Therapeutic potential of oxadiazole or furadiazole containing compounds

Abstract

As we know that, Oxadiazole or furadi azole ring containing derivatives are an important class of heterocyclic compounds. A heterocyclic five-membered ring that possesses two carbons, one oxygen atom, two nitrogen atoms, and two double bonds is known as oxadiazole. They are derived from furan by the replacement of two methylene groups (= CH) with two nitrogen (-N =) atoms. The aromaticity was reduced with the replacement of these groups in the furan ring to such an extent that it shows conjugated diene character. Four different known isomers of oxadiazole were existed such as 1,2,4-oxadiazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole & 1,3,4-oxadiazole. Among them, 1,3,4-oxadiazoles & 1,2,4-oxadiazoles are better known and more widely studied by the researchers due to their broad range of chemical and biological properties. 1,3,4-oxadiazoles have become important synthons in the development of new drugs. The derivatives of the oxadiazole nucleus (1,3,4-oxadiazoles) show various biological activities such as antibacterial, anti-mycobacterial, antitumor, anti-viral and antioxidant activity, etc. as reported in the literature. There are different examples of commercially available drugs which consist of 1,3,4-oxadiazole ring such as nitrofuran derivative (Furamizole) which has strong antibacterial activity, Raltegravir as an antiviral drug and Nesapidil drug is used in anti-arrhythmic therapy. This present review summarized some pharmacological activities and various kinds of synthetic routes for 2, 5-disubstituted 1,3,4-oxadiazole, and their derived products.

Background

Health problems were increasing day by day and become the most serious clinical problem. Recently, medicinal chemists have been looking for new drugs to be used safely to treat these serious clinical problems. There are a lot of heterocyclic compounds that are in clinical use to treat infectious disease [1].

The most common heterocyclic are those having five or six-member fused rings and possess nitrogen, oxygen, sulfur groups as heteroatoms. Some time boron, silicon, and phosphorus atoms can be used as hetero atoms [2].

Heterocyclic compounds containing nitrogen atom such as oxadiazole moieties are of interest to researchers in the fields of medicinal and pharmaceutical chemistry [3].

A heterocycles five-member ring that possesses one oxygen, two carbons, two nitrogen atoms, and two double bonds is known as oxadiazole [4]. This type of ring system is also known as azoximes, oxybiazole, biozole, diazoxole, furadiazole, and furoxans. Oxadiazole was first synthesized in 1965 by Ainsworth through the thermolysis of hydrazine. Its molecular formula is C₂H₂ON₂ and having a molecular mass of 70.05 g/mol which is soluble in water [2].

Oxadiazoles are thermally stable compounds and their calculated resonance energy is equal to 167.4 kJ/mol. The thermal stability of oxadiazoles is increased with the substitution at the second position [5].

1,3,4-oxadiazole heterocyclic ring is one of the most important heterocyclic moieties due to its versatile biological actions [6]. These are the derivatives of furan in which two methylene groups were replaced with two nitrogen atoms. Replacement of these two methylene groups by two nitrogen atoms reduces the aromaticity of the ring & the resulting oxadiazole ring exhibits conjugated diene character [7]. Another heteroatom makes a weak base to the oxadiazole due to the inductive effect [6]. Hydrogen atoms were replaced by nucleophiles which are seen in nucleophilic substitution reaction [8].

Nitrogen atoms are present in oxadiazole ring at different positions and based on the position there are four different possible isomers of oxadiazole such as 1,2,3-oxadiazole (a), 1,2,5-oxadiazole (b), 1,3,4-oxadiazole (c) and 1,2,4-Oxadiazole (d) were showed in Fig. 1 [6].

Fig. 1.

Oxadiazole

Among the different isomers, 1,3,4-oxadiazole isomer shows a lots of therapeutic activities like antibacterial [9, 10], anticonvulsant [11], antitumor [12–22], hypoglycemic, antipyretic [23], anti-tubercular [10, 24], anti-viral [25], immunosuppressive, spasmolytic, antioxidant [13, 26], anti-inflammatory [23, 27, 28], insecticidal [20], CNS stimulant, ant amoebic, antiemetic, antidepressant, anthelmintic activities, vasodilator activity, antimycotic activity [29], anti-allergic, anti-Alzheimer activity, ulcerogenic and antihypertensive activities etc. as reported in the literature [30]. Keeping the view of this, we have discussed different oxadiazole derivatives carrying urea, amide, and sulphonamide groups to investigate their anticancer, antiviral, antimicrobial, antitubercular, and antioxidant activities [31].

The presence of toxophoric –N = C–O– linkage in 1,3,4-oxadiazole ring might be responsible for their potent pharmacological activities. Among these, substituted 1,3,4-oxadiazoles are of considerable pharmaceutical interest. 2,5-disubstituted-1,3,4-oxadiazole derivatives are stable, especially 2,5-diaryl-1,3,4-oxadiazoles are more stable than the corresponding 2,5-dialkyl derivatives. Medicinal chemists have great perseverance in Research and development for the development of newer and safer antitumor agents. Tyrosine kinases (EGFR family) play a very important role in cancer proliferation. So those compounds which inhibit the activity of tyrosine kinases play a substantial role in cancer treatment. Therefore Tyrosine kinases (EGFR family) were selected and explore the binding mode of the novel compounds to EGFR tyrosine kinase active site [32].

There is various kind of synthetic route from which we can synthesize 1,3,4-oxadiazole, and their derived products. In general, 1,3,4-oxadiazole can be synthesized by the reaction of acid hydrazide or hydrazine along with carboxylic acids/acid chlorides and direct ring closure of diacyl hydrazines employing different kinds of the cyclizing agent such as phosphorus oxychloride, thionyl chloride, phosphorus pentaoxide, triflic anhydride, polyphosphoric acid, acetic anhydride and the direct reaction of an acid with (N-isocyananimino-) triphenylphosphorane [33]. In some reaction, carbon disulfide is also used for ring closure [34].

There are different examples of commercially available drugs containing 1,3,4-oxadiazole ring (Fig. 2) such as a nitrofuran derivative (Furamizole) which has strong antibacterial activity [35]. Raltegravir as an antiviral drug and Nesapidil drug is used in anti-arrhythmic therapy. The FDA approved anticancer agent Zibotentan is a 1,3,4-oxadiazole nucleus containing the most privileged derivatives available in the market [36]. Tiodazosin is used as an antihypertensive agent [37]. This present review summarized some pharmacological activities and various kinds of synthetic routes for 2,5-disubstituted 1,3,4-Oxadiazole, and their derived products during the last decade (2005–2020).

Fig. 2.

Commercially available drugs which contain 1,3,4-oxadiazole nucleus

The mechanism for the formation of 2,5-disubstituted 1,3,4-oxadiazole

The probable mechanism for the formation of the 1,3,4-oxadiazole is given in (Fig. 3). The presence of lone pair of electron on the nitrogen atom of acid hydrazide attacks the carbonyl carbon atom of carboxylic acid eliminates a water molecule to form a hydrazide derivative which further reacts with phosphorus oxychloride, undergoes ring closure with the elimination of hydrogen chloride, and form 1,3,4-oxadiazole ring [38].

Fig. 3.

