Design, Synthesis, and the Biological Evaluation of a New Series of Acyclic 1,2,3‐Triazole Nucleosides

Iwona E Głowacka; Graciela Andrei; Dominique Schols; Robert Snoeck; Katarzyna Gawron

doi:10.1002/ardp.201700166

. 2017 Aug 1;350(9):1700166. doi: 10.1002/ardp.201700166

Design, Synthesis, and the Biological Evaluation of a New Series of Acyclic 1,2,3‐Triazole Nucleosides

Iwona E Głowacka ^1,^✉, Graciela Andrei ², Dominique Schols ², Robert Snoeck ², Katarzyna Gawron ¹

PMCID: PMC7161868 PMID: 28763115

Abstract

A new strategy for the synthesis of N ³‐benzoylated‐ and N ³‐benzylated N ¹‐propargylquinazoline‐2,4‐diones 30a−d and 31a−d from isatoic anhydride 41 is reported. The alkynes 30a−d and 31a−d were applied in the 1,3‐dipolar cycloadditions with azides 27 and 28 to synthesize acyclic 1,2,3‐triazole nucleosides. The obtained alkynes and 1,2,3‐triazole were evaluated for antiviral activity against a broad range of DNA and RNA viruses. The alkyne 30d showed activity against adenovirus‐2 (EC₅₀ = 8.3 μM), while compounds 37a and 37d were also active toward herpes simplex virus‐1 wild‐type and thymidine kinase deficient (HSV‐1 TK⁻) strains (EC₅₀ values in the range of 4.6–13.8 μM). In addition, compounds 30a, 30b, 37b, and 37c exhibited activity toward varicella‐zoster virus (VZV) TK ⁺ and TK⁻ strains (EC₅₀ = 2.1–9.5 μM). The compound 30b proved to be the most selective against VZV and displayed marginal activity against human cytomegalovirus (HCMV). Although the compound 30a had improved anti‐HCMV activity, the increase in anti‐HCMV activity was accompanied by significant toxicity. Compounds 37a and 37d showed inhibitory effects toward the human T lymphocyte (CEM) cell line (IC₅₀ = 21 ± 7 and 22 ± 1 μM, respectively), while compound 35 exhibited cytostatic activity toward HMEC‐1 cells (IC₅₀ = 28 ± 2 μM).

Keywords: 1,2,3‐Triazoles; Acyclic nucleosides; Antiviral; Cytostatic; Quinazoline‐2,4‐diones

Alkyne 30a exhibited activity against adenovirus‐2 (EC₅₀ = 8.3 μM), while compounds 30a, 30b, 36b, and 36c were active toward varicella‐zoster virus TK⁺ and TK⁻ strains with EC₅₀ values in the range of 2.1–9.5 μM. Compounds 36a and 36d showed activity against herpes simplex virus‐1 (HSV‐1 TK^–) strains (EC₅₀ = 4.6–13.8 μM) and inhibitory effects toward the human T lymphocyte (CEM) cell line (EC₅₀ = 21 ± 7 μM and 22 ± 1 μM, respectively).

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Introduction

Acyclic analogs of nucleosides belong to the most important class of compounds showing antiviral and antitumor activities 1, 2. Among them, acyclovir and penciclovir exhibit activity against herpes viruses including HSV‐1, HSV‐2, VZV, hepatitis B virus (HBV) 3, 4, 5, 6, 7, while ganciclovir 7, 8, 9, 10 and valganciclovir − its prodrug with significantly improved oral bioavailability 10, 11, 12 − are commonly used as anti‐cytomegalovirus agents. However, in most cases, the clinical applications of nucleosides are limited due to the observed side effects. In addition, an important problem in treatment of viral infections is the emergence of drug‐resistant mutant viruses. For this reason, the search for new antiviral compounds with improved activity has been continuing for decades. This is not limited to modifications of aliphatic chains, but also includes the introduction of additional groups into the structure of nucleosides with well‐documented biological activity. Since the 1,2,3‐triazole moiety has been recognized as bioisosteric with the amide function 13, 14, the incorporation of this structural motive has been widely applied and resulted in a broad spectrum of pharmaceutically important molecules. Furthermore, 1,2,3‐triazoles are able to form hydrogen bonds, they are not protonated at the physiological pH, and are also stable to oxidation and reduction as well as to many enzymatic reactions 15. Several compounds of the 1,2,3‐triazole family have exhibited a broad spectrum of biological activities, such as anti‐inflammatory 16, 17, anticonvulsants 18, antiviral 19, 20, 21, 22, 23, anticancer 24, 25, 26, 27, antimicrobial agents 28, 29, 30, as well as β‐lactamase inhibitors 31 and dopamine D2 receptor ligands related to schizophrenia 32. Since 1997, when the first acyclic 1,2,3‐triazolenucleosides have been obtained by Lazrek et al. 33, 34, many efforts have been made by several research groups to synthesize more potent antiviral and anticancer nucleoside analogs having both natural and modified nucleobases (Fig. 1) 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49.

Examples of acyclic nucleoside analogs containing the 1,2,3‐triazole moiety.

Among various heterocyclic moieties that would serve as modified nucleobase mimetics, substituted quinazoline‐2,4‐diones are of special interest. This structural motive was successfully attached to various biologically active compounds to provide even more active hybrids (Fig. 2) 50, 51, 52, 53, 54, 55, 56.

Known quinazoline‐2,4‐dione derivatives with anticancer and antiviral potency.

In continuation of our involvement in the search for new biologically active acyclic nucleoside analogs 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, a new series of 1,2,3‐triazole nucleosides containing the substituted quinazoline‐2,4‐dione at C4 was designed (compounds 32–37, Scheme 1). Based on the previous observations on analogous heterocyclic conjugates 24–26 synthesized in our research group (Fig. 3) 57, 58, 67, functionalized benzyl and benzoyl groups were carefully selected as suitable substituents to be attached at C3 in the quinazolinone‐2,4‐dione framework. The synthetic strategy for our new series 1,2,3‐triazolenucleosides is presented in Scheme 1.

Scheme 1 — Retrosynthetic analysis of 1,2,3‐triazolenucleosides.

Quinazoline‐2,4‐dione nucleoside analogs obtained in our research group.

Results and discussion

Chemistry

The starting 3‐azidopropanol 27 was prepared from 3‐chloropropanol in 90% yield according to the literature procedure 68. Reaction of 3‐azidopropanol 27 with benzyl bromide gave 28 in 80% yield 69, 70. Initially, we considered the respective N ³‐benzoylated quinazoline‐2,4‐diones as convenient substrates for the preparation of N ³‐benzoyl‐N ¹‐propargylquinazoline‐2,4‐diones 30a (Scheme 2). The N ³‐benzoylquinazoline‐2,4‐dione 40 was previously obtained from 2‐benzoylaminobenzoxazinone, although with low (less than 5%) overall yield 71 Recently, we reported 57 the synthesis of N ³‐benzoyl‐N ¹‐propargylquinazoline‐2,4‐diones 30a from quinazoline‐2,4‐dione 38 in 19% overall yield (Scheme 2).

Scheme 2 — Synthesis of N ³‐benzoyl‐N ¹‐propargylquinazoline‐2,4‐dione **30a**. Reaction and conditions: (a) Benzoyl chloride, pyridine, acetonitrile, r.t., 48 h; (b) 1 M K₂CO₃, dioxane, r.t., 24 h; (c) propargyl bromide, DMF, K₂CO₃, r.t., 24 h.

However, this procedure suffers from several steps including benzoylation of 38 to N ¹,N ³‐dibenzoylquinazoline‐2,4‐dione 39, requires a selective N ¹‐debenzoylation and finally propargylation. Unfortunately, in this method, the selective N ¹‐debenzoylation step appeared less effective and tedious. For this reason, another strategy for the synthesis of N ³‐benzoyl‐N ¹‐propargylquinazoline‐2,4‐diones 30a was devised (Scheme 3). It started from propargylation of commercially available isatoic anhydride 41 followed by the reaction of the compound 42 with urea 72 to give N ¹‐propargylquinazoline‐2,4‐dione 29. Finally, the key compound 29 could be transformed into substituted both N ³‐benzoyl‐ and N ³‐benzyl‐N ¹‐propargylquinazoline‐2,4‐diones 30a−d and 31a−d via the reaction with the respective benzoyl chlorides and benzyl bromides (Scheme 3).

Scheme 3 — Synthesis of compounds **30a**−d and **31a**−d. Reaction and conditions: (a) Propargyl bromide, NaH, DMF, r.t., 24 h; (b) urea, DMF, reflux, 5 h; (c) selected benzoyl chloride, Et₃N, MeCN, r.t., 72 h; (d) benzyl bromide, KOH, MeCN, 105 or 60°C; (e) selected benzyl bromide, K₂CO₃, DMF, r.t., 48 h.

The standard benzoylation of N ¹‐propargylquinazoline‐2,4‐dione 29 with benzoyl chlorides in the presence of triethylamine led to the formation of N ³‐benzoylated N ¹‐propargylquinazoline‐2,4‐diones 30a−d in moderate to good yields without formation of by‐products. At first, attempts at benzylation of N ¹‐propargylquinazoline‐2,4‐dione 29 following the strategy previously described 67 for the synthesis of N ¹‐allylated N ³‐benzoylquinazoline‐2,4‐dione were undertaken. Treatment of 29 with benzyl bromide in the presence of potassium hydroxide at 105°C for 4 h or 60°C for 48 h led to the formation of ca. a 50:50 mixture of an alkyne 31a and an allene 43a in 79% total yield. Unfortunately, several attempts at elaborating the efficient procedure to separate N ³‐benzyl‐N ¹‐propargylquinazoline‐2,4‐diones 31a from N ³‐benzyl‐N ¹‐(propa‐1,2‐dien‐1‐yl)quinazoline‐2,4‐diones 43a on silica gel columns or by crystallization proved fruitless. Fortunately, we were able to chromatographically isolate a small amount of pure allene 43a. Attempts to optimize a procedure for benzylation of 29, thereby avoiding formation of allenes 43 were undertaken. Thus, the treatment of N ¹‐propargylquinazoline‐2,4‐dione 29 with benzyl bromide in the presence of potassium carbonate in DMF at room temperature for 48 h afforded pure N ³‐benzyl‐N ¹‐propargylquinazoline‐2,4‐dione 31a and no traces of the allene 43a were observed.

The Hüisgen reaction of the azide 27 with the alkyne 29 could be accomplished within 21 days when the reaction mixture was heated at 45°C. However, when the reaction was performed at the same temperature under microwave irradiation, the azide was consumed in less than 30 min. For this reason, all cycloadditions of azides 27 and 28 with N ¹‐propargylquinazoline‐2,4‐dione 29, N ³‐benzoylated N ¹‐propargylquinazoline‐2,4‐diones 30a−d, and N ³‐benzylated N ¹‐propargylquinazoline‐2,4‐diones 31a−d were carried out in a microwave oven (Scheme 4) and disappearance of the starting azide was monitored by IR spectroscopy. All compounds were purified chromatographically and by crystallization. Structures and purity of all 1,2,3‐triazole nucleosides were established by ¹H, ¹³C NMR, and IR techniques as well as by elemental analysis.

Scheme 4 — Synthesis of compounds **33a**−d, **34a**−d, **36a**−d, and **37a**−d. Reaction and conditions: CuSO₄ × 5H₂O, sodium ascorbate, EtOH–H₂O, 35–40°C, 30 min, MW.

