Abstract
A series of novel 1,3,4-thiadiazole derivatives bearing an amide moiety were designed, synthesized, and evaluated for their in vitro antitumor activities against HL-60, SKOV-3 and MOLT-4 human tumor cell lines by MTT assay. Ethyl 2-((5-(4-methoxybenzamido)-1,3,4-thiadiazol-2-yl)thio)acetate (5f) showed the best inhibitory effect against SKOV-3 cells, with an IC50 value of 19.5 μm. In addition, the acridine orange/ethidium bromide staining assay in SKOV-3 cells suggested that the cytotoxic activity of 5f occurs via apoptosis.
1 Introduction
Cancer has been proposed as the most serious health problem all over the world and is the leading cause of death in humans [1]. During the last few decades, more than 70 % of all cancer deaths occurred in developing and underdeveloped countries [2]. Chemotherapy, one of the main treatment methods, is accompanied by complicated systemic toxicity, serious side effects, high mortality rate, high costs, and development of resistant strains [3]. Therefore, the development of novel chemical structures with high efficacy, low toxicity, a minimum of undesirable side effects, and acceptable resistance profiles is eagerly being pursued [4].
The 1,3,4-thiadiazole ring system is characterized as an important heterocyclic core playing a significant role in medicinal chemistry, especially in the field of antimicrobial agents and chemotherapy [5]. 1,3,4-Thiadiazole derivatives exhibit a broad spectrum of interesting pharmacological properties like antileishmanial, antioxidant, anti-Helicobacter pylori, fungicidal, antitubercular, anticancer, anti-inflammatory, antiviral, and anticonvulsant [6–23].
High-throughput screening at Bristol–Myers Squibb revealed (2-acetamido-thiazolyl) thioacetic ester 1 as an inhibitor of cyclin-dependent kinase 2 (CDK2) (Fig. 1) [24]. Moreover, 2-amino-1,3,4-thiadiazole derivatives were also introduced as potential anticancer agents; as shown in Fig. 1, compounds 2 and 3, with this effective core structure, exhibited good inhibitory activities against Akt/protein kinase B (PKB) [25, 26].
Recently, Zhang et al. reported the antiproliferative properties of novel hybrid molecules containing 1,3,4-oxadiazole and 1,3,4-thiadiazole moieties exemplified by compound 4 in Fig. 1 [27]. According to the above-mentioned findings and in continuation of our interests in exploration of novel heterocyclic scaffolds with anticancer activities [28–31], herein we describe a new series of 1,3,4-thiadiazole derivatives 5a–n, which were designed by replacing the thiazole with a thiadiazole ring and the methyl group with substituted phenyl moieties in compound 1 to achieve better cytotoxic effects.
2 Results and discussion
2.1 Chemistry
The target compounds 5a–n were prepared via the synthetic route illustrated in Scheme 1. First, 5-amino-1,3,4-thiadiazole-2-thiol (6) was prepared via the reaction of thiosemicarbazide and CS2 in EtOH at reflux temperature [32]. Then, 6 was converted to ethyl 2-((5-amino-1,3,4-thiadiazol-2-yl)thio)acetate (8) by the action of ethyl 2-bromoacetate in the presence of potassium hydroxide [33]. In the next step, 8 was reacted with the corresponding aroyl chlorides in the presence of Et3N at ambient temperature to afford target compounds 5a–n.
![Scheme 1: Synthesis of compounds 5a–n (for substituent Ar, see Table 1). Reagents and conditions: (i) Na2CO3, EtOH, reflux; (ii) KOH, EtOH, r.t.; (iii) Et3N, THF, reflux. For the syntheses of 6 and 8, see references [32] and [33], respectively.](/document/doi/10.1515/znb-2015-0138/asset/graphic/j_znb-2015-0138_scheme_001.jpg)
Synthesis of compounds 5a–n (for substituent Ar, see Table 1). Reagents and conditions: (i) Na2CO3, EtOH, reflux; (ii) KOH, EtOH, r.t.; (iii) Et3N, THF, reflux. For the syntheses of 6 and 8, see references [32] and [33], respectively.