Mechanism for the formation of 2,5-disubstituted 1,3,4-oxadiazole using phosphorus oxychloride

Structure–activity relationship of 1,3,4-oxadiazole derivatives

The structure–activity relationship of 1,3,4-oxadiazole is given in (Fig. 4). Substitution of phenyl ring with different substituents like p-Cl, p-NO₂ & p-^tBu further increases the activity. The conversion of the methylthio group into the methyl-sulfonyl group also increases the activity. The replacement of the phenyl ring along with the pyridine ring decreases the activity. If the acetyl group is present on the nitrogen atom of the oxadiazole ring did not significantly affect the activity [39]. Thus, based on the aforementioned results, we hypothesized that 2,5-disubstituted 1,3,4-oxadiazole scaffold may lead to novel potent agents with broad biological activity profile and improved pharmacokinetic properties.

Fig. 4.

Structure–activity relationship of 1,3,4-oxadiazole

Pharmacological profile of some oxadiazole derivatives

Compound N-(4 chlorophenyl) amino-5-(4-pyridyl)- 1,3,4-oxadiazole having electron-withdrawing group shows better anticonvulsant activity [40]. Compounds with p-methoxy group increase the antimicrobial potential [41] and 3, 4-dimethoxy containing compound increase anti-inflammatory activity as compared to reference drug [42]. 1,3,4-Oxadiazole nucleus containing compounds along with different substituents shows various kinds of activities (Fig. 5).

Fig. 5.

Therapeutic activity of 1,3,4-oxadiazole nucleus

Antimicrobial activity

Bhat et al. [48] developed 4-bromo-N-[(5-(substituted phenyl)-1,3,4-oxadiazol-2yl)methyl]aniline (Scheme 1) and these derivatives were screened for antimicrobial activity against S. aureus, E. coli, B. Subtilis, and P. aeruginosa using amoxicillin as a positive control. The antimycotic activity was evaluated for these compounds against A. niger and C. albicans using ketoconazole as a reference standard. Derivatives with different groups like -OH, -NO₂ [1b, 1c, 1d, 1g] shows good antimicrobial activity against fungal strains. Derivatives with groups like p-methoxy, p-chloro, p-methyl [1e, 1f, 1h] show better antimicrobial potential as compared to amoxicillin. The results of the antimicrobial activity of synthesized 1,3,4-oxadiazole derivatives were presented in (Table 1, Bhat et al. [48]).

Scheme 1.

Synthesis of substituted 1,3,4-oxadiazole (1a-j) with 4-bromoaniline starting material

Table 1.

Antimicrobial activity of titled compounds (1a-j) [48]

Compound	Diameter of zone of inhibition (mm)
	S. aureus	B. subtilis	E. coli	P. aeruginosa	C. albicans
1a 1b 1c 1d 1e 1f 1 g 1 h 1i 1j Amoxicillin Ketoconazole	13 14 14 15 18 19 14 18 16 15 21 –	15 14 15 14 19 17 12 18 15 14 22 –	14 13 14 13 18 18 15 19 14 15 21 –	13 12 15 13 15 16 10 15 13 12 22 –	08 15 14 15 08 09 15 09 10 11 – 23

Chawla et al. [41] developed 1-(5-(3-chlorobenzo[b]thiophen-2-yl)-2-(2,3,4-trisubstituted phenyl)-1,3,4-oxadiazol-3(2H)-yl)ethanone and 2-(3-chlorobenzo[b]thiophen-2-yl)-5-(2,3,4-trisubstituted phenyl)-1,3,4-oxadiazole by using Scheme 2. The antibacterial activity of synthesized derivatives was evaluated against different bacterial strains such as (S. aureus, B. Subtilis, E. coli, and P. aeruginosa) using ciprofloxacin as standard drug. The antimycotic activity of these derivatives was evaluated against A. niger and C. albicans using fluconazole as a reference standard and the results were summarized in (Table 2, Chawla et al. [41]).

Scheme 2.

Synthesis of substituted 1,3,4-oxadiazole derivatives

Table 2.

Antimicrobial activity of titled compounds (2a-h) and (3a-h) [41]

Compound	Diameter of zone of inhibition (mm)
	Antibacterial activity				Antifungal activity
	S. aureus	B. subtilis	E. coli	P. aeruginosa	C. albicans	A. niger
2a	14	21	10	17	09	10
2b	18	19	12	15	10	11
2c	30	27	14	18	09	11
2d	19	22	11	18	10	11
2e	28	28	14	14	10	09
2f	14	19	10	15	10	10
2g	21	23	13	19	11	09
2h	14	20	10	16	09	10
3a	11	12	10	09	11	11
3b	10	12	09	11	12	12
3c	20	21	12	13	11	11
3d	20	22	16	18	10	11
3e	18	19	11	13	11	10
3f	11	13	10	11	10	11
3g	12	14	09	12	10	10
3h	10	13	09	11	10	11
Ciprofloxacin	26	26	28	25	–	–
Fluconazole	–	–	–	–	26	25

Kumar et al. [43] developed 2-((1, 1′-biphenyl)-4-yl)-5-(substituted phenyl)-1,3,4-oxadiazole by using Scheme 3. The antibacterial activity of these derivatives was evaluated against different Gram + ve (S. aureus) and Gram -ve (K. pneumonia, E. coli, and P. aeruginosa) strains using ofloxacin as a reference standard. The cup plate agar diffusion method was used for the determination of the zone of inhibition. The results of antibacterial activity were summarized in (Table 3, Kumar et al. [43]).

Scheme 3.

Synthesis of substituted 1,3,4-oxadiazole with 4-biphenyl carboxylic acid as starting material

Table 3.

In vitro antimicrobial activity of the titled compounds (4a-4 h) [43]

Compound	Diameter of zone of inhibition (mm)
	Antibacterial activity
	S. aureus	P. aeruginosa	K. pneumonia	E. coli
4a	19	17	18	19
4b	17	16	17	15
4c	14	13	16	17
4d	21	19	19	20
4e	12	11	13	12
4f	13	14	15	12
4g	12	13	11	11
4h	17	16	15	17
Ofloxacin	41	38	39	37

Kanthiah et al. [5] developed 5-(2-aminophenyl)-3-(substituted (disubstituted amino) methyl)-1,3,4-oxadiazole-2(3H)-thione by using Scheme 4. The antimicrobial activity of synthesized derivatives was evaluated against different two Gram + ve (S. aureus and S. pyogenes) and Gram -ve (E. coli and K. aerogenes) strains using amikacin as a reference standard. The antimycotic activity was also evaluated for these derivatives against C. albicans using ketoconazole as positive control and the results were summarized in (Table 4, Kanthiah et al. [5]).

Scheme 4.

Synthesis of substituted 1,3,4-oxadiazole with 2-aminobenzoic acid as starting material

Table 4.

Antimicrobial activity of the titled compounds (5a-5f) [5]

Compound	Diameter of zone of inhibition (mm)
	Antibacterial activity				Antifungal activity
	S. aureus	S. pyrogenes	E. coli	P. aeruginosa	C. albicans
5a	10	13	12	08	14
5b	13	11	14	09	12
5c	12	13	15	09	14
5d	12	11	13	10	13
5e	09	09	10	07	11
5f	08	09	09	06	10
Amikacin	16	15	17	18	–
Ketoconazole	–	–	–	–	18

Chikhalia et al. [49] developed 1-substituted-3-(4-morpholino-6-((5-(3,4,5-trimethoxyphenyl)-1,3,4-oxadiazol-2-yl)thio)-1,3,5-triazin-2-yl)substituted urea (Scheme 5) and evaluated for antimicrobial activity against different strains such as (Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa) using ampicillin as a reference standard. The antifungal activity was also evaluated for these derivatives against C. albicans using fluconazole as a reference standard. Compound 6e shows better activity against E. coli and P. aeruginosa as compared to a positive control (ampicillin). Compound 6 g also shows better activity towards P. aeruginosa but lower than that of ampicillin. Compound 7c and 7g showed good activity against C. albicans but slightly lower than that of fluconazole. The results of antimicrobial activity were shown in (Table 5, Chikhalia et al. [49]).