Biological evaluation

Antiviral and cytotoxic evaluation

All synthesized compounds were screened for inhibitory activity against a wide variety of DNA and RNA viruses using the following cell‐based assays: (i) human embryonic lung (HEL) cells: herpes simplex virus‐1 (KOS), herpes simplex virus‐2 (G), thymidine kinase deficient (acyclovir resistant) herpes simplex virus‐1 (TK⁻ KOS ACV^r), vaccinia virus, adenovirus‐2, human coronavirus (229E), cytomegalovirus (AD‐169 strain and Davis strain), varicella‐zoster virus (TK⁺ VZV Oka strain and TK⁻ VZV 07‐1 strain); (ii) HeLa cell cultures: vesicular stomatitis virus, Coxsackie virus B4 and respiratory syncytial virus; (iii) Vero cell cultures: para‐influenza‐3 virus, reovirus‐1, Sindbis virus, Coxsackie virus B4, punta toro virus, yellow fever virus; (iv) MDCK cell cultures: influenza A virus (H1N1 and H3N2 subtypes) and influenza B virus. Ganciclovir, cidofovir, acyclovir, brivudin, zalcitabine, zanamivir, alovudine, amantadine, rimantadine, ribavirin, dextran sulfate (molecular weight 10000, DS‐10000), mycophenolic acid, and Urtica dioica agglutinin (UDA) were used as the reference compounds. The antiviral activity was expressed as the EC₅₀: The effective concentration required to reduce virus plaque formation (VZV, HCMV) by 50% or to reduce virus‐induced cytopathogenicity by 50% (other viruses). Among all the tested compounds, only the alkyne 30d as well as 1,2,3‐triazoles 36a and 36d exhibited antiviral activity against herpes simplex viruses, adenovirus‐2, and human corona virus (229E) in HEL cell cultures (Table 1). It should be noted that these derivatives were equally active against HSV‐1 TK⁺ and TK⁻ HSV‐1 strains in contrast to the gold standard for therapy of HSV infections [EC₅₀ = 6.6 μM (30d), 4.6 μM (36a), and 6.2 μM (36d) vs. 85 μM (acyclovir) for the HSV‐1 TK⁻ strain]. In addition, compound 30d appeared almost as active toward adenovirus‐2 (EC₅₀ = 8.3 μM) as the reference compounds cidofovir (EC₅₀ = 5.8 μM), alovudine (EC₅₀ = 5.8 μM), and zalcitabine (EC₅₀ = 7.2 μM). A 10‐fold lower activity of 36a compared to the reference compound UDA against human corona virus was measured (EC₅₀ of 18.5 μM and 1.8 μM, respectively).

Table 1.

Antiviral activity and cytotoxicity of the tested compounds in HEL cell cultures

	Antiviral activity EC₅₀ (μM) ^a)
Compound	Herpes simplex virus‐1 (KOS)	Herpes simplex virus‐2 (G)	Herpes simplex virus‐1 TK⁻ KOS ACV^r	Vaccinia virus	Adenovirus‐2	Human corona virus (229E)	Minimum cytotoxic concentration ^b) MCC (μM)
30d	13.8 ± 8.8	17.0 ± 4.2	6.6 ± 1.5	>100	8.3 ± 0.9	>100	>100
36a	5.4 ± 2.0	10.5 ± 2.2	4.6 ± 3.2	100	>100	18.5 ± 13.5	≥20
36d	6.8 ± 1.1	11.0 ± 1.4	6.2 ± 0.9	>100	>100	>100	≥20
Brivudin	0.02	146	85	2	ND	ND	>250
Cidofovir	2.8	1.0	1.0	22	5.8	ND	>250
Acyclovir	0.7	0.2	85	>250	ND	ND	>250
Ganciclovir	0.16	0.03	1.0	>100	ND	ND	>100
Zalcitabine	ND	ND	ND	ND	7.2	ND	>250
Alovudine	ND	ND	ND	ND	5.8	ND	>250
UDA	ND	ND	ND	ND	ND	1.8	>100
Ribavirin	ND	ND	ND	ND	ND	>250	>250

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ND: not determined.

^{^a)}

Required to reduce virus‐induced cytopathogenicity by 50%.

^{^b)}

Required to cause a microscopically detectable alteration of normal cell morphology.

Moreover, several synthesized quinazoline‐2,4‐diones inhibited the replication of both TK⁺ and TK⁻ VZV strains at EC₅₀ in the 2–70 µM range (Table 2). In particular, alkynes 30a (EC₅₀ = 6.5 μM), 30b (EC₅₀ = 9.5 μM), and 30d (EC₅₀ = 5.9 μM) as well as 1,2,3‐triazoles 36a (EC₅₀ = 5.9 μM), 36b (EC₅₀ = 6.2 μM), 36c (EC₅₀ = 8.3 μM), and 37a (EC₅₀ = 14.2 μM), as well as 37b (EC₅₀ = 8.2 μM) showed marked activity toward TK⁻ VZV strain, which was higher than that of the reference drugs acyclovir and brivudin (EC₅₀ = 40.7 and 32.0 µM, respectively). However, they were significantly less active than the reference anti‐VZV drugs against the TK⁺ VZV strain Oka. Except for 36c, these derivatives had a minimum cytotoxic concentration ≥100 μM. However, compounds 30a (CC₅₀ = 11.3 μM) and 30d (CC₅₀ = 9.1 μM) as well as 36a (CC₅₀ = 10.6 μM) and 36b (CC₅₀ = 12.5 μM) reduced cell growth (as measured by the 50% cytostatic concentration, i.e., CC₅₀) at lower concentrations than acyclovir and brivudin (CC₅₀ > 350 µM), resulting in low selectivity (ratio CC₅₀/EC₅₀). Interestingly, 30b emerged as the most selective anti‐VZV quinazoline‐2,4‐diones since it did not inhibit growth of HEL cells up to a concentration of 100 μM.

Table 2.

Activity of the tested compounds against varicella‐zoster virus (VZV) and cytomegalovirus (HCMV) in human embryonic lung (HEL) cells

	Antiviral activity EC₅₀(μM) ^a)				Cytotoxicity (μM)
Compound	TK⁺ VZV strain Oka	TK⁻ VZV strain 07‐1	HCMV strain AD‐169	HCMV Davis strain	Cell morphology (MCC) ^b)	Cell growth (CC₅₀) ^c)
30a	5.4 ± 4.1	6.5 ± 5.1	>4	44.7	>100	11.3 ± 2.8
30b	2.8 ± 1.8	9.5 ± 3.5	44.7	63.1	100	>100
30c	17.03	48.12	>100	>100	100	ND
30d	2.7 ± 0.1	5.9 ± 2.7	44.7	44.7	100	9.1 ± 0.1
33a	41.57	49.5	44.7	54.7	>100	ND
33c	43.04	46.35	>20	>100	>100	ND
33d	36.19	48.35	44.7	44.7	>100	ND
34d	42.04	69.95	>100	>100	>100	ND
36a	2.8 ± 0.1	5.9 ± 3.3	10.8 ± 2.6	14.5 ± 7.8	100	10.6 ± 1.6
36b	3.3 ± 0.9	6.2 ± 2.4	20	>20	100	12.5 ± 0.5
36c	2.1	8.3	>20	>20	20	ND
36d	5.03	>4	12.6	8.9	100	ND
37a	>20	14.2	>20	>100	100	ND
37b	6.8	8.2	>4	>4	20	ND
37d	12.3	>20	>20	>100	20	ND
Acyclovir	1.6 ± 1.0	40.7 ± 1.4	ND	ND	>440	>350
Brivudin	0.023 ± 0.001	32.0 ± 16.3	ND	ND	>300	>300
Ganciclovir	ND	ND	16.9 ± 6.9	7.7 ± 0.9	>350	>350
Cidofovir	ND	ND	1.5 ± 0.2	1.7 ± 0.4	>350	>350

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ND: not determined.

^{^a)}

Effective concentration required to reduce virus plaque formation by 50%. Virus input was 20 plaque‐forming units (PFU).

^{^b)}

Minimum cytotoxic concentration that causes a microscopically detectable alternation of cell morphology.

^{^c)}

Cytotoxic concentration required to reduce cell growth by 50%.

All synthesized compounds were also subjected to antiviral screening against HCMV, and among them, 36a (EC₅₀ = 10.8–14.5 μM) and 36d (EC₅₀ = 12.6 and 8.9 μM) showed some activity; however, at the same time, 36a showed cytotoxicity toward HEL cells (CC₅₀ = 10.6 μM).

Cytostatic activity

The cytostatic activity of the tested compounds was defined as the 50% cytostatic inhibitory concentration (IC₅₀) causing a 50% decrease in cell proliferation and was determined against the transformed cells murine leukemia L1210, human lymphocyte CEM, human cervix carcinoma HeLa compared to human dermal microvascular endothelial HMEC‐1 cells.

In these series, several compounds showed inhibitory activity against the proliferation of tumor cell lines (Table 3). From the entire library of compounds, 36a and 36d appeared to be the most inhibitory toward the growth of human T‐lymphocyte (CEM) cell line with an inhibitory effect of 21 μM and 22 μM, respectively, comparable to that of the reference drug 5‐fluorouracil (IC₅₀ = 18 ± 5 μM). 36a and 36d weakly inhibited the proliferation of L1210, HeLa, and HMEC‐1 cells with IC₅₀ values in the range of 83–136 μM and 106–113 μM, respectively. Among all tested compounds, only 35 exhibited cytostatic activity (IC₅₀: 28 ± 2 μM) toward HMEC‐1 cell line.

Table 3.

Inhibitory effects of the tested compounds against the proliferation of murine leukemia cells (L1210), human T‐lymphocyte cells (CEM), human cervix carcinoma cells (HeLa), and human dermal microvascular endothelial cells (HMEC‐1)

	IC₅₀ (μM) ^a)
Compound	L1210	CEM	HeLa	HMEC‐1
29	>250	>250	>250	>250
30a	>250	>250	>250	≥250
30b	>250	52 ± 46	>250	>250
30c	>250	>250	>250	≥250
30d	>250	>250	≥250	≥250
31a	>250	>250	>250	>250
31b	>250	>250	>250	>250
31c	>250	>250	>250	>250
31d	>250	>250	>250	>250
32	>250	>250	>250	>250
33a	≥250	≥250	>250	>250
33b	182 ± 80	≥250	>250	>250
33c	188 ± 60	≥250	>250	>250
33d	≥250	≥250	>250	>250
34a	>250	184 ± 5	>250	>250
34b	>250	165 ± 15	>250	>250
34c	173 ± 42	127 ± 13	>250	>250
34d	156 ± 37	97 ± 79	>250	>250
35	>250	>250	≥250	28 ± 2
36a	83 ± 59	21 ± 7	136 ± 66	119 ± 67
36b	>250	>250	>250	≥250
36c	132 ± 43	137 ± 107	168 ± 39	>250
36d	106 ± 57	22 ± 1	115 ± 31	113 ± 86
37a	93 ± 13	88 ± 39	118 ± 4	143 ± 136
37b	≥250	>250	>250	>250
37c	206 ± 62	88 ± 72	>250	>50
37d	72 ± 14	81 ± 45	65 ± 1	>50
5‐Fluorouracil	0.33 ± 0.17	18 ± 5	0.54 ± 0.12	ND

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ND, not determined.

^{^a)}

50% Inhibitory concentration or compound concentration required to inhibit tumor cell proliferation by 50%.

Conclusion

The N ³‐benzoylated‐ and N ³‐benzylated N ¹‐propargylquinazoline‐2,4‐diones 30a–d and 31a−d were efficiently synthesized from isatoic anhydride 41.

The copper(I)‐catalyzed 1,3‐dipolar cycloadditions of the azides 27 and 28 with the selected N ³‐benzoylated‐ and N ³‐benzylated N ¹‐propargylquinazoline‐2,4‐diones 30a−d and 31a−d under microwave irradiation led to the formation of 1,2,3‐triazole acyclonucleosides 32, 35 and 33–34a−d as well as 36–37a−d in good yields.

All synthesized compounds were tested for their antiviral activities against DNA and RNA viruses as well as cytostatic activity and cytotoxicity. Among all tested compounds, 30d (EC₅₀ = 7.6 μM) showed activity against adenovirus‐2 comparable to that of the reference compounds cidofovir, alovudine, and zalcitabine. Compounds 30d, 36a, and 36d proved equally active against HSV‐1 and VZV TK⁺ and TK⁻ strains. In addition, the derivatives 30a, 30b, and 36b were also inhibitory for TK⁺ and TK⁻ VZV strains. The highest selectivity (ratio cytostatic effect [CC₅₀]/antiviral activity [EC₅₀]) was found for the compound 30b (CC₅₀ ≥ 100 μM and MCC = 100). The selectivity for the compounds 30a, 30d, 36a, and 36b was low as they reduced cell growth (CC₅₀) at concentrations of 9–12.5 µM. Furthermore, several compounds (30c [EC₅₀ = 48.12 μM], 33a [EC₅₀ = 49.45 μM], 33c [EC₅₀ = 46.31 μM], and 33d [EC₅₀ = 48.34 μM]) exhibited marginal activity against VZV strains and at the same time, they were not cytotoxic to uninfected HEL cells (MCC ≥ 100 μM).