2.2 Pharmacology
2.2.1 Cytotoxic assay
The in vitro effect of synthesized compounds 5a–n on cancer cell viability was assessed using MTT (3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay against HL-60 (human promyelocytic leukemia), SKOV-3 (human ovarian carcinoma), and MOLT-4 (human acute lymphoblastic leukemia) cell lines [28].
The results of cytotoxic data indicated that all synthesized (2-amido-thiadiazolyl)acetic ester derivatives 5a–n possess lower cytotoxic potential than doxorubicin and cisplatin in all three cell lines. Moreover, these compounds were inactive against the MOLT-4 cell line, which could be attributed to rapid hydrolysis of the compounds.
Compound 5f was the most potent compound against SKOV-3 and HL-60 cell lines with IC50 values of 19.5 and 30.1 μm, respectively. In case of the SKOV-3 cell line, compounds 5c and 5h exhibited the highest growth inhibitory activities at concentrations of 26.3 and 22.2 μm, respectively. Compounds 5a, 5c, and 5h showed inhibitory effects on viability of HL-60 cells at concentrations <35 μm. As can be seen in Table 1, 5n showed no growth-inhibiting potential on cancer cell lines within the tested concentrations. According to the obtained data (Table 1), the following structure-activity relationship could be constructed:
The presence of an electron-withdrawing group diminishes the cytotoxic activity of the synthesized compounds.
Introduction of different substituents such as chlorine, methoxy, and methyl groups into the ortho position of the phenyl moiety decreases the cytotoxic potential of the thiadiazole derivatives.
Substitution of different groups such as chlorine, methoxy, and methyl at the meta and para positions of the phenyl moiety potentiates the anticancer activity of the studied compounds.
Replacement of the phenyl moiety with other five-membered heterocyclic rings, such as furan and thiophene, leads to a reduced cytotoxic activity.
Cell growth inhibitory activity of synthetic compounds 5a–n assessed by the MTT reduction assay.
| Compound | Ar | IC50 (μm)a | ||
|---|---|---|---|---|
| HL-60 cells | SKOV-3 cells | MOLT-4 cells | ||
| 5a | C6H5 | 32.4 ± 4.2 | 27.2 ± 3.0 | >100 |
| 5b | 2-MeC6H4 | >100 | 59.8 ± 19.9 | >100 |
| 5c | 3-MeC6H4 | 30.8 ± 6.4 | 26.3 ± 5.0 | >100 |
| 5d | 4-MeC6H4 | 68.8 ± 14.9 | 45.4 ± 13.2 | >100 |
| 5e | 2-OMeC6H4 | 38.5 ± 4.7 | 42.3 ± 11.9 | >100 |
| 5f | 4-OMeC6H4 | 30.1 ± 2.7 | 19.5 ± 2.1 | >100 |
| 5g | 2-ClC6H4 | >100 | 79.2 ± 11.8 | >100 |
| 5h | 2-ClC6H4 | 33.8 ± 4.4 | 22.2 ± 0.7 | >100 |
| 5i | 4-ClC6H4 | 88.6 ±10.8 | 45.0 ± 5.1 | >100 |
| 5j | 2,4-Cl2C6H4 | 59.7 ± 3.3 | 37.0 ± 6.2 | >100 |
| 5k | 3-FC6H4 | 45.3 ± 9.2 | 34.5 ± 4.4 | >100 |
| 5l | 3-NO2C6H4 | >100 | 72.7 ± 10.3 | >100 |
| 5m | 2-Thienyl | >100 | 75.1 ± 6.3 | >100 |
| 5n | 2-Furyl | >100 | >100 | >100 |
| Doxorubicin | – | 0.013 ± 0.002 | 0.018 ± 0.016 | 0.047 ± 0.015 |
| Cisplatin | – | 2.1 ± 0.3 | 8.5 ± 4.8 | 3.1 ± 0.1 |
aValues represent mean ± SEM. When compounds were inactive, IC50 was reported as more than the maximum tested concentrations.