Scheme 5.

Synthesis of substituted 1,3,4-oxadiazole with 3, 4, 5-trimethoxybenzoic acid as starting material

Table 5.

Minimum inhibitory concentration (MIC) of titled compounds [49]

Compound			S. aureus	B. subtilis	P. aeruginosa	E. coli	C. albicans
	R	X	ATCC 25923	ATCC 6633	ATCC 27853	ATCC 27853	ATCC 10231
6a	C6H5	O	0.3	0.15	0.15	1.25	2.5
6b	2-CH3 C6H5	O	0.31	0.07	1.25	0.625	5.0
6c	3-CH3 C6H5	O	0.625	0.15	5.0	2.5	10
6d	4-CH3 C6H5	O	2.5	2.5	0.03	5.0	1.25
6e	2-Cl C6H5	O	0.15	1.25	0.019	0.019	5.0
6f	3-Cl C6H5	O	0.15	0.625	1.25	1.25	2.5
6g	4-Cl C6H5	O	0.15	0.3	0.019	0.07	0.15
6h	3-NO2 C6H5	O	-	10	1.25	–	–
6i	4-NO2 C6H5	O	2.5	–	0.625	5.0	10
7a	2-CH3 C6H5	S	1.25	–	2.5	10	–
7b	4-CH3 C6H5	S	1.25	5.0	2.5	1.25	5.0
7c	3-OH C6H5	S	2.5	1.25	0.019	2.5	10
7d	4-OH C6H5	S	0.15	0.625	2.5	0.625	1.25
7e	4-Cl C6H5	S	0.625	0.07	5.0	0.03	0.31
7f	3-NO2 C6H5	S	2.5	2.5	10	1.25	2.5
7g	4-NO2 C6H5	S	2.5	5.0	5.0	0.1	0.15
Ampicillin			0.019	0.005	0.005	0.01	–
Fluconazole			–	–	–	–	0.01

Antitumor activity

Srinivas et al. [30] developed (E)-1-(1-((5-substituted-1,3,4-oxadiazol-2-yl)methyl)-1H-indol-3-yl)-4-(thiazol-2-ylamino)but-2-en-1-one (Scheme 6) and evaluated for antitumor activity by MTT assay against four different cancer cell lines such as HT-29 (colon), A375 (melanoma), MCF-7 (breast) and A549 (lung) using combretastatin-A4 as reference standard. All derivatives of 1,3,4-oxadiazole fused indole ring was showed a variable degree of anticancer activity along with IC₅₀ values ranging from 0.010 ± 0.004 and 18.50 ± 0.86 μM. Among the different derivatives 9a, 9b, 9f, 9g, 9h, and 9j were exhibited more potent than the positive control. The results of antitumor activity were presented in (Table 6, Srinivas et al. [30]).

Scheme 6.

Synthesis of substituted 1,3,4-oxadiazole derivatives

Table 6.

In vitro cytotoxicity (IC₅₀Μ)^a data of compounds (9a-j) [30]

Compound	A549bc	MCF-7d	A375e	HT-29f
9a	1.20 ± 0.16	0.098 ± 0.004	2.56 ± 0.36	0.012 ± 0.001
9b	0.023 ± 0.006	0.011 ± 0.001	–	1.90 ± 0.71
9c	2.30 ± 0.21	2.19 ± 0.28	–	8.30 ± 1.60
9d	3.56 ± 0.19	2.11 ± 0.23	6.13 ± 1.12	7.14 ± 0.86
9e	5.02 ± 1.02	12.4 ± 0.96	–	–
9f	0.27 ± 0.02	1.07 ± 0.59	2.81 ± 0.25	1.55 ± 0.65
9 g	0.013 ± 0.001	0.80 ± 0.15	1.05 ± 0.53	1.24 ± 0.17
9 h	1.02 ± 0.50	0.010 ± 0.004	1.99 ± 0.29	3.78 ± 0.16
9i	13.9 ± 0.54	18.50 ± 0.86	8.23 ± 1.35	–
9j	0.90 ± 0.09	0.12 ± 0.01	0.39 ± 0.012	1.10 ± 0.54
Combretastatin-A4	0.11 ± 0.01	0.18 ± 0.01	0.21 ± 0.02	0.93 ± 0.03

^aEach data represented as mean ± S.D values. From three different experiments performed in triplicates, ^bcA549: Human lung cancer cell line, ^dMCF-7: Human breast cancer cell line, ^eA375: Human melanoma cancer cell line, ^fHT-29: Human colon cancer cell line. –: Not active

Vinayak et al. [50] developed N-[(5-(6-(4-fluorophenyl)pyridine-3-yl)1,3,4-oxadiazol-2-yl)methyl]-substituted-1-amine by using Scheme 7 and evaluated for antiproliferative activity against different cell lines such as HeLa, HepG2, and Caco by MTT assay using 5-Fluorouracil as a reference standard. The derivative 10a and 10d showed excellent activity against HepG2 cell lines. The compound 10f gives better results against the Caco-2 cancer cell line. The results of the anti-proliferative activity of synthesized derivatives were showed in (Table 7a, b, and c, Vinayak et al. [50]).

Scheme 7.

Synthesis of substituted 1,3,4-oxadiazole derivatives

Table 7.

(a) IC₅₀ values of the synthesized novel amine derivatives. (b) CC₅₀ values of the synthesized novel amine derivatives. (c) Selectivity index (SI) of the synthesized novel amine derivatives [50]

Panel (a)
Compound	IC50#values of 10(a-h) in (μM)
	HeLa	Caco-2	HepG2
10a	212.4 ± 1.2	203.6 ± 2.3		2.6 ± 0.5
10b	85.6 ± 0.8	112.5 ± 1.2		45.6 ± 1.1
10c	34.8 ± 1.3	123.8 ± 1.4		128.9 ± 3.5
10d	112.9 ± 0.4	145.6 ± 0.4		5.8 ± 1.6
10e	118.4 ± 0.5	212.3 ± 0.4		32.2 ± 0.3
10f	78.3 ± 5.4	2.3 ± 0.5		23.5 ± 4.6
10 g	56.4 ± 3.4	56.8 ± 1.2		156.7 ± 2.3
10 h	88.6 ± 1.2	34.6 ± 0.9		176.4 ± 1.6
5-FU	7.6 ± 0.3	8.8 ± 0.6		7.6 ± 0.2

Panel (b)
Compound	CC50* of the compound 10(a-h) in (μM)
	HeLa	Caco-2	HepG2
10a	120 ± 1.2	112 ± 1.3		34 ± 0.5
10b	7.6 ± 0.6	145 ± 1.1		129 ± 0.3
10c	200	178 ± 2.3		102 ± 1.1
10d	450	100 ± 2.6		112 ± 1.4
10e	56 ± 2.4	62 ± 1.2		76 ± 3.4
10f	127 ± 3.4	87 ± 2.6		77 ± 0.4
10 g	200	23 ± 1.5		91 ± 4.3
10 h	123 ± 2.3	156 ± 0.4		73 ± 1.4
5-FU	57 ± 0.3	69 ± 2.3		52 ± 1.8