Among all tested quinazoline‐2,4‐diones, compounds 36a and 36d were the most inhibitory toward the human T‐lymphocyte (CEM) cell line and they showed inhibitory effects (IC₅₀ = 21 ± 7 and 22 ± 1 μM, respectively) comparable to that of the reference compound 5‐fluorouracil (IC₅₀ = 18 ± 5 μM). The compound 35 exhibited also cytostatic activity (IC₅₀: 28 ± 2 μM) toward HMEC‐1 cell line.

Experimental

Chemistry

General

¹H NMR spectra were taken in CDCl₃ or DMSO‐d₆ on a Bruker Avance III (600 MHz) with TMS as an internal standard; chemical shifts δ are given in ppm with respect to TMS and coupling constants J in Hz. ¹³C NMR spectra were recorded for CDCl₃ or DMSO‐d₆ solutions on the Bruker Avance III (600 MHz) spectrometer at 151 MHz. IR spectral data were measured on an Infinity MI‐60 FT‐IR spectrometer. Melting points were determined on a Boetius apparatus and are uncorrected. Elemental analyses were performed by the Microanalytical Laboratory of the Faculty of Pharmacy (Medical University of Lodz) on a Perkin Elmer PE 2400 CHNS analyzer.

The following adsorbents were used: column chromatography, Merck silica gel 60 (70–230 mesh); analytical TLC, Merck TLC plastic sheets silica gel 60 F₂₅₄. TLC plates were developed in chloroform–methanol solvent systems. Visualization of spots was effected with iodine vapors. All solvents were purified by methods described in the literature.

All microwave irradiation experiments were carried out in a microwave reactor Plazmatronika RM 800.

3‐Azidopropan‐1‐ol 27 68, (3‐azidopropoxy)methylbenzene 28 69, 70, N ¹‐(prop‐2‐yn‐1‐yl)isatoic anhydride 73, and N ³‐benzoyl‐N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 30a 57 were obtained according to the literature procedures.

The InChI codes of the investigated compounds together with some biological activity data are provided as Supporting Information.

Synthesis of N¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 29

To a solution of the N ¹‐(prop‐2‐yn‐1‐yl)isatoic anhydride 42 (2.46 g, 12.2 mmol) in dry DMF (70 mL), urea (1.38 g, 23.0 mmol) was added and the mixture was heated under reflux for 5 h. Solvent was removed in vacuo and the residue was crystallized from ethanol to afford 29 (2.032 g, 83%) as a beige powder. M.p.: 240−245°C; IR (KBr, cm⁻¹) ν_max: 3248, 3170, 3046, 2984, 2119, 1711, 1683, 1608, 1501; ¹H NMR (600 MHz, DMSO‐d ₆): δ = 11.69 (s, 1H, NH), 8.04 (dd, J = 7.8 Hz, J = 1.6 Hz, 1H, H5), 7.82 (ddd, J = 8.4 Hz, J = 7.8 Hz, J = 1.6 Hz, 1H, H7), 7.49 (d, J = 8.4 Hz, 1H, H8), 7.33 (t, J = 7.8 Hz, 1H, H6), 4.90 (d, J = 2.4 Hz, 2H, CH₂ C≡CH), 3.29 (t, J = 2.4 Hz, 1H, CH₂C≡CH); ¹³C NMR (151 MHz, DMSO‐d₆ ): δ = 160.06 (s, C=O), 150.14 (s, C=O), 140.48, 135.75, 128.09, 123.48, 116.26, 115.44, 79.99, 75.50, 32.32. Anal. calcd. for C₁₁H₈N₂O₂: C, 65.99; H, 4.03; N, 14.00. Found: C, 65.76; H, 4.01; N, 14.14.

General procedure for benzoylation of N¹‐(prop‐2‐yn‐1‐yl)‐quinazoline‐2,4‐dione 29

To a suspension of the N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 29 (1.00 mmol) in dry acetonitrile (6 mL), benzoyl chloride (2.20 mmol) and TEA (3.00 mmol) were added. The mixture was stirred at room temperature for 48 h. The solvent was removed and the residue was suspended in dichloromethane (20 mL) and extracted with water (3 × 20 mL). The organic phase was dried (MgSO₄), concentrated, and chromatographed and/or crystallized to give pure 30a−d.

N³‐Benzoyl‐N¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 30a

A yellowish solid; 62% yield; m.p.: 178–181°C (lit. m.p.: 180–182°C) 57.

N³‐(2‐Fluorobenzoyl)‐N¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 30b

From N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 29 (0.10 g, 0.50 mmol) and 2‐fluorobenzoyl chloride (0.13 mL, 1.1 mmol), N ³‐(2‐fluorobenzoyl)‐N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 30b (0.098 g, 61%) was obtained as a white solid after purification on a silica gel column with dichloromethane and crystallization from a chloroform–diethyl ether mixture. M.p.: 214−217°C; IR (KBr, cm⁻¹) ν_max: 3255, 3106, 3080, 3064, 3042, 2979, 2125, 1695, 1656, 1608, 1483, 1105, 757; ¹H NMR (600 MHz, CDCl₃): δ = 8.27 (dd, J = 7.9 Hz, J = 1.4 Hz, 1H, H5), 8.15 (dt, J = 9.5 Hz, J = 7.7 Hz, J = 1.8 Hz, 1H), 7.82 (ddd, J = 8.5 Hz, J = 7.9 Hz, J = 1.4 Hz, 1H, H7), 7.67−7.63 (m, 1H), 7.48 (d, J = 8.5 Hz, 1H, H8), 7.39−7.36 (m, 1H), 7.36−7.33 (m, 1H), 7.14 (ddd, J = 9.3 Hz, J = 8.3 Hz, J = 0.8 Hz, 1H), 4.96 (d, J = 2.5 Hz, 2H, CH₂ C≡CH), 2.36 (t, J = 2.5 Hz, 1H, CH₂C≡CH); ¹³C NMR (151 MHz, CDCl₃): δ = 164.49 (s, C=O), 162.12 (d, J = 259.9 Hz, C2′), 160.61 (s, C=O), 148.66 (s, C=O), 139.57, 136.85 (d, J = 9.9 Hz, C1′), 135.90, 133.07, 129.12, 125.00 (d, J = 3.6 Hz, C5′), 123.83, 120.47 (d, J = 7.9 Hz, C4′), 117.24 (d, J = 23.1 Hz, C3′), 115.97, 114.63, 73.65, 32.68. Anal. calcd. for C₁₈H₁₁FN₂O₃ × 0.25H₂O: C, 66.16; H, 3.55; N, 8.57. Found: C, 66.36; H, 3.34; N, 8.68.

N³‐(3‐Fluorobenzoyl)‐N¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 30c

According to the general procedure from N ¹‐(prop‐2‐yn‐1‐yl)‐quinazoline‐2,4‐dione 29 (0.10 g, 0.50 mmol) and 3‐fluorobenzoyl chloride (0.13 mL, 1.10 mmol), N ³‐(3‐fluorobenzoyl)‐N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 30c (0.089 g, 55%) was obtained as a white solid after purification on a silica gel column with dichloromethane and crystallization from a chloroform–diethyl ether mixture. M.p.: 197−198°C; IR (KBr, cm⁻¹) ν_max: 3262, 3109, 3080, 3055, 2127, 1698, 1660, 1610, 1483, 1025, 893, 793, 775, 759; ¹H NMR (600 MHz, CDCl₃): δ = 8.28 (dd, J = 7.8 Hz, J = 1.5 Hz, 1H, H5), 7.85 (ddd, J = 8.7 Hz, J = 7.8 Hz, J = 1.5 Hz, 1H, H7), 7.79 (dt, J = 7.9 Hz, J = 2.3 Hz, J = 1.2 Hz, 1H), 7.69 (d, J = 8.7 Hz, 1H, H8), 7.54−7.50 (m, 2H), 7.42−7.38 (m, 2H), 4.97 (d, J = 2.4 Hz, 2H, CH₂ C≡CH), 2.39 (t, J = 2.4 Hz, 1H, CH₂C≡CH); ¹³C NMR (151 MHz, CDCl₃): δ = 167.46 (d, J = 3.2 Hz, C=O), 162.93 (d, J = 248.7 Hz, C3′), 160.87 (s, C=O), 148.73 (s, C=O), 139.60, 136.14, 133.83 (d, J = 7.7 Hz, C1′), 130.90 (d, J = 8.2 Hz, C5′), 129.19, 126.23 (d, J = 3.3 Hz, C6′), 124.04, 122.21 (d, J = 21.8 Hz, C2′), 117.16 (d, J = 23.2 Hz, C4′), 115.73, 114.76, 73.89, 32.80. Anal. calcd. for C₁₈H₁₁FN₂O₃ × 0.25H₂O: C, 66.16; H, 3.55; N, 8.57. Found: C, 66.45; H, 3.28; N, 8.82.

N³‐(4‐Fluorobenzoyl)‐N¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 30d

According to the general procedure from N ¹‐(prop‐2‐yn‐1‐yl)‐quinazoline‐2,4‐dione 29 (0.10 g, 0.50 mmol) and 4‐fluorobenzoyl chloride (0.13 mL, 1.10 mmol), N ³‐(4‐fluorobenzoyl)‐N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 30d (0.13 g, 81%) was obtained as a white solid after purification on a silica gel column with dichloromethane and crystallization from a chloroform–diethyl ether mixture. M.p.: 160−161°C; IR (KBr, cm⁻¹) ν_max: 3264, 3080, 3056, 2982, 2128, 1702, 1595, 1482, 1426, 1057, 1023, 845; ¹H NMR (600 MHz, CDCl₃): δ = 8.26 (dd, J = 7.8 Hz, J = 1.3 Hz, 1H, H5), 8.04−8.01 (m, 2H), 7.84−7.81 (m, 1H, H7), 7.50 (d, J = 8.5 Hz, 1H, H8), 7.38 (t, J = 7.8 Hz, 1H, H6), 7.21−7.18 (m, 2H), 4.96 (d, J = 2.4 Hz, 2H, CH₂ C≡CH), 2.38 (t, J = 2.4 Hz, 1H, CH₂C≡CH); ¹³C NMR (151 MHz, CDCl₃): δ = 167.18 (s, C=O), 166.99 (d, J = 257.9 Hz, C4′), 160.89 (s, C=O), 148.77 (s, C=O), 139.60, 136.08, 133.40 (d, J = 9.9 Hz, C2′, C6′), 129.16, 128.19 (d, J = 3.3 Hz, C1′), 123.99, 116.56 (d, J = 22.0 Hz, C3′, C5′), 115.76, 114.73, 73.84, 32.78. Anal. calcd. for C₁₈H₁₁FN₂O₃: C, 67.08; H, 3.44; N, 8.69. Found: C, 66.78; H, 3.17; N, 8.74.

General procedure for benzylation of N¹‐(prop‐2‐yn‐1‐yl)‐quinazoline‐2,4‐dione 29: Method A

To a suspension of N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 29 (0.50 mmol) and potassium hydroxide (1.5 mmol) in anhydrous acetonitrile (35 mL), benzyl bromide (0.55 mmol) was added. The mixture was stirred at 105°C for 4 h or 60°C for 48 h, then the solvent was removed by vacuum evaporation. The residue was suspended in dichloromethane and extracted with water (3 × 20 mL). The organic phase was dried (MgSO₄) and concentrated to give a crude product as a mixture of an alkyne 31a and an allene 43a (50:50). Then purification on a silica gel column with chloroform and crystallization from a chloroform–diethyl ether mixture gave a mixture of 31a and 43a (0.149 g, 53%) and pure 43a (0.026 g, 9%) as a white powder.

N³‐Benzyl‐N¹‐(propa‐1,2‐dien‐1‐yl)quinazoline‐2,4‐dione 43a

M.p.: 97−100°C; IR (KBr, cm⁻¹) ν_max: 3425, 3061, 3027, 3008, 1704, 1664, 1609, 1477, 1432; ¹H NMR (600 MHz, CDCl₃): δ = 8.26 (dd, J = 7.9 Hz, J = 1.4 Hz, 1H, H5), 7.66 (t, J = 8.5 Hz, 1H, H7), 7.57 (d, J = 7.4 Hz, 2H), 7.49 (d, J = 8.5 Hz, 1H, H8), 7.34−7.32 (m, 2H), 7.29−7.27 (m, 2H), 6.63 (t, J = 6.4 Hz, 1H, CHCCH₂), 5.44 (d, J = 6.4 Hz, 2H, CHC=CH₂ ), 5.31 (s, 2H, NCH₂ Ph); ¹³C NMR (151 MHz, CDCl₃): δ = 207.62 (CH=C=CH₂), 161.58 (s, C=O), 150.00 (s, C=O), 139.65, 136.83, 134.84, 129.21, 129.13, 128.43, 127.67, 123.40, 115.68, 114.84, 93.78, 84.73, 45.01. Anal. calcd. for C₁₈H₁₄N₂O₂: C, 74.47; H, 4.86; N, 9.65. Found: C, 73.95; H, 4.85; N, 9.45.