The acridine orange (AO)/ethidium bromide (EB) double staining technique was used to evaluate the occurrence of apoptosis in SKOV-3 cells, which had been treated with 5a. AO, a nucleic acid fluorescent cationic dye, permeates all cells and makes the nuclei appear green. EB is only taken up by cells when cytoplasmic membrane integrity is lost, and then stains the nucleus red. Analysis of the AO/EB staining revealed that compound 5f induced apoptosis in the SKOV-3 cell line. As shown in Fig. 2, the non-apoptotic control cells were stained green, and the late apoptotic cells incorporate EB, thus staining orange, and show condensed and fragmented nuclei.
AO/EB double staining of SKOV-3 cells with characteristic symptoms of apoptosis: (a) DMSO 2 % as control and (b) cells treated with IC50 concentration of compound 5f, respectively, for 24 h. The images of cells were taken with a fluorescence microscope at 400×.
3 Conclusion
A novel series of ethyl 2-((5-(benzamido)-1,3,4-thiadiazol-2-yl)thio)acetates 5a–n were synthesized with an objective to study their antitumor activities. The designed compounds showed good antiproliferative activities against different cell lines. Some tested compounds including 5c, 5f, and 5h exhibited cytotoxic activities against SKOV-3 and HL-60. Meanwhile, all compounds were inactive against the MOLT-4 cell line, probably due to the rapid hydrolysis of these compounds. The results of an AO/EB staining assay of compound 5f suggested that the cytotoxic activity of this compound against SKOV-3 cell line occurs via apoptosis. These results are therefore conclusive in showing that different benzamide moieties attached to the 1,3,4-thiadiazole core make some of them lead molecules for further optimization in the development of a novel anticancer agent.
4 Experimental section
4.1 Procedure for the synthesis of compound 5a
To a solution of compound 8 [33] (1 mmol, 0.22 g) in anhydrous THF (10 mL) containing triethyl amine (1.5 mmol, 0.15 g), benzoyl chloride (1 mmol, 0.14 g) was added. The reaction mixture was refluxed and monitored by TLC. Upon completion, the reaction mixture was cooled, and the precipitated solid was filtered off and recrystallized from ethanol to give compound 5a.
4.1.1 Ethyl 2-((5-benzamido-1,3,4-thiadiazol-2-yl)thio)acetate (5a)
Yield: 81 % (0.26 g). M.p. 174–176 °C. – IR (KBr): ν = 1726, 1659 (C=O) cm–1. – 1H NMR (400.0 MHz, CDCl3, 25 °C, TMS): δ ppm = 1.26 (t, J = 7.2 Hz, 3H), 4.07 (s, 2H), 4.21 (q, J = 7.2 Hz, 2H), 7.54–7.60 (m, 2H), 7.65 (dt, J = 7.2, 1.2 Hz, 1H), 8.23–8.26 (m, 2H), 12.73 (s, NH). – MS: m/z = 323 [M]+. – C13H13N3O3S2: anal. calcd. C 48.28, H 4.05, N 12.99; found C 48.55, H 4.21, N 12.66.
4.1.2 Ethyl 2-((5-(2-methylbenzamido)-1,3,4-thiadiazol-2-yl)thio)acetate (5b)
Yield: 80 % (0.27 g). M.p. 150–152 °C. – IR (KBr): ν = 1727, 1655 (C=O) cm–1. – 1H NMR (400.0 MHz, CDCl3, 25 °C, TMS): δ ppm = 1.31 (t, J = 7.2 Hz, 3H), 2.55 (s, 3H), 4.00 (s, 2H), 4.25 (q, J = 7.2 Hz, 2H), 7.31–7.38 (m, 2H), 7.47 (tt, J = 7.6, 1.2 H, 1H), 7.80 (dd, J = 7.7, 1.2 Hz, 1H), 12.48 (s, 1H). – 13C NMR (100.0 MHz, CDCl3, 25 °C, TMS): δ ppm = 14.1 (CH3), 21.4 (SCH2), 35.1 (CH3), 62.1 (OCH2), 126.1 (CH2Ar), 128.5 (CH2Ar), 131.6 (CH2Ar), 131.7 (CH2Ar), 132.0 (CHAr), 138.3 (CHAr), 158.2 (CAr), 160.9 (CHAr), 167.2 (C=O), 168.0 (C=O). – MS: m/z = 337 [M]+. – C14H15N3O3S2: anal. calcd. C 49.83, H 4.48, N 12.45; found C 49.56, H 4.37, N 12.74.