Panel (c)
Compound	SI of the compound 10(a-h)
	HeLa	Caco-2	HepG2
10a	0.566	0.551		13.06
10b	0.887	1.288		2.828
10c	5.747	1.437		0.791
10d	3.985	0.686		19.31
10e	0.472	0.292		0.236
10f	1.621	37.8		3.276
10g	3.546	0.404		0.580
10h	1.388	4.508		0.413
5-FU	7.5	7.84		6.84

*Concentration of compound at 50% of the remaining viable cells

^#Inhibitory concentration at 50% of the viable cells

 ± Average value of the two independent experiments

Kapoor et al. [51] developed 2-(substituted phenyl)-5-(2-(2-(substituted phenyl)-1H-benzo[d]imidazol-1-yl)phenyl)-1,3,4-oxadiazole by using Scheme 8 and evaluated for antitumor activity against MCF-7 (breast) cancer cell line by MTT assay. Compound 11e shows better cytotoxic activity as compare to 11a, 11b, and 11c. Compounds 11f, 11g, 11h also show the excellent cytotoxic activity as compared to the rest of the derivatives. Compounds 11e and 11h flourished potent cytotoxic activity with minimum percentage viability. Each compound was tested to calculate the percentage viability of cell line against the different concentrations which is presented in (Table 8, Kapoor et al. [51]).

Scheme 8.

Synthesis of substituted 1,3,4-oxadiazole with benzene 1, 2-diamine as starting material

Table 8.

In-vitro cytotoxicity of synthesized compounds against Breast cancer cell line (MCF-7) [51]

Compound	% Viability
	6.25 μg/ml	12.5 μg/ml	25 μg/ml	50 μg/ml	100 μg/ml
11a	38.04	37.15	39.68	35.11	40.31
11b	38.26	42.70	37.90	38.84	43.24
11c	44.35	41.6	41.81	39.64	37.24
11d	42.70	39.46	40.48	37.61	37.37
11e	30.60	32.20	34.48	33.86	37.54
11f	32.57	33.09	30.88	30.75	24.87
11 g	34.39	33.58	28.80	32.40	30.96
11 h	32.03	35.40	31.25	33.69	34.45

Control % viability = 100

Kavitha et al. [31] developed N-substituted-(3-(5-cyclohexyl-1,3,4-oxadiazol-2-yl)phenyl)benzamide, urea, and substituted benzenesulfonamide derivatives by using Scheme 9. The anticancer activity of synthesized derivatives was evaluated against different cancer cell lines like HeLa and MCF-7 using cisplatin as a reference standard. Among the different derivatives, compounds 12a, 12b, 12c, 13c, 13d, and 14b showed significant activity after 48 h exposures. Further derivatives 12a, 13c, 13d, and 14b also showed excellent antitumor activity as compared to the positive control. Compound 12b showed excellent antitumor activity as compared to the rest of other compounds. The results of the antitumor activity of these derivatives were presented in (Table 9, Kavitha et al. [31]).

Scheme 9.

Synthesis of 1,3,4-oxadiazole derivatives

Table 9.

Preliminary cytotoxicity screening of synthesized 1,3,4-oxadiazole derivatives [31]

Compound	IC50 μM
	HeLa	MCF-7
12a	79.7	81.6
12b	30.4	23.5
12c	45.6	28.6
13a	≥ 100	≥ 100
13b	≥ 100	≥ 100
13c	80.1	78.3
13d	58.8	62.4
13e	≥ 100	≥ 100
13f	100.3	≥ 100
13 g	≥ 100	≥ 100
13 h	≥ 100	≥ 100
13i	≥ 100	≥ 100
14a	≥ 100	≥ 100
14b	62.9	60.9
14c	≥ 100	≥ 100
Standard	3.5	3.5

Chakrapani et al. [52] developed 3-(6-chloro-2-methylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)-5-(substituted phenyl)-1,2,4-oxadiazole by using Scheme 10. The antitumor activity of the synthesized derivatives was evaluated by MTT assay against ACHN (renal), MCF-7 (breast), and A375 (melanoma) tumor cell line using doxorubicin as a reference standard. The compound 16b shows good cytotoxic activity in comparison to the reference drug. The compound 16j exhibits excellent activity towards melanoma cancer cell line (A375) and potent activities towards MCF-7 and ACHN cancer cell lines. The results of the antitumor activity of synthesized derivatives were presented in (Table 10, Chakrapani et al. [52]).

Scheme 10.

Synthesis of 1,2,4-oxadiazole derivatives

Table 10.

Cytotoxicity data for compound 16a-j [52]

Compound	IC50 values, μM
	A375	MCF-7	ACHN
16a	11.4	10.2	18.5
16b	1.22	0.23	0.11
16c	2.98	0.70	1.89
16d	14.6	19.1	6.47
16e	8.20	11.2	7.7
16f	2.70	8.41	17.6
16 g	17.7	9.7	12.2
16 h	2.20	5.98	10.6
16i	9.56	13.7	2.44
16j	0.37	1.47	0.33
Doxorubicin	5.51	2.02	0.79

Gudipati et al. [53] developed (Z)-3-[(4-(5-mercapto-1,3,4-oxadiazol-2-yl)phenyl) imino]-5 or 7-substituted indolin-2-one (Scheme 11) and evaluated for antitumor activity by MTT assay against MCF-7, IMR-32, and HeLa tumor cell lines using cisplatin as a reference standard. The compounds 17b-17d showed the most potent antitumor activity than the rest of other derivatives. The results of antitumor activity were summarized in (Table 11, Gudipati et al. [53]).

Scheme 11.

Synthesis of substituted 1,3,4-oxadiazole with p-amino benzoic acid as starting material

Table 11.

Anticancer activity of synthesized compounds against HeLa, IMR-32 & MCF-7 cancer cells using MTT assay [53]

Compound	R1	R2	IC50 (μM)*(HeLa)	IC50 (μM)*(IMR-32)	IC50 (μM)* (MCF-7)
Isatin			521.9	352.74	410.95
17	Intermediate		309.59	176.85	206.95
17a	H	H	25.47	30.65	33.62
17b	F	H	11.99	13.48	15.57
17c	Cl	H	12.84	15.84	16.68
17d	Br	H	10.64	12.68	16.06
17e	CH3	H	22.59	27.25	29.38
17f	NO2	H	18.60	22.51	24.48
17 g	COOH	H	17.25	20.85	22.95
17 h	H	Cl	18.69	22.51	24.92
17i	H	NO2	16.20	19.35	20.38
17j	H	CH3	15.12	18.32	20.95
17 k	H	COOH	20.36	24.28	25.98
17 l	H	COOCH3	19.32	23.85	25.18
Cisplatin			14.08	13.64	13.54

Values are expressed as means (n = 4)

Polothi et al. [54] developed 5-(substituted phenyl)-3-(4-(5-(3,4,5-trimethoxyphenyl)-1,3,4-oxadiazol-2-yl)phenyl)-1,2,4-oxadiazole by using Scheme 12 and evaluated for antitumor activity by MTT assay against MDA MB-231, MCF-7 (breast cell line), A549 (lung cell line) cancer cell lines using doxorubicin as a reference standard. Among the different derivatives, compounds 19b, 19g, 19h, and 19i showed good cytotoxic activity as compared to the reference standard. The compound 19b with 3, 4, 5-trimethoxy group on phenyl ring shows excellent antitumor activity against human cancer cell lines such as A549 and MCF-7. The results of the antitumor activity of synthesized derivatives were showed in (Table 12, Polothi et al. [54]).