General procedure for benzylation of N¹‐(prop‐2‐yn‐1‐yl)‐quinazoline‐2,4‐dione 29: Method B

To a suspension of N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 29 (0.50 mmol) and anhydrous potassium carbonate (0.50 mmol) in anhydrous DMF (5 mL), substituted benzyl bromide (0.60 mmol) was added. The mixture was stirred at room temperature for 48 h. Then water (10 mL) was added and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phases were combined, dried (MgSO₄), and concentrated. The crude products were purified by chromatography on the silica gel columns and crystallized to give 31a−d.

N³‐Benzyl‐N¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 31a

According to the general procedure (method B) from N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 29 (0.10 g, 0.50 mmol) and benzyl bromide (0.071 mL, 0.60 mmol), the alkyne 31a (0.12 g, 80%) was obtained as colorless needles after column chromatography with dichloromethane and crystallization from a chloroform–diethyl ether mixture. M.p.: 144−147°C; IR (KBr, cm⁻¹) ν_max: 3243, 3070, 3031, 2970, 2117, 1698, 1662, 1610, 1457; ¹H NMR (600 MHz, CDCl₃): δ = 8.28 (dd, J = 7.9 Hz, J = 1.6 Hz, 1H, H5), 7.74−7.71 (m, 1H, H7), 7.56 (d, J = 7.3 Hz, 2H), 7.38 (d, J = 8.4 Hz, 1H, H8), 7.35−7.32 (m, 3H), 7.30−7.27 (m, 1H), 5.31 (s, 2H, NCH₂ Ph), 4.96 (d, J = 2.4 Hz, 2H, CH₂ C≡CH), 2.33 (t, J = 2.4 Hz, 1H, CH₂C≡CH); ¹³C NMR (151 MHz, CDCl₃): δ = 161.58 (s, C=O), 150.49 (s, C=O), 139.01, 136.82, 135.16, 129.25, 129.13, 128.45, 127.69, 123.42, 115.88, 114.02, 73.32, 45.20, 33.37. Anal. calcd. for C₁₈H₁₄N₂O₂: C, 74.47; H, 4.86; N, 9.65. Found: C, 74.36; H, 4.60; N, 9.75.

N³‐(2‐Fluorobenzyl)‐N¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 31b

According to the general procedure (method B) from N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 29 (0.10 g, 0.50 mmol) and 2‐fluorobenzyl bromide (0.073 mL, 0.60 mmol), the alkyne 31b (0.11 g, 72%) was obtained as a white powder after chromatography on a silica gel column with dichloromethane and crystallization from a chloroform–diethyl ether mixture. M.p.: 151−153°C; IR (KBr, cm⁻¹) ν_max: 3272, 3065, 2991, 2964, 2123, 1666, 1655, 1482, 1096, 1059, 1027, 750; ¹H NMR (600 MHz, CDCl₃): δ = 8.29 (d, J = 7.8 Hz, 1H, H5), 7.77−7.74 (m, 1H, H7), 7.42 (d, J = 8.5 Hz, 1H, H8), 7.35−7.31 (m, 2H), 7.27−7.23 (m, 1H), 7.09−7.06 (m, 2H), 5.40 (s, 2H, NCH₂ Ph), 4.98 (d, J = 2.2 Hz, 2H, CH₂ C≡CH), 2.33 (t, J = 2.2 Hz, 1H, CH₂C≡CH); ¹³C NMR (151 MHz, CDCl₃): δ = 161.48 (s, C=O), 160.80 (d, J = 247.1 Hz, C2′), 150.35 (s, C=O), 139.07, 135.26, 129.41 (d, J = 3.9 Hz, C6′), 129.34, 129.07 (d, J = 7.9 Hz, C4′), 124.06 (d, J = 3.3 Hz, C5′), 123.72 (d, J = 14.3 Hz, C1′), 123.50, 115.77, 115.49 (d, J = 21.8 Hz, C3′), 114.10, 73.35, 39.02 (d, J = 4.9 Hz, NCH₂Ph), 32.40. Anal. calcd. for C₁₈H₁₃FN₂O₂: C, 70.12; H, 4.25; N, 9.09. Found: C, 70.05; H, 4.00; N, 9.19.

N³‐(3‐Fluorobenzyl)‐N¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 31c

According to the general procedure (method B) from N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 29 (0.10 g, 0.50 mmol) and 3‐fluorobenzyl bromide (0.075 mL, 0.60 mmol), the product 31c (0.11 g, 73%) was obtained as a white powder after chromatography on a silica gel column with dichloromethane and crystallization from a chloroform–diethyl ether mixture. M.p.: 167−170°C; IR (KBr, cm⁻¹) ν_max: 3246, 3073, 2991, 2972, 2116, 1699, 1663, 1589, 1485, 1078, 1056, 1027, 877, 862, 799, 759; ¹H NMR (600 MHz, CDCl₃): δ = 8.28 (dd, J = 7.9 Hz, J = 1.6 Hz, 1H, H5), 7.74 (ddd, J = 8.4 Hz, J = 7.9 Hz, J = 1.6 Hz, 1H, H7), 7.40 (d, J = 8.4 Hz, 1H, H8), 7.34−7.31 (m, 2H), 7.30−7.28 (m, 1H), 7.25−7.23 (m, 1H), 6.99−6.96 (m, 1H), 5.28 (s, 2H, NCH₂ Ph), 4.97 (d, J = 2.5 Hz, 2H, CH₂ C≡CH), 2.34 (t, J = 2.5 Hz, 1H, CH₂C≡CH); ¹³C NMR (151 MHz, CDCl₃): δ = 162.56 (d, J = 318.8 Hz, C3′), 161.99 (s, C=O), 150.41 (s, C=O), 139.14 (d, J = 7.0 Hz, C1′), 139.02, 135.29, 129.90 (d, J = 7.9 Hz, C5′), 129.28, 124.65 (d, J = 3.0 Hz, C6′), 123.53, 115.92 (d, J = 22.0 Hz, C4′), 115.76, 114.63 (d, J = 21.3 Hz, C2′), 114.09, 73.40, 44.69 (d, J = 1.7 Hz, NCH₂Ph), 33.42. Anal. calcd. for C₁₈H₁₃FN₂O₂: C, 70.12; H, 4.25; N, 9.09. Found: C, 69.89; H, 3.98; N, 9.18.

N³‐(4‐Fluorobenzyl)‐N¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 31d

According to general procedure (method B) from N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 29 (0.10 g, 0.50 mmol) and 4‐fluorobenzyl bromide (0.074 mL, 0.60 mmol), the product 31d (0.13 g, 81%) was obtained as a white powder after chromatography on a silica gel column with dichloromethane and crystallization from a chloroform–diethyl ether mixture. M.p.: 178−181°C; IR (KBr, cm⁻¹) ν_max: 3255, 3041, 2974, 2114, 1700, 1664, 1606, 1510, 1481, 1095, 1054, 853, 836; ¹H NMR (600 MHz, CDCl₃): δ = 8.28 (dd, J = 7.9 Hz, J = 1.5 Hz, 1H, H5), 7.74 (ddd, J = 8.3 Hz, J = 7.9 Hz, J = 1.5 Hz, 1H, H7), 7.58−7.55 (m, 2H), 7.39 (d, J = 8.3 Hz, 1H, H8), 7.32 (t, J = 7.9 Hz, 1H, H6), 7.03−7.00 (m, 2H), 5.26 (s, 2H, NCH₂ Ph), 4.96 (d, J = 2.5 Hz, 2H, CH₂ C≡CH), 2.33 (t, J = 2.5 Hz, 1H, CH₂C≡CH); ¹³C NMR (151 MHz, CDCl₃): δ = 162.36 (d, J = 247.2 Hz, C4′), 161.54 (s, C=O), 150.44 (s, C=O), 138.99, 135.23, 132.63 (d, J = 3.2 Hz, C1′), 131.17 (d, J = 7.9 Hz, C2′, C6′), 129.23, 115.83, 115.24 (d, J = 21.2 Hz, C3′, C5′), 114.05, 73.35, 44.45, 33.38. Anal. calcd. for C₁₈H₁₃FN₂O₂: C, 70.12; H, 4.25; N, 9.09. Found: C, 70.27; H, 3.99; N, 8.98.

General procedure for the preparation of 1,2,3‐triazoles 32, 33–34a−d and 35, 36–37a−d: Method A

To a solution of 3‐azidopropan‐1‐ol 27 (0.025 g, 0.25 mmol) in ethanol (3 mL) and H₂O (1 mL), CuSO₄ × 5H₂O (0.006 g, 0.025 mmol), sodium ascorbate (0.010 g, 0.050 mmol), and N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 29 (0.050 g, 0.25 mmol) were added. The mixture was stirred at 45°C for 21 days. After cooling, the solvent was removed by vacuum evaporation. The crude product was purified by crystallization from water to give N ¹‐{[1‐(3‐hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}quinazoline‐2,4‐dione 32 (0.065 g, 85%) as colorless needles.

General procedure for the preparation of 1,2,3‐triazoles 32, 33–34a−d and 35, 36–37a−d: Method B

To a solution of an azide (1.00 mmol) in EtOH (1 mL) and H₂O (1 mL), CuSO₄ × 5H₂O (0.10 mmol), sodium ascorbate (0.20 mmol), and alkynes (1.00 mmol) were added. The suspension was irradiated in the microwave reactor (Plazmatronika RM800, 800 W) at 40−45°C for 30 min. After cooling, the solvent was removed, the residue was suspended in dry chloroform (3 mL), and filtered through a layer of Celite. The solution was concentrated in vacuo and the crude product was purified on a silica gel column with chloroform or chloroform–methanol mixtures (100:1, 50:1 or 25:1, v/v) and crystallized to give the 1,2,3‐triazoles 32, 33–34a−d and 35, 36–37a−d.

N¹‐{[1‐(3‐Hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}‐quinazoline‐2,4‐dione 32

According to general procedure (method B) for the preparation of 1,2,3‐triazoles from 3‐azidopropan‐1‐ol 27 (0.051 g, 0.50 mmol) and N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 29, the 1,2,3‐triazole 32 (0.14 g, 90%) was obtained as colorless needles after crystallization from water. M.p.: 241−244°C; IR (KBr, cm⁻¹) ν_max: 3475, 3086, 3044, 2959, 2928, 1694, 1483, 1317; ¹H NMR (600 MHz, DMSO‐d₆ ): δ = 11.66 (s, 1H, NH), 8.04 (s, 1H, HC5′), 8.02 (d, J = 7.8 Hz, 1H, H5), 7.72 (brt, J = 8.3 Hz, 1H, H7), 7.53 (d, J = 8.3 Hz, 1H, H8), 7.27 (t, J = 7.8 Hz, 1H, H6), 5.32 (s, 2H, CH₂ ), 4.64 (t, J = 5.0 Hz, 1H, OH), 4.35 (t, J = 7.1 Hz, 2H, NCH₂ CH₂CH₂OH), 3.38−3.35 (m, 2H, NCH₂CH₂CH₂ OH), 1.92 (qu, J = 7.1 Hz, 2H, NCH₂CH₂ CH₂OH); ¹³C NMR (151 MHz, DMSO‐d₆ ): δ = 162.29 (s, C=O), 150.67 (s, C=O), 142.78, 141.23, 135.65, 127.99, 123.91, 123.17, 116.27, 115.55, 57.91, 47.16, 38.31, 33.29. Anal. calcd. for C₁₄H₁₅N₅O₃ × 0.25H₂O: C, 54.99; H, 5.11; N, 22.90. Found: C, 54.80; H, 4.89; N, 22.78.