4.1.3 Ethyl 2-((5-(3-methylbenzamido)-1,3,4-thiadiazol-2-yl)thio)acetate (5c)
Yield: 76 % (0.25 g). M.p. 175–177 °C. – IR (KBr): ν = 1727, 1655 (C=O) cm–1. – 1H NMR (400.0 MHz, CDCl3, 25 °C, TMS): δ ppm = 1.26 (t, J = 7.2 Hz, 3H), 2.46 (s, 3H), 4.02 (s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 7.44–7.46 (m, 2H), 7.98 (brs, 1H), 8.20–8.60 (m, 1H), 12.68 (s, NH). – 13C NMR (100.0 MHz, CDCl3, 25 °C, TMS): δ ppm =14.1 (CH3), 21.3 (SCH2), 35.6 (CH3), 62.1 (OCH2), 125.7 (CHAr), 128.7 (CHAr), 129.2 (CH2Ar), 130.8 (CHAr), 134.2 (CH2Ar), 138.8 (CH2Ar), 158.5 (CH2Ar), 161.82 (CAr), 165.7 (C=O), 168.0 (C=O). – MS: m/z = 337 [M]+. – C14H15N3O3S2: anal. calcd. C 49.83, H 4.48, N 12.45; found C 49.57, H 4.17, N 12.72.
4.1.4 Ethyl 2-((5-(4-methylbenzamido)-1,3,4-thiadiazol-2-yl)thio)acetate (5d)
Yield: 72 % (0.24 g). M.p. 151–153 °C. – IR (KBr): ν = 1727, 1654 (C=O) cm–1. – 1H NMR (400.0 MHz, CDCl3, 25 °C, TMS): δ ppm = 1.27 (t, J = 6.8 Hz, 3H), 2.49 (s, 3H), 4.09 (s, 2H), 4.22 (q, J = 6.8 Hz, 2H), 7.36 (d, J = 7.8 Hz, 2H), 8.12 (d, J = 7.8 Hz, 2H), 12.42 (s, NH). – 13C NMR (100.0 MHz, CDCl3): δ ppm = 14.1 (CH3), 21.7 (SCH2), 35.4 (CH3), 62.1 (OCH2), 128.1 (CHAr), 128.6 (CH2Ar), 129.5 (CH2Ar), 144.2 (CHAr), 158.4 (CAr), 161.6 (CAr), 165.8 (C=O), 168.0 (C=O). – MS: m/z = 337 [M]+. – C14H15N3O3S2: anal. calcd. C 49.83, H 4.48, N 12.45; found C 49.57, H 4.29, N 12.77.
4.1.5 Ethyl 2-((5-(2-methoxybenzamido)-1,3,4-thiadiazol-2-yl)thio)acetate (5e)
Yield: 84 % (0.29 g). M.p. 184–186 °C. – IR (KBr): ν = 1726, 1654 (C=O) cm–1. – 1H NMR (400.0 MHz, CDCl3, 25 °C, TMS): δ ppm = 1.26 (t, J = 7.2 Hz, 3H), 4.03 (s, 3H), 4.06 (s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 7.04 (d, J = 8.4 Hz, 1H), 7.11 (dt, J = 7.8, 1.2 Hz, 1H), 7.55 (dt, J = 7.8, 1.2 Hz, 1H), 8.20 (dd, J = 7.8, 1.6 Hz, 1H), 11.20 (s, NH). – MS: m/z = 353 [M]+. – C14H15N3O4S2: anal. calcd. C 47.58, H 4.28, N 11.89; found C 47.25, H 4.19, N 11.97.