Scheme 12.

Synthesis of substituted 1,3,4-oxadiazole linked 1,2,4-oxadiazole

Table 12.

In vitro cytotoxic activity [IC₅₀ (μM)^a] of compounds (19a-j) [54]

Compound	Lung cancerA549c	Breast cancer
		MCF-7b	MDA MB-231d
19a	9.78 ± 0.27	34.55 ± 2.34	–
19b	0.45 ± 0.03	1.76 ± 0.34	2.11 ± 0.21
19c	3.67 ± 0.18	2.89 ± 0.67	12.76 ± 0.81
19d	4.56 ± 0.19	2.33 ± 0.56	7.34 ± 0.26
19e	13.78 ± 1.78	12.4 ± 0.79	19.5 ± 2.11
19f	34.9 ± 2.30	15.3 ± 1.72	–
19g	1.03 ± 0.17	1.23 ± 0.30	1.89 ± 0.35
19h	2.45 ± 0.23	0.34 ± 0.025	1.11 ± 0.18
19i	1.89 ± 0.38	1.90 ± 0.41	3.78 ± 0.29
19j	87.5 ± 4.67	6.30 ± 0.35	22.5 ± 1.28
Doxorubicin	2.10 ± 0.14	3.12 ± 0.17	3.41 ± 0.23

(–) not active, ^aEach data represents as mean ± S.D values. From three different experiments performed in triplicates. MCF-7: Human breast cancer cell line. ^cA549: Human lung cancer cell line. MDA MB-231^d: Human breast cancer cell line

Antitubercular activity

Pattan et al. [55] developed 2-(5-(substituted thio)-1,3,4-oxadiazol-2-yl) phenol and 4-(substituted-1-ylmethyl)-1-(2-hydroxy benzoyl)-3-methyl-1H-pyrazol-5(4H)-one by using Scheme 13. The antimycobacterial activity of the synthesized derivatives was evaluated against Mycobacterium tuberculosis (H₃₇Rv) by MB 7H9 agar medium. Streptomycin was used as a reference standard. Compounds 20a, 21b, 22a, 22b, 22c, and 22e showed promising antitubercular activity. Compounds 20b, 20c, and 22d showed moderate activity and the results of activity were presented in (Table 13, Pattan et al. [55]).

Scheme 13.

Synthesis of 1,3,4-oxadiazole derivatives

Table 13.

Antitubercular activity data of the synthesized compounds [55]

Compound	Antitubercular activity
	50 μg/mL	100 μg/mL
20a	S	S
20b	R	R
20c	R	R
21a	R	R
21b	S	S
21c	R	R
22a	S	S
22b	S	S
22c	S	S
22d	R	R
22e	S	S
Streptomycin	S	S

R Resistant; S Sensitive

Martinez et al. [44] developed N-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl) substituted amide by using Scheme 14. The antimycobacterial activity of synthesized derivatives was evaluated against different Mycobacterium tuberculosis strains such as 209, H37Ra, and H₃₇Rv using rifampin as a reference standard. Compound 23a shows more potent activity in comparison to the rest of other compounds. The results of the antitubercular activity of the synthesized derivatives were presented in (Table 14, Martinez et al. [44]).

Scheme 14.

Synthesis of substituted 1,3,4-oxadiazole derivatives

Table 14.

MIC₁₀₀ values of 23a-e against virulent, non-virulent and RIF-resistant M. tuberculosis bacteria [44]

Compound	R	MIC100 (μg/ml) in H37Rv ATCC 27294	MIC100 (μg/ml) inH37Ra	MIC100 (μg/ml) in Mtb-209 (resistant)
23a	5-NO2C4H2O	7.80	1–2.00	7.8
23b	5-NO2C4H2S	15.60	15.60	15.60
23c	5-NO2C4H3O	31.25	7.8	7.8
23d	5-NO2C6H4	15.60	31.30	15.60
23e	5-C6H5	15.60	62.50	31.25
Rifampin	-	0.06	0.008	> 64

M. tuberculosis H₃₇Rv ATCC 27294 reference strain; Mtb. M. tuberculosis H₃₇Ra non-virulent strain; Mtb-209 RIF-resistant clinical isolate of M. tuberculosis

Das et al. [56] synthesized 6-(pyrazin-2-yl)-[1,3,4]oxadiazolo[3,2-d]tetrazole and 6-(pyrazin-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]oxadiazole (Scheme 15) and antimycobacterial activity of these derivatives were evaluated by (LJ) agar method against Mycobacterium tuberculosis H₃₇Rv (MTCC200) using isoniazid and rifampicin as a reference standard. The compound 25 shows more potent antitubercular activity but still, it is lesser active than the reference standard. The results of antimycobacterial activity were showed in (Table 15, Das et al. [56]).

Scheme 15.

Synthesis of 1,3,4-oxadiazole linked triazole and tetrazole compounds

Table 15.

Anti Tuberculosis activity against Mycobacterium tuberculosis H₃₇Rv (MTCC200) [56]

Compound	MIC̽ (μg/ml)
24	> 100
25	6.25
26	50
27	50
Rifampicin	0.25
Isoniazid	0.20

MIC Minimum inhibitory concentration

Raval et al. [57] developed S-(5-(pyridin-4-yl)-1, 3, 4-oxadiazol-2-yl)2-((substituted phenyl)amino)ethanethioate using Scheme 16. The antitubercular activity of synthesized derivatives was evaluated against Mycobacterium tuberculosis H₃₇Rv (ATCC27294). Rifampin was used as a reference standard. Compounds 29e, 29g, and 29k show better activity and exhibited > 90% inhibition. The conclusion of antimycobacterial activity was presented in (Table 16, Raval et al. [57]).

Scheme 16.

Synthesis of substituted 1,3,4-oxadiazole

Table 16.

Antitubercular activity of the synthesized compounds (29a-l) against M. tuberculosis H₃₇Rv [57]

Compound	Primary screen (6.25 μg/ml)	% inhibition	Concentration (μM)	Actual MIC (μg/Ml)	Clog P̽
29a	> 6.25	64	0.0354	–	0.4996
29b	> 6.25	12	0.1640	–	1.5150
29c	> 6.25	32	0.1706	–	1.5150
29d	> 6.25	28	0.1735	–	1.5150
29e	> 6.25	92	0.0077	6.05	0.8964
29f	> 6.25	86	0.00132	5.92	0.8964
29g	> 6.25	96	0.0052	6.00	0.8964
29h	> 6.25	63	0.1130	–	0.9986
29i	6.25	62	0.1138	–	0.9986
29j	> 6.25	64	0.1133	–	0.9986
29k	> 6.25	96	0.0089	5.77	− 0.8943
29l	6.25	69	0.1184	–	− 9.1673
Isoniazid	> 6.25	98	0.025	0.05	− 0.6680

Somani et al. [58] developed 3-((substituted amino) methyl)-5-phenyl-1,3,4-oxadiazole-2(3H)-thione by using Scheme 17. The antimycobacterial activity of synthesized derivatives was evaluated against Mycobacterium tuberculosis H₃₇Rv strain in MB 7H-9 agar medium using rifampicin as a reference standard. The conclusion of the antimycobacterial activity of synthesized derivatives was presented in (Table 17, Somani et al. [58]).

Scheme 17.

Synthesis of substituted 1,3,4-oxadiazole

Table 17.