N³‐Benzoyl‐N¹‐{[1‐(3‐hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]‐methyl}quinazoline‐2,4‐dione 33a

According to general procedure (method B) from 3‐azidopropan‐1‐ol 27 (0.051 g, 0.50 mmol) and N ³‐benzoyl‐N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 30a, the 1,2,3‐triazole 33a (0.21 g, 98%) was obtained as a white powder after purification on silica gel with chloroform and crystallization from a chloroform–diethyl ether mixture. M.p.: 156−158°C; IR (KBr, cm⁻¹) ν_max: 3546, 3340, 3088, 3061, 2945, 1659, 1608, 1481, 1393; ¹H NMR (600 MHz, CDCl₃): δ = 8.23 (dd, J = 7.9 Hz, J = 1.5 Hz, 1H, H5), 8.01−7.99 (m, 2H), 7.94 (d, J = 8.5 Hz, 1H, H8), 7.80 (ddd, J = 8.5 Hz, J = 7.9 Hz, J = 1.5 Hz, 1H, H7), 7.70−7.68 (m, 1H), 7.54−7.52 (m, 2H), 7.34 (dt, J = 7.9 Hz, 1H, H6), 5.42 (s, 2H, CH₂ ), 4.49 (t, J = 6.8 Hz, 2H, CH₂ CH₂CH₂OH), 3.66−3.63 (m, 2H, CH₂CH₂CH₂ OH), 2.12 (qu, J = 6.8 Hz, 2H, CH₂CH₂ CH₂OH), 1.86 (t, J = 5.0 Hz, 1H, OH); ¹³C NMR (151 MHz, CDCl₃): δ = 168.68 (s, C=O), 161.09 (s, C=O), 149.61 (s, C=O), 142.39, 140.28, 136.27, 135.15, 131.70, 130.53, 129.23, 128.96, 124.12, 123.83, 115.61, 115.32, 58.81, 47.14, 38.91, 32.40. Anal. calcd. for C₂₁H₁₉N₅O₄ × 0.25H₂O: C, 61.53; H, 4.79; N, 17.09. Found: C, 61.25; H, 4.50; N, 16.88.

N³‐(2‐Fluorobenzoyl)‐N¹‐{[1‐(3‐hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}quinazoline‐2,4‐dione 33b

According to general procedure (method B) from 3‐azidopropan‐1‐ol 27 (0.031 g, 0.31 mmol) and N ³‐(2‐fluorobenzoyl)‐N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 30b (0.10 g, 0.31 mmol), the 1,2,3‐triazole 33b (0.13 g, 99%) was obtained as a white powder after purification on silica gel with chloroform−methanol (50:1 to 25:1, v/v) and crystallization from a chloroform–diethyl ether mixture. M.p.: 148−152°C; IR (KBr, cm⁻¹) ν_max: 3332, 3083, 2950, 1662, 1607, 1482, 1456, 1079, 1052, 1033, 758, 696; ¹H NMR (600 MHz, CDCl₃): δ = 8.21 (dd, J = 7.9 Hz, J = 1.4 Hz, 1H, H5), 8.16 (dt, J = 7.7 Hz, J = 1.7 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H, H8), 7.78 (ddd, J = 8.5 Hz, J = 7.9 Hz, J = 1.4 Hz, 1H, H7), 7.69 (s, 1H, HC5′), 7.68−7.64 (m, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.32 (t, J = 7.4 Hz, 1H), 7.14 (dd, J = 8.5 Hz, 1H), 4.50 (t, J = 6.8 Hz, 2H, CH₂CH₂CH₂ OH), 3.65 (t, J = 6.8 Hz, 2H, CH₂ CH₂CH₂OH), 2.13 (qu, J = 6.8 Hz, 2H, CH₂CH₂ CH₂OH), 1.75 (brs, 1H, OH); ¹³C NMR (151 MHz, CDCl₃): δ = 164.77 (s, C=O), 162.09 (d, J = 259.9 Hz, C2′), 160.76 (s, C=O), 149.44, 142.57, 140.15, 136.92 (d, J = 9.8 Hz, C4′), 136.21, 133.10, 128.89, 125.11 (d, J = 3.3 Hz, C5′), 123.82 (d, J = 20.2 Hz, C1′), 120.53 (d, J = 7.8 Hz, C6′), 117.20 (d, J = 23.2 Hz, C3′), 115.72, 115.25, 58.80, 47.12, 38.88, 32.41. Anal. calcd. for C₂₁H₁₈FN₅O₄ × 0.25H₂O: C, 58.94; H, 4.36; N, 16.37. Found: C, 59.24; H, 4.05; N, 16.35.

N³‐(3‐Fluorobenzoyl)‐N¹‐{[1‐(3‐hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}quinazoline‐2,4‐dione 33c

According to general procedure (method B) from 3‐azidopropan‐1‐ol 27 (0.031 g, 0.31 mmol) and N ³‐(3‐fluorobenzoyl)‐N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 30c (0.10 g, 0.31 mmol), the 1,2,3‐triazole 33c (0.12 g, 95%) was obtained as a white powder after purification on silica gel with chloroform–methanol (50:1 to 25:1, v/v) and crystallization from a chloroform–diethyl ether mixture. M.p.: 134−136°C; IR (KBr, cm⁻¹) ν_max: 3549, 3351, 3084, 3057, 3042, 2967, 2945, 1657, 1608, 1481, 1442, 1048, 1001, 876, 861, 798, 782, 759; ¹H NMR (600 MHz, CDCl₃): δ = 8.21 (dd, J = 7.9 Hz, J = 1.4 Hz, 1H, H5), 7.94 (d, J = 8.5 Hz, 1H, H8), 7.82−7.77 (m, 2H), 7.72 (s, 1H, HC5′), 7.66 (dt, J = 8.5 Hz, J = 1.4 Hz, 1H, H7), 7.51 (dt, J = 8.0 Hz, J = 5.3 Hz, 1H), 7.39 (dt, J = 8.5 Hz, J = 2.1 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H, H6), 4.49 (t, J = 6.8 Hz, 2H, CH₂ CH₂CH₂OH), 3.64 (t, J = 6.8 Hz, 2H, CH₂CH₂CH₂ OH), 2.12 (qu, J = 6.8 Hz, 2H, CH₂CH₂ CH₂OH), 1.96 (brs, 1H, OH); ¹³C NMR (151 MHz, CDCl₃): δ = 167.78 (d, J = 2.6 Hz, C=O), 162.94 (d, J = 249.4 Hz, C3′), 161.04 (s, C=O), 149.52 (s, C=O), 142.29, 140.26, 136.42, 133.87 (d, J = 7.3 Hz, C1′), 130.96 (d, J = 7.9 Hz, C5′), 128.95, 126.23 (d, J = 2.8 Hz, C6′), 124.07, 123.95, 122.26 (d, J = 21.2 Hz, C2′), 117.11 (d, J = 23.2 Hz, C4′), 115.50, 115.41, 58.79, 47.18, 38.92, 32.42. Anal. calcd. for C₂₁H₁₈FN₅O₄ × 0.25H₂O: C, 58.95; H, 4.36; N, 16.37. Found: C, 58.84; H, 4.02; N, 16.28.

N³‐(4‐Fluorobenzoyl)‐N¹‐{[1‐(3‐hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}quinazoline‐2,4‐dione 33d

According to general procedure (method B) from 3‐azidopropan‐1‐ol 27 (0.039 g, 0.39 mmol) and N ³‐(4‐fluorobenzoyl)‐N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 30d (0.13 g, 0.39 mmol), the 1,2,3‐triazole 33d (0.15 g, 93%) was obtained as a white powder after purification on silica gel with chloroform–methanol (100:1 to 25:1, v/v) and crystallization from a chloroform–diethyl ether mixture. M.p.: 148−150°C; IR (KBr, cm⁻¹) ν_max: 3546, 3381, 2961, 2942, 1658, 1598, 1481, 1440, 1011, 848; ¹H NMR (600 MHz, CDCl₃): δ = 8.21 (d, J = 7.8 Hz, 1H, H5), 8.04−8.02 (m, 2H), 7.94 (d, J = 8.5 Hz, 1H, H8), 7.80 (t, J = 8.5 Hz, 1H, H7), 7.73 (s, 1H, HC5′), 7.33 (t, J = 7.8 Hz, 1H, H6), 7.20 (t, J = 8.3 Hz, 2H), 4.50 (t, J = 6.2 Hz, 2H, CH₂ CH₂CH₂OH), 3.65 (t, J = 6.2 Hz, 2H, CH₂CH₂CH₂ OH), 2.12 (qu, J = 6.2 Hz, 2H, CH₂CH₂ CH₂OH), 1.85 (brs, 1H, OH); ¹³C NMR (151 MHz, CDCl₃): δ = 167.49 (s, C=O), 166.97 (d, J = 258.8 Hz, C4′), 161.07 (s, C=O), 149.56 (s, C=O), 140.27, 136.35, 133.40 (d, J = 9.9 Hz, C2′, C6′), 128.95, 128.22 (d, J = 2.8 Hz, C1′), 123.90, 116.61 (d, J = 22.3 Hz, C3′, C5′), 115.54, 115.37, 58.85, 47.18, 38.92, 32.42. Anal. calcd. for C₂₁H₁₈FN₅O₄ × 0.25H₂O: C, 58.95; H, 4.36; N, 16.37. Found: C, 58.79; H, 4.07; N, 16.02.

N³‐Benzyl‐N¹‐{[1‐(3‐hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]‐methyl}quinazoline‐2,4‐dione 34a

According to general procedure (method B) from 3‐azidopropan‐1‐ol 27 (0.052 g, 0.52 mmol) and N ³‐benzyl‐N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 31a (0.15 g, 0.52 mmol), the 1,2,3‐triazole 34a (0.19 g, 96%) was obtained as white needles after purification on silica gel with chloroform–methanol (50:1 to 25:1, v/v) and crystallization from a chloroform–diethyl ether mixture. M.p.: 121−122°C; IR (KBr, cm⁻¹) ν_max: 3486, 2957, 2946, 2928, 1649, 1606, 1482; ¹H NMR (600 MHz, CDCl₃): δ = 8.24 (dd, J = 7.9 Hz, J = 1.6 Hz, 1H, H5), 7.78 (d, J = 8.5 Hz, 1H, H8), 7.70 (ddd, J = 8.5 Hz, J = 7.9 Hz, J = 1.6 Hz, 1H, H7), 7.66 (s, 1H, HC5′), 7.54−7.53 (m, 2H), 7.35−7.32 (m, 2H), 7.30−7.26 (m, 2H), 5.41 (s, 2H, CH₂ ), 5.32 (s, 2H, NCH₂ Ph), 4.48 (t, J = 6.8 Hz, 2H, CH₂CH₂CH₂ OH), 3.65−3.62 (m, 2H, CH₂ CH₂CH₂OH), 2.12 (qu, J = 6.8 Hz, 2H, CH₂CH₂ CH₂OH), 1.75 (brs, 1H, OH); ¹³C NMR (151 MHz, CDCl₃): δ = 161.74 (s, C=O), 151.16 (s, C=O), 142.98, 139.65, 136.96, 135.40, 129.04, 128.86, 128.44, 127.62, 123.77, 123.31, 115.65, 114.65, 58.81, 47.06, 45.02, 39.53, 32.41. Anal. calcd. for C₂₁H₂₁N₅O₃: C, 64.44; H, 5.41; N, 17.89. Found: C, 64.23; H, 5.11; N, 17.75.

N³‐(2‐Fluorobenzyl)‐N¹‐{[1‐(3‐hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}quinazoline‐2,4‐dione 34b

According to general procedure (method B) from 3‐azidopropan‐1‐ol 27 (0.045 g, 0.45 mmol) and N ³‐(2‐fluorobenzyl)‐N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 31b (0.14 g, 0.45 mmol), the 1,2,3‐triazole 34b (0.18 g, 97%) was obtained as a white powder after purification on silica gel with chloroform and crystallization from a chloroform–diethyl ether mixture. M.p.: 121−123°C; IR (KBr, cm⁻¹) ν_max: 3399, 3342, 3072, 2927, 1662, 1606, 1484, 1404, 1097, 1056, 768, 694; ¹H NMR (600 MHz, CDCl₃): δ = 8.24 (dd, J = 7.8 Hz, J = 1.0 Hz, 1H, H5), 7.82 (d, J = 8.5 Hz, 1H, H8), 7.74−7.71 (m, 1H, H7), 7.69 (s, 1H, HC5′), 7.31−7.24 (m, 3H), 7.07 (t, J = 8.4 Hz, 2H), 5.43 (s, 2H, CH₂ ), 5.41 (s, 2H, NCH₂ Ph), 4.49 (t, J = 6.4 Hz, 2H, CH₂CH₂CH₂ OH), 3.64 (t, J = 6.4 Hz, 2H, CH₂ CH₂CH₂OH), 2.12 (qu, J = 6.4 Hz, 2H, CH₂CH₂ CH₂OH), 1.96 (s, 1H, OH); ¹³C NMR (151 MHz, CDCl₃): δ = 161.70 (s, C=O), 160.78 (d, J = 247.6 Hz, C2′), 151.00 (s, C=O), 139.70, 135.52, 129.31 (d, J = 4.0 Hz, C6′), 129.09, 129.04 (d, J = 8.1 Hz, C4′), 124.07 (d, J = 3.4 Hz, C5′), 123.81 (d, J = 14.3 Hz, C1′), 123.39, 115.53, 115.49 (d, J = 21.8 Hz, C3′), 114.73, 58.77, 47.08, 39.54, 38.97 (d, J = 4.6 Hz, NCH₂ Ph), 32.42. Anal. calcd. for C₂₁H₂₀FN₅O₃ × 0.5H₂O: C, 60.28; H, 5.06; N, 16.74. Found: C, 60.34; H, 4.72; N, 16.39.

