-resistant cancers.

Jun-Cai Li, B.S., received his B.S. in pharmaceutical engineering from School of Life Science and Engineering of South-west Jiaotong University in 2016, and he is currently a M.S. student in the School of Pharmacy at Lanzhou University. His research interests include the design and synthesis of bioactive compounds and natural products, as well as the development of novel methodologies in medicinal chemistry.

Guan-Zhou Yang, B.S., received his B.S. degree in pharmacy from Lanzhou University in 2016, and he is currently a M.S. student in the School of Pharmacy at Lanzhou University. His research interests include the design, synthesis and bioactivity of natural products and bioactive compounds, as well as development of novel methodologies in medicinal chemistry.

Kuo-Hsiung Lee, Ph.D., received his B.S. in pharmacy from Kaohsiung Medical University, Taiwan (1961), M.S. in pharmaceutical chemistry from Kyoto University, Japan (1965), and Ph.D. in medicinal chemistry from University of Minnesota, Minneapolis (1968). He joined the faculty of UNC Eshelman School of Pharmacy, University of North Carolina-Chapel Hill, in 1970 and is now Kenan Distinguished Professor of Medicinal Chemistry and Director of the Natural Products Research Laboratories. He has published more than 868 research articles, been granted more than 117 patents, and received numerous awards, including most recently, the Third Cheung On Tak International Award for Outstanding Achievement in Chinese Medicine from Hong Kong Baptist University in 2016.