Antitubercular activity of the synthesized compounds (30a-3g) against M. tuberculosis H₃₇Rv [58]

Compound	Antitubercular activity
	25 (µg/ml)	50 (µg/ml)	100 (µg/ml)
30a	R	R	S
30b	R	S	S
30c	S	S	S
30d	S	S	S
30e	S	S	S
30f	R	R	S
30g	R	R	S
Rifampicin	S	S	S

Gavarkar et al. [59] developed 3-(5-substituted-1,3,4-oxadiazol-2-yl) naphthalen-2-ol using Scheme 18. These derivatives were evaluated for antimycobacterial activity by tube dilution method against Mycobacterium tuberculosis H₃₇Rv strain using MB 7H-9 agar broth. Streptomycin and Pyrazinamide were used as a reference standard. Compounds 31, 33c, and 33d exhibited good antitubercular activity as compare to reference standards and the results were summarized in (Table 18, Gavarkar et al. [59]).

Scheme 18.

Synthesis of substituted 1,3,4-oxadiazole

Table 18.

Antitubercular activity of the titled compounds against M. tuberculosis H₃₇Rv [59]

Compound	Antitubercular activity
	5 (µg/mL)	10 (µg/mL)	25 (µg/mL)
31	R	S	S
32	R	R	R
33a	R	R	R
33b	R	R	R
33c	R	S	S
33d	S	S	S
33e	R	R	R
33f	R	R	R
34	R	S	R
Streptomycin	R	S	S
Pyrazinamide	R	S	S

Antiviral activity

Somani et al. [47] developed N'-substituted-2-((5-(pyridin-4-yl)-1,3,4- oxadiazol-2-yl)thio)acetohydrazide (Scheme 19) and evaluated for antiviral activity against a different type of strains such as HIV-2 ROD and HIV-1 IIIB using MTT assay in MT-4 cells. Nevirapine was used as a reference standard. These derivatives were also evaluated for cytotoxic activity using MTT assay in uninfected MT-4 cells. The results of synthesized derivatives were expressed as CC₅₀, IC₅₀, and SI values which were summarized in Table 19a. The results of the antiviral activity of synthesized derivatives against other viruses in (HEL) and (Vero) culture were reported in (Table 19b, c, Somani et al. [47]).

Scheme 19.

Synthesis of substituted 1,3,4-oxadiazole

Table 19.

(a) Anti HIV activity of synthesized compounds. (b) Cytotoxicity and antiviral activity of titled compounds in Vero cell cultures. (c) Cytotoxicity and antiviral activity of titled compounds in HEL cell cultures [47]

Panel (a)
Compound	HIV I (μg/ml)		SI	HIV II (μg/ml))		SI
	IC50	CC50		IC50	CC50
35a	> 50	= 50	< 1	> 57	= 57	< 1
35b	> 65	= 65	< 1	> 60	= 60	< 1
35c	> 125	> 125	X1	> 125	> 125	X1
35f	> 125	> 125	X1	> 38	> 125	> 3
35 g	> 125	> 125	X1	> 125	> 125	X1
35 h	> 125	> 125	X1	> 125	> 125	X1
35i	> 125	> 125	X1	> 125	> 125	X1
35j	> 125	> 125	X1	> 125	> 125	X1
Nevirapine(μM)	> 0.25	> 200	> 800	–	–	–
DDI (μM)	> 5.37	> 529	> 98	2.71	> 529	> 195

Panel (b)
Compound	Minimum cytotocic concentrationa (μg/mL)	EC50b (μg/mL)
		Para-influenza-3 virus	Retrovirus	Sindbis virus	Coxasacide B4 virus	Punta Toro virus
35a	20	> 20	> 20	> 20	> 20	> 20
35b	100	> 20	> 20	> 20	> 20	> 20
35c	100	> 20	> 20	> 20	> 20	> 20
35f	> 100	> 100	> 100	> 100	> 100	> 100
35 g	> 100	> 100	> 100	> 100	> 100	> 100
35 h	> 100	> 100	> 100	> 100	> 100	> 100
35i	> 100	> 100	> 100	> 100	> 100	> 100
35j	> 100	> 100	> 100	> 100	> 100	> 100
Ribavirin (μM)	> 250	146	250	> 250	> 250	146

Panel (c)
Compound	Minimum cytotocic concentrationa (μg/mL)	EC50b (μg/mL)
		Herpes simplex virus-1	Herpes simplex virus-2	Vaccinia virus	Vesicular stomatitis virus
35a	> 100	50	100	45	> 100
35b	100	> 20	> 20	> 20	> 20
35c	> 100	> 100	> 100	> 100	> 100
35f	> 100	> 100	> 100	> 100	> 100
35g	> 100	> 100	> 100	> 100	> 100
35h	> 100	> 100	> 100	> 100	> 100
35i	> 100	> 100	> 100	> 100	> 100
35j	> 100	> 100	> 100	> 100	> 100
Brivudin (μM)	> 250	0.04	50	2	250
Cidofovir (μM)	> 250	1	1	2	> 250
Ganciclovir (μM)	> 100	0.02	0.07	> 100	> 100

^aConcentration required to cause a microscopically detectable alteration of normal cell morphology, ^bConcentration required to reduce virus-induced cytopathogenicity by 50%

Gan et al. [25] developed (1E, 4E)-1-(substituted)-5-(4-(2-((5-substituted)-1,3,4-oxadiazol-2-yl)thio)ethoxy)phenyl)Penta-1,4-dien-3-one by using Scheme 20. The antiviral activity of synthesized compounds was evaluated against (TMV) using ribavirin as a reference standard. Among the synthesized derivatives, compounds 37a, 37c, 37f, 38a, 38b, 38c, 38d, 38e, 38f, 38g, 38h, 38i, 39e, and 39f exhibited potent curative activities as compared to a reference standard. Compounds 37a-37h and 38a-38g showed good protective activity against TMV as compared to the reference standard. Moreover, compounds 37a-37g, 38c, 38e, 38f, 38g, 38i, and 39a-39j showed better activities as compared to the positive control. Among them, compound 38f shows the best curative, inactivation, and protective activity as compare to the reference standard. The results of the antiviral activity of different derivatives were showed in (Table 20, Gan et al. [25]).

Scheme 20.

Synthesis of substituted 1,3,4-oxadiazole with benzoic acid as starting material

Table 20.

Antiviral activity of the titled compounds [25]