4.1.6 Ethyl 2-((5-(4-methoxybenzamido)- 1,3,4-thiadiazol-2-yl)thio)acetate (5f)
Yield: 68 % (0.24 g). M.p. 144–146 °C. – IR (KBr): ν = 1729, 1664 (C=O) cm–1. – 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ ppm = 1.25 (t, J = 6.8 Hz, 3H), 3.92 (s, 3H), 4.08 (s, 2H), 4.20 (q, J = 6.8 Hz, 2H), 7.04 (d, J = 8.2 Hz, 2H), 8.23 (d, J = 8.2 Hz, 2H), 12.61 (s, NH). – 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ ppm = 14.0 (CH3), 33.5 (SCH2), 55.5 (OCH3), 62.1 (OCH2), 114.1 (2CAr), 123.0 (CAr), 130.8 (2CAr), 158.3 (COCH3), 162.0 (CAr), 163.8 (CAr), 164.8 (C=O), 168.0 (C=O). – MS: m/z = 353 [M]+. – C14H15N3O4S2: anal. calcd. C 47.58, H 4.28, N 11.89; found C 47.81, H 4.46, N 11.60.
4.1.7 Ethyl 2-((5-(2-chlorobenzamido)-1,3,4-thiadiazol-2-yl)thio)acetate (5g)
Yield: 81 % (0.29 g). M.p. 157–159 °C. – IR (KBr): ν = 1729, 1660 (C=O) cm–1. – 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ ppm 1.31 (t, J = 7.2 Hz, 3H), 3.94 (s, 2H), 4.24 (q, J = 7.2 Hz, 2H), 7.41–7.47 (m, 1H), 7.51–7.53 (m, 2H), 7.77 (d, J = 7.6 Hz, 1H), 12.95 (s, NH). – 13C NMR (100.0 MHz, CDCl3, 25 °C, TMS): δ 14.1 (CH3), 35.1 (SCH2), 62.2 (OCH2), 127.1 (CH2Ar), 130.4 (CH2Ar), 130.6 (CH2Ar), 132.2 (CHAr), 132.4 (CHAr), 132.5 (CH2Ar), 158.6 (CAr), 160.5 (CAr), 164.7 (C=O), 167.8 (C=O). – MS: m/z = 357 [M]+. – C13H12ClN3O3S2: anal. calcd. C 43.63, H 3.38, N 11.74; found C 43.50, H 3.59, N 11.51.
4.1.8 Ethyl 2-((5-(3-chlorobenzamido)-1,3,4-thiadiazol-2-yl)thio)acetate (5h)
Yield: 73 % (0.26 g). M.p. 168–170 °C. – IR (KBr): ν = 1728, 1661 (C=O) cm–1. – 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ ppm = 1.26 (t, J = 7.2 Hz, 3H), 4.12 (s, 2H), 4.22 (q, J = 7.2 Hz, 2H), 7.25–7.28 (m, 1H), 7.29 (s, 1H), 7.73 (dd, J = 6.8, 1.2 Hz, 1H), 8.48 (dd, J = 6.8, 1.2 Hz, 1H), 12.67 (s, 1H). – MS: m/z = 357 [M]+. – C13H12ClN3O3S2: anal. calcd. C 43.63, H 3.38, N 11.74; found C 43.39, H 3.16, N 11.91.
4.1.9 Ethyl 2-((5-(4-chlorobenzamido)-1,3,4-thiadiazol-2-yl)thio)acetate (5i)
Yield: 80 % (0.28 g). M.p. 181–183 °C. – IR (KBr): ν = 1729, 1660 (C=O) cm–1. – 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ ppm = 1.29 (t, J = 7.2 Hz, 3H), 4.09 (s, 2H), 4.25 (q, J = 7.2 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 8.07 (d, J = 8.4 Hz, 2H), 11.24 (s, NH). – MS: m/z = 357 [M]+. – C13H12ClN3O3S2: anal. calcd. C 43.63, H 3.38, N 11.74; found C 43.31, H 3.19, N 12.08.