N³‐(3‐Fluorobenzyl)‐N¹‐{[1‐(3‐hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}quinazoline‐2,4‐dione 34c

According to general procedure (method B) from 3‐azidopropan‐1‐ol 27 (0.033 g, 0.32 mmol) and N ³‐(3‐fluorobenzyl)‐N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 31c (0.100 g, 0.32 mmol), the 1,2,3‐triazole 34c (0.12 g, 94%) was obtained as a white powder after purification on silica gel with chloroform and crystallization from a chloroform–diethyl ether mixture. M.p.: 83−85°C; IR (KBr, cm⁻¹) ν_max: 3417, 2956, 2926, 1658, 1609, 1484, 1050, 874, 756; ¹H NMR (600 MHz, CDCl₃): δ = 8.24 (dd, J = 7.9 Hz, J = 1.4 Hz, 1H, H5), 7.81 (d, J = 8.5 Hz, 1H, H8), 7.74−7.71 (m, 1H, H7), 7.68 (s, 1H, HC5′), 7.31−7.27 (m, 3H), 7.23−7.21 (m, 1H), 7.00−6.96 (m, 1H), 5.43 (s, 2H, CH₂ ), 5.30 (s, 2H, NCH₂ Ph), 4.50 (t, J = 6.5 Hz, 2H, CH₂CH₂CH₂ OH), 3.65 (t, J = 6.5 Hz, 2H, CH₂ CH₂CH₂OH), 2.12 (qu, J = 6.5 Hz, 2H, CH₂CH₂ CH₂OH), 1.79 (s, 1H, OH); ¹³C NMR (151 MHz, CDCl₃): δ = 162.82 (d, J = 245.9 Hz, C3′), 161.65 (s, C=O), 151.10 (s, C=O), 139.65, 139.30 (d, J = 7.4 Hz, C1′), 135.54, 129.93 (d, J = 8.1 Hz, C5′), 124.48 (d, J = 2.9 Hz, C6′), 123.78, 123.42, 115.63 (d, J = 21.8 Hz, C4′), 115.54, 114.74, 114.56 (d, J = 21.1 Hz, C2′), 58.79, 47.09, 44.51, 39.54, 32.42. Anal. calcd. for C₂₁H₂₀FN₅O₃ × 0.25H₂O: C, 60.94; H, 4.99; N, 16.92. Found: C, 60.88; H, 4,67; N, 16,64.

N³‐(4‐Fluorobenzyl)‐N¹‐{[1‐(3‐hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}quinazoline‐2,4‐dione 34d

According to general procedure (method B) from 3‐azidopropan‐1‐ol 27 (0.033 g, 0.32 mmol) and N ³‐(4‐fluorobenzyl)‐N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 31d (0.10 g, 0.32 mmol), the 1,2,3‐triazole 34d (0.12 g, 92%) was obtained as a white powder after purification on silica gel with chloroform and crystallization from a chloroform–diethyl ether mixture. M.p.: 107−110°C; IR (KBr, cm⁻¹) ν_max: 3330, 2966, 2926, 1699, 1656, 1608, 1486, 1403, 1089, 1058, 1040, 857, 823; ¹H NMR (600 MHz, CDCl₃): δ = 8.22 (d, J = 7.8 Hz, 1H, H5), 7.76 (d, J = 8.4 Hz, 1H, H8), 7.69 (t, J = 8.4 Hz, 1H, H7), 7.66 (s, 1H, HC5′), 7.54−7.52 (m, 2H), 7.26 (t, J = 7.8 Hz, 1H, H6), 7.00 (t, J = 8.6 Hz, 2H), 5.40 (s, 2H, CH₂ ), 5.25 (s, 2H, NCH₂ Ph), 4.48 (t, J = 6.3 Hz, 2H, CH₂CH₂CH₂ OH), 3.64 (t, J = 6.3 Hz, 2H, CH₂ CH₂CH₂OH), 2.11 (qu, J = 6.3 Hz, 2H, CH₂CH₂ CH₂OH), 2.05 (brs, 1H, OH); ¹³C NMR (151 MHz, CDCl₃): δ = 162.31 (d, J = 245.9 Hz, C4′), 161.70 (s, C=O), 151.10 (s, C=O), 139.63, 135.47, 132.76 (d, J = 3.1 Hz, C1′), 130.93 (d, J = 8.0 Hz, C2′, C6′), 128.99, 123.74, 123.37, 115.59, 115.23 (d, J = 21.1 Hz, C3′, C5′), 114.69, 58.78, 47.12, 44.30, 39.53, 32.48. Anal. calcd. for C₂₁H₂₀FN₅O₃ × 0.25H₂O: C, 60.94; H, 4.99; N, 16.92. Found: C, 60.82; H, 4.67; N, 16.67.

N¹‐{[1‐(3‐Benzyloxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}‐quinazoline‐2,4‐dione 35

According to general procedure (method B) from (3‐azidopropoxy)methylbenzene 28 (0.052 g, 0.26 mmol) and N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 29 (0.051 g, 0.26 mmol), pure 1,2,3‐triazole 35 (0.091 g, 90%) was obtained as a white powder after purification on silica gel with chloroform and crystallization from a chloroform–diethyl ether mixture. M.p.: 203−205°C; IR (KBr, cm⁻¹) ν_max: 3043, 2960, 1682, 1608, 1501, 1482, 1403; ¹H NMR (600 MHz, DMSO‐d₆ ): δ = 11.64 (s, 1H, NH), 8.02−8.01 (m, 2H), 7.71−7.68 (m, 1H), 7.52 (d, J = 8.5 Hz, 1H, H8), 7.34−7.24 (m, 6H), 5.32 (s, 2H, CH₂ ), 4.40−4.37 (m, 4H, NCH₂ Ph, NCH₂ CH₂CH₂OBn), 3.39–3.36 (m, 2H, NCH₂CH₂CH₂ OBn), 2.06 (qu, J = 6.4 Hz, 2H, NCH₂CH₂ CH₂OBn); ¹³C NMR (151 MHz, DMSO‐d₆ ): δ = 162.26 (s, C=O), 150.66 (s, C=O), 142.79, 141.21, 138.76, 135.56, 128.64, 127.98, 127.89, 127.83, 123.93, 123.10, 116.30, 115.49, 79.61, 79.39, 79.17, 72.44, 66.76, 47.28, 38.31, 30.28. Anal. calcd. for C₂₁H₂₁N₅O₃ × 0.25H₂O: C, 63.71; H, 5.47; N, 17.69. Found: C, 63.53; H, 5.15; N, 17.65.

N³‐Benzoyl‐N¹‐{[1‐(3‐benzyloxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}quinazoline‐2,4‐dione 36a

According to general procedure (method B) from (3‐azidopropoxy)methylbenzene 28 (0.084 g, 0.44 mmol) and N ³‐benzoyl‐N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 30a (0.13 g, 0.44 mmol), the 1,2,3‐triazole 36a (0.20 g, 93%) was obtained as a white powder after purification on silica gel with chloroform and crystallization from a chloroform–diethyl ether mixture. M.p.: 111−113°C; IR (KBr, cm⁻¹) ν_max: 3065, 3037, 3007, 2965, 2947, 2929, 1700, 1661, 1482; ¹H NMR (600 MHz, CDCl₃): δ = 8.23 (dd, J = 7.9 Hz, J = 1.4 Hz, 1H, H5), 8.00−7.99 (m, 2H), 7.94 (d, J = 8.5 Hz, 1H, H8), 7.81−7.78 (m, 1H, H7), 7.68 (t, J = 7.5 Hz, 1H), 7.64 (s, 1H, HC5′), 7.52 (t, J = 7.9 Hz, 2H), 7.36−7.30 (m, 6H), 5.41 (s, 2H, CH ₂ ), 4.47−4.45 (m, 4H, NCH₂ Ph, NCH₂ CH₂CH₂OBn), 3.46 (t, J = 6.2 Hz, 2H, NCH₂CH₂CH₂ OBn), 2.19 (qu, J = 6.2 Hz, 2H, NCH₂CH₂ CH₂OBn); ¹³C NMR (151 MHz, CDCl₃): δ = 168.66 (s, C=O), 161.11 (s, C=O), 149.56 (s, C=O), 140.33, 137.93, 136.25, 135.10, 131.76, 130.53, 129.22, 128.93, 128.47, 127.81, 127.76, 123.78, 115.62, 115.37, 73.16, 66.19, 47.67, 38.86, 30.26. Anal. calcd. for C₂₈H₂₅N₅O₄ × 0.25H₂O: C, 67.26; H, 5.14; N, 14.01. Found: C, 67.31; H, 4.86; N, 14.17.

N¹‐{[1‐(3‐Benzyloxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}‐N³‐(2‐fluorobenzoyl)‐quinazoline‐2,4‐dione 36b

According to general procedure (method B) from (3‐azidopropoxy)methylbenzene 28 (0.065 g, 0.34 mmol) and N ³‐(2‐fluorobenzoyl)‐N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 30b (0.11 g, 0.34 mmol), the product 36b (0.16 g, 92%) was obtained as a white powder after purification on silica gel with chloroform and crystallization from a chloroform–diethyl ether mixture. M.p.: 88−90°C; IR (KBr, cm⁻¹) ν_max: 3035, 2948, 2929, 1661, 1609, 1482, 1455, 1040, 741, 700; ¹H NMR (600 MHz, CDCl₃): δ = 8.22 (d, J = 7.6 Hz, 1H, H5), 8.16 (dt, J = 8.5 Hz, J = 7.6 Hz, J = 1.1 Hz, 1H, H7), 7.87 (d, J = 8.5 Hz, 1H, H8), 7.77 (t, J = 7.6 Hz, 1H, H6), 7.66−7.63 (m, 1H), 7.61 (s, 1H, HC5′), 7.36−7.29 (m, 7H), 7.11 (dd, J = 8.4 Hz, 1H), 5.43 (s, 2H, CH₂ ), 4.48−4.46 (m, 4H, NCH₂ Ph, NCH₂ CH₂CH₂OBn), 3.46 (t, J = 6.4 Hz, 2H, NCH₂CH₂CH₂ OBn), 2.19 (qu, J = 6.4 Hz, 2H, NCH₂CH₂ CH₂OBn); ¹³C NMR (151 MHz, CDCl₃): δ = 164.76 (s, C=O), 162.07 (d, J = 259.0 Hz, C2′), 160.77 (s, C=O), 149.40, 142.42, 140.19, 137.92, 136.88 (d, J = 9.6 Hz, C4′), 136.19, 133.10, 128.88, 128.47, 127.81, 127.74, 125.10 (d, J = 3.6 Hz, C5′), 123.74 (d, J = 10.8 Hz, C1′), 120.55 (d, J = 7.8 Hz, C6′), 117.20 (d, J = 23.2 Hz, C3′), 115.73, 115.30, 73.17, 66.16, 47.53, 38.91, 30.30. Anal. calcd. for C₂₈H₂₄FN₅O₄: C, 65.49; H, 4.71; N, 13.64. Found: C, 65.16; H, 4.39; N, 13.88.