Compound	R1	R2	Curative activity(%)	Protective activity(%)	Inactivation activity(%)
37a	4-F	4-F	43.2 ± 2.1	55.9 ± 1.7	84.4 ± 1.2
37b	4-F	4-Cl	25.9 ± 1.8	52.5 ± 1.5	88.4 ± 0.8
37c	4-F	4-Br	45.6 ± 1.9	67.9 ± 3.9	74.8 ± 1.3
37d	4-F	2-F	31.1 ± 2.3	68.4 ± 3.2	83.4 ± 1.6
37e	4-F	2-Cl	23.7 ± 3.1	56.8 ± 2.6	56.2 ± 1.9
37f	4-F	2,4-Di-Cl	52.9 ± 4.5	65.1 ± 3.2	83.5 ± 2.7
37g	4-F	H	28.2 ± 1.1	52.9 ± 0.7	74.5 ± 0.9
37h	4-F	4-CH3	19.2 ± 0.9	60.5 ± 1.1	61.3 ± 0.8
37i	4-F	4-OCH3	27.5 ± 2.1	50.0 ± 1.5	61.4 ± 1.0
37j	4-F	2-CF3	28.3 ± 2.3	47.5 ± 2.4	60.2 ± 1.7
38a	H	4-F	45.8 ± 1.8	61.5 ± 2.9	69.1 ± 1.2
38b	H	4-Cl	44.1 ± 2.5	55.7 ± 1.6	59.4 ± 2.5
38c	H	4-Br	47.2 ± 3.6	53.8 ± 3.9	83.1 ± 2.4
38d	H	2-F	38.1 ± 2.6	66.3 ± 1.9	70.1 ± 2.0
38e	H	2-Cl	41.1 ± 4.2	61.5 ± 3.1	75.6 ± 2.1
38f	H	2,4-Di-Cl	49.8 ± 3.9	69.2 ± 2.1	90.4 ± 2.8
38g	H	H	20.9 ± 2.1	66.7 ± 2.8	78.0 ± 2.5
38h	H	4-CH3	48.1 ± 3.6	57.5 ± 2.7	72.7 ± 3.3
38i	H	4-OCH3	40.6 ± 3.2	58.4 ± 3.8	79.3 ± 4.1
38j	H	2-CF3	35.5 ± 1.7	50.5 ± 1.9	56.8 ± 2.1
39a	4-OCH3	4-F	20.8 ± 1.2	44.0 ± 0.9	83.0 ± 1.1
39b	4- OCH3	4-Cl	18.4 ± 0.9	34.4 ± 1.1	87.1 ± 1.8
39c	4- OCH3	4-Br	34.8 ± 2.1	41.1 ± 3.6	82.3 ± 5.1
39d	4- OCH3	2-F	25.4 ± 1.7	35.8 ± 1.4	81.3 ± 2.1
39e	4- OCH3	2-Cl	43.5 ± 2.2	46.1 ± 2.6	77.7 ± 2.0
39f	4- OCH3	2,4-Di-Cl	43.9 ± 2.4	49.6 ± 1.8	85.6 ± 1.9
39g	4- OCH3	H	37.8 ± 1.6	42.5 ± 2.0	78.8 ± 2.1
39h	4- OCH3	4-CH3	26.5 ± 1.2	42.1 ± 2.1	86.3 ± 5.4
39i	4- OCH3	4-OCH3	35.1 ± 1.5	41.5 ± 1.8	81.5 ± 2.6
39j	4- OCH3	2-CF3	30.5 ± 2.1	49.3 ± 2.3	77.9 ± 4.5
38k	H	2,4-Di-F	55.4 ± 2.8	71.3 ± 1.9	85.2 ± 4.0
Ribavirin			37.9 ± 1.9	51.8 ± 2.3	72.9 ± 2.4

Wang et al. [1] developed N-((5-mercapto-1,3,4-oxadiazol-2-yl)methyl)-2-nitro benzamide, N-((5-(methylthio)-1,3,4-oxadiazol-2-yl)methyl)-2-nitro benzamide, 2-amino-N-((5-(methylthio)-1,3,4-oxadiazol-2-yl)methyl)benzamide and 2-(substituted)-N-((5-(methylthio)-1,3,4-oxadiazol-2-yl) methyl)benzamide (Scheme 21) and evaluated for antiviral activity. NNM was used as a reference standard. Among the synthesized derivatives, compounds 44₆, 44₈, and 44₁₅ showed a more potent activity than the reference standard. The position of the substituent’s also affected the antiviral activity and the results of antiviral activity were represented in (Table 21, Wang et al. [1]).

Scheme 21.

Synthesis of 1,3,4-oxadiazole derivatives with 2-nitrobenzoic acid as starting material

Table 21.

Anti-TMV activities of titled compounds at 500 μg/mL in vivo [1]

Compounds	Rate (%)		Compounds	Rate (%)
	Curative activity	Protective activity		Curative activity	Protective activity
40	38.5 ± 1.2	35.2 ± 3.1	448	60.0 ± 5.6	36.4 ± 1.0
41	36.9 ± 5.1	14.4 ± 2.9	449	26.9 ± 2.9	43.3 ± 3.0
42	26.8 ± 5.2	54.5 ± 2.9	4410	48.7 ± 5.1	25.2 ± 2.9
43a	22.3 ± 6.4	54.6 ± 5.2	4415	51.9 ± 3.0	45.6 ± 4.2
43b	47.2 ± 2.8	38.8 ± 4.5	40’	41.8 ± 1.0	41.7 ± 1.7
43c	44.8 ± 9.5	36.8 ± 0.8	41’	17.5 ± 1.2	32.2 ± 1.6
444	7.1 ± 1.7	51.2 ± 7.6	42’	17.7 ± 1.2	42.6 ± 2.2
445	37.4 ± 3.5	27.8 ± 5.5	432’	49.3 ± 2.0	19.6 ± 2.4
446	50.6 ± 4.7	42.9 ± 2.5	4410’	33.9 ± 1.3	20.2 ± 1.0
447	37.1 ± 3.3	23.5 ± 1.1	4415’	35.3 ± 2.3	19.3 ± 0.8
NNM	54.2 ± 2.9	65.7 ± 2.2

EI-Sayed et al. [60] developed 1,2,3,4,5-Penta-O-acetyl-D-galactopentitolyl and 2,3,4,5-tetra-O-acetyl-D-xylotetritolyl, hydrazide, and imidrazone of 1,3,4-oxadiazole by using Scheme 22a, b respectively. The antiviral activity of synthesized derivatives was evaluated as reverse transcriptase inhibitors with fresh human peripheral blood mononuclear cells. Compound 47b shows good antiviral activity followed by compounds 45 and 49a. Compounds 48b and 52 showed moderate activity while 47a and 48a showed the weakest activity among the series of tested compounds. The results of the antiviral activity of synthesized derivatives were presented in (Table 22, EI-Sayed et al. [60]).

Scheme 22.

a Synthesis of disubstituted 1,3,4-oxadiazoles.b Synthesis of hydrazide and imidrazone of 1,3,4-oxadiazoles

Table 22.

HIV inhibition activities (reverse transcriptase inhibitor) with therapeutic index [60]

Compound	EC50 (μM)	IC50 (μM)	Therapeutic index
45	3.24. 10–3	1.88	2.88. 10–7
47a	1.1. 10–5	12.89	66.24. 10–8
47b	5.26. 10–4	1.44	3.15. 10–7
48a	5.23. 10–4	12.44	5.78. 10–6
48b	1.56. 10–3	3.11	3.45. 10–6
49a	3.81. 10–3	2.12	8.14. 10–6
52	2.72. 10–3	2.9	5.12. 10–6

Antioxidant activity

Malhotra et al. [46] developed (Z)-2-(5-[(1, 1-biphenyl)-4-yl]-3-(1-((substituted)imino) ethyl)-2,3-dihydro-1,3,4-oxadiazol-2yl)phenol (Scheme 23) and evaluated for antioxidant activity in terms of hydrogen peroxide scavenging activity. The results of the antioxidant activity of the synthesized derivatives were presented in (Table 23, Malhotra et al. [46]).

Scheme 23.

Synthesis of substituted 1,3,4-oxadiazole with 4-biphenyl carboxylic acid as starting material

Table 23.

Hydrogen peroxide scavenging activity of synthesized compounds [46]

Compound	Scavenging of hydrogen peroxide at different concentration (%)
	100 (µg/ml)	300 (µg/ml)	500 (µg/ml)
53a	41.55	39.84	41.22
53b	46.34	44.55	45.77
53c	51.11	48.12	44.59
53d	41.92	42.33	41.72
53e	45.65	46.19	45.91
53f	51.21	43.12	39.57
53g	39.58	42.61	43.18
53h	43.45	41.37	45.27
53i	41.88	45.19	48.11
53j	47.52	54.15	53.18
53k	45.35	50.27	52.15
53l	51.15	52.27	58.18
53m	45.87	41.37	41.93
53n	42.98	39.72	39.57
53o	41.03	43.06	44.14
53p	51.62	52.18	52.91
53q	54.18	53.76	57.36
53r	49.87	51.35	48.74
BHA	63.27	66.19	68.25
Ascorbic acid	51.47	53.45	55.38

Rahul R. et al. [8] synthesized 5-(4-(4-chlorophenyl)thiazol-2-yl)-3-(substituted benzyl) -1,3,4-oxadiazole-2(3H)-thione by using Scheme 24 and evaluated for antioxidant activity by different methods such as Hydrogen peroxide scavenging, Nitric oxide scavenging, and DPPH assay. In DPPH assay compound 54c shows more significant activity in comparison to ascorbic acid. In other methods such as hydrogen peroxide and nitric oxide scavenging assay, compound 54c gives more potent activity than the rest of the other compounds but was not significant as compare to the results obtained in the DPPH assay. This shows that compound 54c gives more potent antioxidant activity as compared to the rest of the synthesized compounds. The results of the antioxidant activity of synthesized derivatives were presented in (Table 24, Rahul R. et al. [8]).

Scheme 24.

Synthesis of substituted 1,3,4-oxadiazole

Table 24.

(a) DPPH assay of synthesized compounds. (b) Nitric oxide scavenging of synthesized compounds. (c) Hydrogen peroxide scavenging of synthesized compounds

Compound	% Scavenging activity at different concentrations					IC50
	20 (µg/ml)	40 (µg/ml)	60 (µg/ml)	80 (µg/ml)	100 (µg/ml)
Panel (a)
54a	39.94 ± 0.521	59.14 ± 0.652	61.38 ± 0.631	63.59 ± 0.245	65.34 ± 0.534	29.7
54b	46.63 ± 0.342	49.7 ± 0.352	57.51 ± 0.421	60.51 ± 0.634	62.65 ± 0.453	43.3
54c	44.86 ± 0.245	62.22 ± 0.214	64.66 ± 0.341	65.82 ± 0.372	67.76 ± 0.215	26.7
54d	44.64 ± 0.234	53.89 ± 0.123	62.73 ± 0.223	64.02 ± 0.321	66.92 ± 0.431	27.1
54e	47.34 ± 0.235	48.16 ± 0.516	49.54 ± 0.461	52.98 ± 0.371	55.75 ± 0.297	61.3
Ascorbic acid	49.38 ± 0.515	67.03 ± 0.541	75.78 ± 0.223	91.92 ± 0.561	95.34 ± 0.111	21.3
Panel (b)
54a	34.83 ± 0.527	40.63 ± 0.654	43.87 ± 0.691	52.15 ± 0.215	53.11 ± 0.514	72.1
54b	27.34 ± 0.372	29.81 ± 0.352	38.25 ± 0.421	42.55 ± 0.639	50.54 ± 0.450	98.3
54c	33.57 ± 0.243	44.97 ± 0.211	48.69 ± 0.348	52.35 ± 0.442	53.15 ± 0.218	66.2
54d	33.28 ± 0.232	44.40 ± 0.128	45.70 ± 0.224	52.01 ± 0.331	54.29 ± 0.481	69.8
54e	26.67 ± 0.295	29.30 ± 0.506	44.95 ± 0.411	51.98 ± 0.381	52.07 ± 0.297	70.6
Ascorbic acid	47.53 ± 0.624	63.44 ± 0.521	84.28 ± 0.623	90.53 ± 0.411	93.56 ± 0.221	25.2
Panel (c)
54a	35.75 ± 0.612	44.97 ± 0.237	55.19 ± 0.226	65.93 ± 0.662	67.14 ± 0.653	47.1
54b	34.01 ± 0.563	43.51 ± 0.464	58.83 ± 0.152	60.48 ± 0.353	62.50 ± 0.452	49.1
54c	34.24 ± 0.263	46.06 ± 0.533	58.82 ± 0.623	62.12 ± 0.621	63.63 ± 0.236	43.3
54d	33.93 ± 0.235	46.81 ± 0.516	56.52 ± 0.532	59.89 ± 0.623	61.39 ± 0.425	45.6
54e	34.48 ± 0.342	44.88 ± 0.345	55.57 ± 0.173	56.61 ± 0.535	58.63 ± 0.654	50.6
Ascorbic acid	44.53 ± 0.526	64.65 ± 0.653	71.74 ± 0.36	89.22 ± 0.621	96.19 ± 0.456	26.9

IC₅₀ values in µg/ml for samples were determined using ED50 plus V 1.0 software. Data are the mean of three or more experiments and reported as mean ± standard error of the mean (SEM)

Dureja [61] developed 3-(4-acetyl-5-(substituted phenyl)-4, 5-dihydro-1,3,4-oxadiazol-2-yl)-2H-chromen-2-one (Scheme 25) and evaluated for antioxidant activity by using DPPH assay. Ascorbic acid was used as a reference standard and the results were summarized in (Table 25, Dureja [61]).

Scheme 25.

Synthesis of substituted 1,3,4-oxadiazole with 2-hydroxy benzaldehyde carboxylic acid as starting material

Table 25.

Antioxidant activity of synthesized compounds by DPPH method [61]

Compound	% Scavenging activity	IC50
55a	19.97–85.95	47.47 ± 2.473
55b	3.07–64.92	197.96 ± 2.454
55c	7.4–48.75	> 500
55d	13.87–77.45	60.93 ± 1.560
55e	12.60–85.95	> 500
55f	14.70–69.70	130.8 ± 3.602
55g	4.9–74.77	90.26 ± 2.442
55h	6.85–69.42	91.70 ± 2.778
Ascorbic acid	44.95–95.5	12.7 ± 0.68

Conclusion

In this present review article, we have summarized different pharmacological activities of 1,3,4-oxadiazole containing compounds. From this study, we have found that 1,3,4-oxadiazole containing compounds can be synthesized by various kinds of synthetic routes, and these derivatives having a wide range of biological activities such as antitumor, antitubercular, antimicrobial, antiviral and antioxidant, etc. This review article established the fact that 1,3,4-oxadiazole as useful templates for further modification or derivatization to design more potent biologically active compounds.

Abbreviations

CNS

Central Nervous System

FDA

Food and Drug Administration

MTT

3-(4, 5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

IC₅₀

Half maximal inhibitory concentration

L.J

Lowenstein-Jensen

MB

Middle brook

HeLa

Henrietta Lacks

MIC

Minimum inhibitory concentration

HIV

Human immunodeficiency virus

CC₅₀

Half maximal cytotoxic concentration

SI

Selectivity index

HEL

Human embryonic lung fibroblast

VERO

Verda reno (means green kidney)

TMV

Tobacco mosaic virus

DPPH

2, 2-Diphenyl-1-picrylhydrazyl

MTCC

Microbial type cell cultures

Authors’ contributions

PKV- endeavored and accomplished the scheme; AS-completed review work and wrote the manuscript. Both authors read and approved the final manuscript.

Funding

No funding was obtained for this study.

Availability of data and materials

All data are provided in the manuscript or cited in the references.

Ethics approval and consent to participate

Not applicable.

Competing interests

The author(s) have no conflicts of interest.