N¹‐{[1‐(3‐Benzyloxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}‐N³‐(3‐fluorobenzoyl)‐quinazoline‐2,4‐dione 36c

According to general procedure (method B) from (3‐azidopropoxy)methylbenzene 28 (0.080 g, 0.42 mmol) and N ³‐(3‐fluorobenzoyl)‐N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 30c (0.14 g, 0.42 mmol), the 1,2,3‐triazole 36c (0.20 g, 93%) was obtained as a white powder after purification on silica gel with chloroform and crystallization from a chloroform–diethyl ether mixture. M.p.: 100−102°C; IR (KBr, cm⁻¹) ν_max: 3086, 3036, 2929, 1663, 1483, 1040, 1028, 896, 782; ¹H NMR (600 MHz, CDCl₃): δ = 8.23 (d, J = 7.7 Hz, 1H, H5), 7.96 (d, J = 8.5 Hz, 1H, H8), 7.83−7.78 (m, 2H), 7.68 (d, J = 8.8 Hz, 1H), 7.62 (s, 1H, HC5′), 7.52−7.49 (m, 1H), 7.40−7.29 (m, 7H), 5.41 (s, 2H, CH₂ ), 4.48−4.46 (m, 4H, NCH₂ Ph, NCH₂ ‐CH₂CH₂OBn), 3.46 (t, J = 6.4 Hz, 2H, NCH₂CH₂CH₂ OBn), 2.19 (qu, J = 6.4 Hz, 2H, NCH₂CH₂ CH₂OBn); ¹³C NMR (151 MHz, CDCl₃): δ = 167.75 (d, J = 3.1 Hz, CO), 162.95 (d, J = 249.1 Hz, C3′), 161.05 (s, C=O), 149.48, 142.14, 140.30, 137.92, 136.40, 133.92 (d, J = 7.3 Hz, C1′), 130.94 (d, J = 7.7 Hz, C5′), 128.96, 128.47, 127.82, 127.76, 122.22 (d, J = 21.2 Hz, C2′), 117.13 (d, J = 23.2 Hz, C4′), 115.49 (d, J = 5.4 Hz, C6′), 73.17, 66.16, 47.56, 38.93, 30.30. Anal. calcd. for C₂₈H₂₄FN₅O₄: C, 65.49; H, 4.71; N, 13.64. Found: C, 65.47; H, 4.66; N, 13.95.

N¹‐{[1‐(3‐Benzyloxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}‐N³‐(4‐fluorobenzoyl)‐quinazoline‐2,4‐dione 36d

According to general procedure (method B) from (3‐azidopropoxy)methylbenzene 28 (0.080 g, 0.42 mmol) and N ³‐(4‐fluorobenzoyl)‐N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 30d (0.14 g, 0.42 mmol), the 1,2,3‐triazole 36d (0.20 g, 95%) was obtained as white needles after purification on silica gel with chloroform and crystallization from a chloroform–diethyl ether mixture. M.p.: 103−105°C; IR (KBr, cm⁻¹) ν_max: 3069, 3039, 2965, 2948, 2930, 1661, 1482, 1041, 827; ¹H NMR (600 MHz, CDCl₃): δ = 8.22 (dd, J = 7.9 Hz, J = 1.6 Hz, 1H, H5), 8.04−8.02 (m, 2H), 7.96 (d, J = 8.5 Hz, 1H, H8), 7.81 (ddd, J = 8.5 Hz, J = 7.9 Hz, J = 1.6 Hz, 1H H7), 7.62 (s, 1H, HC5′), 7.37−7.29 (m, 6H), 7.21−7.18 (m, 2H), 5.40 (s, 2H, CH ₂), 4.48−4.46 (m, 4H, NCH₂ Ph, NCH₂ CH₂CH₂OBn), 3.46 (t, J = 6.4 Hz, 2H, NCH₂CH₂CH₂ OBn), 2.19 (qu, J = 6.4 Hz, 2H, NCH₂CH₂ CH₂OBn); ¹³C NMR (151 MHz, CDCl₃): δ = 167.45 (s, C=O), 166.99 (d, J = 258.6 Hz, C4′), 161.08 (s, C=O), 149.52, 142.17, 140.32, 137.90, 136.33, 133.39 (d, J = 9.9 Hz, C2′, C6′), 128.94, 128.47, 128.27 (d, J = 2.9 Hz, C1′), 127.82, 127.76, 123.97, 123.85, 116.59 (d, J = 22.2 Hz, C3′, C5′), 115.55, 115.42, 73.18, 66.16, 47.56, 38.94, 30.30. Anal. calcd. for C₂₈H₂₄FN₅O₄ × 0.25H₂O: C, 64.91; H, 4.77; N, 13.52. Found: C, 64.97; H, 4.65; N, 13.82.

N³‐Benzyl‐N¹‐{[1‐(3‐benzyloxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}quinazoline‐2,4‐dione 37a

According to general procedure (method B) from (3‐azidopropoxy)methylbenzene 28 (0.025 g, 0.17 mmol) and N ³‐benzyl‐N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 31a (0.050 g, 0.17 mmol), the 1,2,3‐triazole 37a (0.076 g, 91%) was obtained as a white powder after purification on silica gel with chloroform–methanol (100:1 to 50:1, v/v) and crystallization from a chloroform–diethyl ether mixture. M.p.: 143−145°C; IR (KBr, cm⁻¹) ν_max: 3138, 3086, 3063, 2959, 2931, 1668, 1651, 1612, 1486, 1402; ¹H NMR (600 MHz, CDCl₃): δ = 8.25 (dd, J = 7.9 Hz, J = 1.6 Hz, 1H, H5), 7.78 (d, J = 8.6 Hz, 1H, H8), 7.70 (ddd, J = 8.6 Hz, J = 7.9 Hz, J = 1.6 Hz, 1H, H7), 7.58 (s, 1H, HC5′), 7.54 (d, J = 7.3 Hz, 2H), 7.38−7.30 (m, 7H), 7.28−7.25 (m, 2H), 5.40 (s, 2H, CH₂ ), 5.31 (s, 2H, NCH₂ Ph), 4.46 (s, 2H, OCH₂ Ph), 4.45 (t, J = 6.8 Hz, 2H, NCH₂ CH₂CH₂OBn), 3.45 (t, J = 6.8 Hz, 2H, NCH₂CH₂CH₂ OBn), 2.18 (qu, J = 6.8 Hz, 2H, NCH₂CH₂ CH₂OBn); ¹³C NMR (151 MHz, CDCl₃): δ = 161.76 (s, C=O), 151.14 (s, C=O), 142.84, 139.69, 137.94, 136.96, 135.38, 129.02, 128.90, 128.48, 128.46, 127.82, 127.73, 127.63, 123.65, 123.27, 115.65, 114.71, 73.17, 66.21, 47.47, 45.03, 39.58, 30.31. Anal. calcd. for C₂₈H₂₇N₅O₃ × 0.25H₂O: C, 69.19; H, 5.70; N, 14.41. Found: C, 69.22; H, 5.50; N, 14.26.

N¹‐{[1‐(3‐Benzyloxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}‐N³‐(2‐fluorobenzyl)quinazoline‐2,4‐dione 37b

According to general procedure (method B) from (3‐azidopropoxy)methylbenzene 28 (0.062 g, 0.32 mmol) and N ³‐(2‐fluorobenzyl)‐N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 31b (0.10 g, 0.32 mmol), pure product 37b (0.15 g, 90%) was obtained as a white solid after purification on silica gel with chloroform and crystallization from a chloroform–diethyl ether mixture. M.p.: 103−105°C; IR (KBr, cm⁻¹) ν_max: 3337, 3062, 3031, 2927, 1698, 1656, 1486, 1454, 1057, 1024, 757, 694; ¹H NMR (600 MHz, CDCl₃): δ = 8.25 (d, J = 7.9 Hz, 1H, H5), 7.82 (d, J = 8.5 Hz, 1H, H8), 7.72 (t, J = 8.5 Hz, 1H, H7), 7.59 (s, 1H, HC5′), 7.37−7.24 (m, 8H), 7.07 (t, J = 7.3 Hz, 2H), 5.41 (s, 4H, CH₂ , OCH₂ Ph), 4.46−4.45 (m, 4H, NCH₂ Ph, NCH₂ CH₂CH₂OBn), 3.45 (t, J = 6.4 Hz, 2H, NCH₂CH₂CH₂ OBn), 2.18 (qu, J = 6.4 Hz, 2H, NCH₂CH₂ CH₂OBn); ¹³C NMR (151 MHz, CDCl₃): δ = 161.71 (s, C=O), 160.79 (d, J = 247.2 Hz, C2′), 150.97 (s, C=O), 142.80, 139.75, 137.94, 135.50, 129.29 (d, J = 4.0 Hz, C6′), 129.08, 129.03 (d, J = 8.0 Hz, C4′), 128.47, 127.81, 127.72, 124.08 (d, J = 3.4 Hz, C5′), 123.84 (d, J = 14.2 Hz, C1′), 123.70, 123.34, 115.58, 115.49 (d, J = 15.8 Hz, C3′), 114.79, 73.17, 66.21, 47.48, 39.58, 38.96 (d, J = 4.6 Hz, NCH₂Ph), 30.30. Anal. calcd. for C₂₈H₂₆FN₅O₃ × 0.25H₂O: C, 66.72; H, 5.30; N, 13.89. Found: C, 66.76; H, 5.24; N, 13.83.

N¹‐{[1‐(3‐Benzyloxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}‐N³‐(3‐fluorobenzyl)quinazoline‐2,4‐dione 37c

According to general procedure (method B) from (3‐azidopropoxy)methylbenzene 28 (0.062 g, 0.32 mmol) and N ³‐(3‐fluorobenzyl)‐N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 31c (0.10 g, 0.32 mmol), the 1,2,3‐triazole 37c (0.15 g, 91%) was obtained as a white solid after purification on silica gel with chloroform and crystallization from a chloroform–diethyl ether mixture. M.p.: 74–76°C; IR (KBr, cm⁻¹) ν_max: 3146, 3088, 3077, 3033, 2969, 2923, 1656, 1609, 1485, 1090, 1056, 1023, 892, 789; ¹H NMR (600 MHz, CDCl₃): δ = 8.24 (d, J = 7.9 Hz, 1H, H5), 7.80 (d, J = 8.5 Hz, 1H, H8), 7.71 (t, J = 8.5 Hz, 1H, H7), 7.59 (s, 1H, HC5′), 7.38−7.22 (m, 9H), 6.97 (t, J = 7.3 Hz, 1H), 5.41 (s, 2H, CH ₂), 5.29 (s, 2H, OCH ₂Ph), 4.47–4.45 (m, 4H, NCH ₂Ph, NCH₂ CH₂CH₂OBn), 3.46 (t, J = 6.2 Hz, 2H, NCH₂CH₂CH₂ OBn), 2.18 (qu, J = 6.2 Hz, 2H, NCH₂CH₂ CH₂OBn); ¹³C NMR (151 MHz, CDCl₃): δ = 162.83 (d, J = 245.6 Hz, C3′), 161.66 (s, C=O), 151.06 (s, C=O), 142.74, 139.70, 139.31 (d, J = 7.6 Hz, C1′), 137.95, 135.51, 129.93 (d, J = 7.9 Hz, C5′), 129.04, 128.46, 127.81, 127.72, 124.48 (d, J = 3.2 Hz, C6′), 123.64, 123.37, 115.70 (d, J = 22.0 Hz, C4′), 115.84, 114.80, 114.58 (d, J = 21.0 Hz, C2′), 73.16, 66.22, 47.49, 44.52 (d, J = 1.9 Hz, NCH₂Ph), 39.59, 30.30. Anal. calcd. for C₂₈H₂₆FN₅O₃: C, 67.32; H, 5.25; N, 14.02. Found: C, 67.27; H, 4.92; N, 13.97.

N¹‐{[1‐(3‐Benzyloxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}‐N³‐(4‐fluorobenzyl)quinazoline‐2,4‐dione 37d

According to general procedure (method B) from (3‐azidopropoxy)methylbenzene 28 (0.062 g, 0.32 mmol) and N ³‐(4‐fluorobenzyl)‐N ¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 31d (0.10 g, 0.32 mmol), the 1,2,3‐triazole 37d (0.15 g, 95%) was obtained as a white solid after purification on silica gel with chloroform and crystallization from a chloroform–diethyl ether mixture. M.p.: 96−97°C; IR (KBr, cm⁻¹) ν_max: 3331, 3078, 3030, 2999, 2971, 2950, 1653, 1609, 1509, 1485, 1084, 1057, 852, 825; ¹H NMR (600 MHz, CDCl₃): δ = 8.23 (dd, J = 7.9 Hz, J = 1.6 Hz, 1H, H5), 7.77 (d, J = 8.5 Hz, 1H, H8), 7.69 (ddd, J = 8.5 Hz, J = 7.9 Hz, J = 1.6 Hz, 1H, H7), 7.58 (s, 1H, HC5′), 7.56−7.53 (m, 2H), 7.38−7.25 (m, 6H), 7.01−6.98 (m, 2H), 5.39 (s, 2H, CH₂ ), 5.26 (s, 2H, OCH₂ Ph), 4.47−4.44 (m, 4H, NCH ₂Ph, NCH₂ CH₂CH₂OBn), 3.46 (t, J = 6.2 Hz, 2H, NCH₂CH₂CH₂ OBn), 2.18 (qu, J = 6.2 Hz, 2H, NCH₂CH₂ CH₂OBn); ¹³C NMR (151 MHz, CDCl₃): δ = 162.32 (d, J = 245.9 Hz, C4′), 161.71 (s, C=O), 151.07 (s, C=O), 142.76, 139.68, 137.93, 135.45, 132.78 (d, J = 3.1 Hz, C1′), 130.98 (d, J = 7.8 Hz, C2′, C6′), 128.98, 128.48, 127.83, 127.73, 123.61, 123.32, 115.59, 115.25 (d, J = 20.8 Hz, C3′, C5′), 114.76, 73.16, 66.22, 47.49, 44.30, 39.58, 30.31. Anal. calcd. for C₂₈H₂₆FN₅O₃ × 0.25H₂O: C, 66.72; H, 5.30; N, 13.89. Found: C, 66.95; H, 4.95; N, 13.98.

Biological assays

The antiviral assays were based on inhibition of virus‐induced cytopathicity or plaque formation in HEL [herpes simplex virus 1 (HSV‐1) (KOS), HSV‐2 (G), vaccinia virus, vesicular stomatitis virus, cytomegalovirus (HCMV), varicella‐zoster virus (VZV), adenovirus‐2, and human corona virus (299E)], Vero (parainfluenza‐3, reovirus‐1, Sindbis virus, and Coxsackie B4), HeLa (vesicular stomatitis virus, Coxsackie virus B4, and respiratory syncytial virus), or MDCK [influenza A (H1N1; H3N2) and influenza B] cell cultures. Confluent cell cultures (or nearly confluent for MDCK cells) in microtiter 96‐well plates were inoculated with 100 CCID₅₀ of virus (1 CCID₅₀ being the virus dose to infect 50% of the cell cultures) or with 20 plaque‐forming units (PFU). After 1–2 h virus adsorption period, residual virus was removed, and the cell cultures were incubated in the presence of varying concentrations (200, 40, 8, 1.6, 0.32 μM) of the test compounds. Viral cytopathicity was recorded as soon as it reached completion in the control virus‐infected cell cultures that were not treated with the test compounds. Antiviral activity was expressed as the EC₅₀ or concentration required reducing virus‐induced cytopathogenicity or viral plaque (VZV) formation by 50%. The minimal cytotoxic concentration (MCC) of the compounds was defined as the compound concentration that caused a microscopically visible alteration of cell morphology. Alternatively, cytotoxicity of the test compounds was measured based on inhibition of cell growth. HEL cells were seeded at a rate of 5 × 10³ cells/well into 96‐well microtiter plates and allowed to proliferate for 24 h. Then, medium containing different concentrations of the test compounds was added. After 3 days of incubation at 37°C, the cell number was determined with a Coulter counter. The cytostatic concentration was calculated as the CC₅₀, or the compound concentration required reducing cell proliferation by 50% relative to the number of cells in the untreated controls.

The authors wish to express their gratitude to Mrs. Leentje Persoons, Mrs. Lies Van Den Heurck, Mrs. Ellen De Waegenaere, and Mrs. Lizette van Berckelaer for excellent technical assistance. The synthetic part of the project was supported by the National Science Centre (synthesis of N³‐substituted N¹‐propargylquinazoline‐2,4‐diones − grant UMO‐2015/17/B/ST5/00076) and by the Medical University of Lodz internal funds (synthesis of 1,2,3‐triazole derivatives − 503/3‐014‐01/503‐31‐001 and 502‐03/3‐014‐01/502‐34‐078). The biological part of this work was supported by the KU Leuven (GOA 15/19 TBA).

The authors have declared no conflict of interest.

Supporting information

As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.

Supporting Table S1.

Click here for additional data file.^{(323.6KB, pdf)}

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supporting Table S1.

Click here for additional data file.^{(323.6KB, pdf)}

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PERMALINK

Design, Synthesis, and the Biological Evaluation of a New Series of Acyclic 1,2,3‐Triazole Nucleosides

Iwona E Głowacka

Graciela Andrei

Dominique Schols

Robert Snoeck

Katarzyna Gawron

Abstract

Introduction

Figure 1.

Figure 2.

Scheme 1.

Figure 3.

Results and discussion

Chemistry

Scheme 2.

Scheme 3.

Scheme 4.

Biological evaluation

Antiviral and cytotoxic evaluation

Table 1.

Table 2.

Cytostatic activity

Table 3.

Conclusion

Experimental

Chemistry

General

Synthesis of N1‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 29

General procedure for benzoylation of N1‐(prop‐2‐yn‐1‐yl)‐quinazoline‐2,4‐dione 29

N3‐Benzoyl‐N1‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 30a

N3‐(2‐Fluorobenzoyl)‐N1‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 30b

N3‐(3‐Fluorobenzoyl)‐N1‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 30c

N3‐(4‐Fluorobenzoyl)‐N1‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 30d

General procedure for benzylation of N1‐(prop‐2‐yn‐1‐yl)‐quinazoline‐2,4‐dione 29: Method A

N3‐Benzyl‐N1‐(propa‐1,2‐dien‐1‐yl)quinazoline‐2,4‐dione 43a

General procedure for benzylation of N1‐(prop‐2‐yn‐1‐yl)‐quinazoline‐2,4‐dione 29: Method B

N3‐Benzyl‐N1‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 31a

N3‐(2‐Fluorobenzyl)‐N1‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 31b

N3‐(3‐Fluorobenzyl)‐N1‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 31c

N3‐(4‐Fluorobenzyl)‐N1‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 31d

General procedure for the preparation of 1,2,3‐triazoles 32, 33–34a−d and 35, 36–37a−d: Method A

General procedure for the preparation of 1,2,3‐triazoles 32, 33–34a−d and 35, 36–37a−d: Method B

N1‐{[1‐(3‐Hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}‐quinazoline‐2,4‐dione 32

N3‐Benzoyl‐N1‐{[1‐(3‐hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]‐methyl}quinazoline‐2,4‐dione 33a

N3‐(2‐Fluorobenzoyl)‐N1‐{[1‐(3‐hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}quinazoline‐2,4‐dione 33b

N3‐(3‐Fluorobenzoyl)‐N1‐{[1‐(3‐hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}quinazoline‐2,4‐dione 33c

N3‐(4‐Fluorobenzoyl)‐N1‐{[1‐(3‐hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}quinazoline‐2,4‐dione 33d

N3‐Benzyl‐N1‐{[1‐(3‐hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]‐methyl}quinazoline‐2,4‐dione 34a

N3‐(2‐Fluorobenzyl)‐N1‐{[1‐(3‐hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}quinazoline‐2,4‐dione 34b

N3‐(3‐Fluorobenzyl)‐N1‐{[1‐(3‐hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}quinazoline‐2,4‐dione 34c

N3‐(4‐Fluorobenzyl)‐N1‐{[1‐(3‐hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}quinazoline‐2,4‐dione 34d

N1‐{[1‐(3‐Benzyloxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}‐quinazoline‐2,4‐dione 35

N3‐Benzoyl‐N1‐{[1‐(3‐benzyloxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}quinazoline‐2,4‐dione 36a

N1‐{[1‐(3‐Benzyloxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}‐N3‐(2‐fluorobenzoyl)‐quinazoline‐2,4‐dione 36b

N1‐{[1‐(3‐Benzyloxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}‐N3‐(3‐fluorobenzoyl)‐quinazoline‐2,4‐dione 36c

N1‐{[1‐(3‐Benzyloxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}‐N3‐(4‐fluorobenzoyl)‐quinazoline‐2,4‐dione 36d

N3‐Benzyl‐N1‐{[1‐(3‐benzyloxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}quinazoline‐2,4‐dione 37a

N1‐{[1‐(3‐Benzyloxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}‐N3‐(2‐fluorobenzyl)quinazoline‐2,4‐dione 37b

N1‐{[1‐(3‐Benzyloxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}‐N3‐(3‐fluorobenzyl)quinazoline‐2,4‐dione 37c

N1‐{[1‐(3‐Benzyloxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}‐N3‐(4‐fluorobenzyl)quinazoline‐2,4‐dione 37d

Biological assays

Supporting information

References

Associated Data

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Synthesis of N¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 29

General procedure for benzoylation of N¹‐(prop‐2‐yn‐1‐yl)‐quinazoline‐2,4‐dione 29

N³‐Benzoyl‐N¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 30a

N³‐(2‐Fluorobenzoyl)‐N¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 30b

N³‐(3‐Fluorobenzoyl)‐N¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 30c

N³‐(4‐Fluorobenzoyl)‐N¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 30d

General procedure for benzylation of N¹‐(prop‐2‐yn‐1‐yl)‐quinazoline‐2,4‐dione 29: Method A

N³‐Benzyl‐N¹‐(propa‐1,2‐dien‐1‐yl)quinazoline‐2,4‐dione 43a

General procedure for benzylation of N¹‐(prop‐2‐yn‐1‐yl)‐quinazoline‐2,4‐dione 29: Method B

N³‐Benzyl‐N¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 31a

N³‐(2‐Fluorobenzyl)‐N¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 31b

N³‐(3‐Fluorobenzyl)‐N¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 31c

N³‐(4‐Fluorobenzyl)‐N¹‐(prop‐2‐yn‐1‐yl)quinazoline‐2,4‐dione 31d

N¹‐{[1‐(3‐Hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}‐quinazoline‐2,4‐dione 32

N³‐Benzoyl‐N¹‐{[1‐(3‐hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]‐methyl}quinazoline‐2,4‐dione 33a

N³‐(2‐Fluorobenzoyl)‐N¹‐{[1‐(3‐hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}quinazoline‐2,4‐dione 33b

N³‐(3‐Fluorobenzoyl)‐N¹‐{[1‐(3‐hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}quinazoline‐2,4‐dione 33c

N³‐(4‐Fluorobenzoyl)‐N¹‐{[1‐(3‐hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}quinazoline‐2,4‐dione 33d

N³‐Benzyl‐N¹‐{[1‐(3‐hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]‐methyl}quinazoline‐2,4‐dione 34a

N³‐(2‐Fluorobenzyl)‐N¹‐{[1‐(3‐hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}quinazoline‐2,4‐dione 34b

N³‐(3‐Fluorobenzyl)‐N¹‐{[1‐(3‐hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}quinazoline‐2,4‐dione 34c

N³‐(4‐Fluorobenzyl)‐N¹‐{[1‐(3‐hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}quinazoline‐2,4‐dione 34d

N¹‐{[1‐(3‐Benzyloxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}‐quinazoline‐2,4‐dione 35

N³‐Benzoyl‐N¹‐{[1‐(3‐benzyloxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}quinazoline‐2,4‐dione 36a

N¹‐{[1‐(3‐Benzyloxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}‐N³‐(2‐fluorobenzoyl)‐quinazoline‐2,4‐dione 36b

N¹‐{[1‐(3‐Benzyloxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}‐N³‐(3‐fluorobenzoyl)‐quinazoline‐2,4‐dione 36c

N¹‐{[1‐(3‐Benzyloxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}‐N³‐(4‐fluorobenzoyl)‐quinazoline‐2,4‐dione 36d

N³‐Benzyl‐N¹‐{[1‐(3‐benzyloxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}quinazoline‐2,4‐dione 37a

N¹‐{[1‐(3‐Benzyloxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}‐N³‐(2‐fluorobenzyl)quinazoline‐2,4‐dione 37b

N¹‐{[1‐(3‐Benzyloxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}‐N³‐(3‐fluorobenzyl)quinazoline‐2,4‐dione 37c

N¹‐{[1‐(3‐Benzyloxypropyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl}‐N³‐(4‐fluorobenzyl)quinazoline‐2,4‐dione 37d