4.1.10 Ethyl 2-((5-(2,4-dichlorobenzamido)- 1,3,4-thiadiazol-2-yl)thio)acetate (5j)
Yield: 76 % (0.30 g). M.p. 164–166 °C. – IR (KBr): ν = 1727, 1662 (C=O) cm–1. – 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ ppm = 1.31 (t, J = 7.2 Hz, 3H), 3.98 (s, 2H), 4.25 (q, J = 7.2 Hz, 2H), 7.65 (d, J = 8.4 Hz, 1H), 7.56 (brs, 1H), 7.75 (d, J = 8.4 Hz, 1H), 12.89 (s, NH). – 13C NMR (100.0 MHz, CDCl3, 25 °C, TMS): δ ppm = 14.1 (CH3), 34.9 (SCH2), 62.2 (OCH2), 127.6 (CHAr), 130.63 (CHAr), 130.66 (CH2Ar), 130.7 (CHAr), 131.4 (CH2Ar), 133.2 (CH2Ar), 138.3 (CH2Ar), 158.9 (CAr), 160.37 (CAr), 163.75 (C=O), 167.82 (C=O). – MS: m/z = 391 [M]+. – C13H11Cl2N3O3S2: anal. calcd. C 39.80, H 2.83, N 10.71; found C 39.51, H 2.92, N 11.03.
4.1.11 Ethyl 2-((5-(3-fluorobenzamido)-1,3,4-thiadiazol-2-yl)thio)acetate (5k)
Yield: 87 % (0.33 g). M.p. 189–191 °C. – IR (KBr): ν = 1730, 1668 (C=O) cm–1. – 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ ppm = 1.25 (t, J = 7.2 Hz, 3H), 4.09 (s, 2H), 4.19 (q, J = 7.2 Hz, 2H), 7.35 (t, J = 8.0 Hz, 1H), 7.55 (q, J = 7.6 Hz, 1H), 7.98 (d, J = 9.2 Hz, 1H), 8.06 (d, J = 7.6 Hz, 1H), 13.07 (s, NH). – 13C NMR (100.0 MHz, CDCl3, 25 °C, TMS): δ ppm = 14.1 (CH3), 33.1 (SCH2), 62.1 (OCH2), 115.9 (d, CH2CAr, J = 92.8 Hz), 120.4 (d, CH2Ar, J = 84.4 Hz), 124.6 (d, CH2Ar, J = 11.6 Hz), 130.5 (d, CH2Ar, J = 31.2 Hz), 133.1 (d, CH2Ar, J = 29.2 Hz), 159.0 (CAr), 161.7 (CAr), 163.95 (C=O), 164.42 (C-FAr, J = 10 Hz), 167.95 (C=O). – MS: m/z = 341 [M]+. – C13H12FN3O3S2: anal. calcd. C 45.74, H 3.54, N 12.31; found C 45.38, H 3.25, N 12.13.
4.1.12 Ethyl 2-((5-(3-nitrobenzamido)-1,3,4-thiadiazol-2-yl)thio)acetate (5l)
Yield: 89 % (0.33 g). M.p. 180–182 °C. – IR (KBr): ν = 1730, 1669 (C=O) cm–1. – 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ ppm = 1.25 (t, J = 7.2 Hz, 3H), 4.12 (s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 7.28 (t, J = 4.6 Hz, 1H), 7.73 (d, J = 4.6 Hz, 1H), 8.49 (d, J = 4.6 Hz, 1H), 12.69 (s, NH). – MS: m/z = 368 [M]+. – C13H12N4O5S2: anal. calcd. C 42.38, H 3.28, N 15.21; found C 42.61, H 3.09, N 15.54.
4.1.13 Ethyl 2-((5-(thiophene-2-carboxamido)- 1,3,4-thiadiazol-2-yl)thio)acetate (5m)
Yield: 82 % (0.27 g). M.p. 175–177 °C. – IR (KBr): ν = 1728, 1663 (C=O) cm–1. – 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 1.25 (t, J = 7.2 Hz, 3H), 4.12 (s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 7.28 (t, J = 4.6 Hz, 1H), 7.73 (d, J = 4.6 Hz, 1H), 8.49 (d, J = 4.6 Hz, 1H), 12.69 (s, NH). – MS: m/z = 329 [M]+. – C11H11N3O3S3: anal. calcd. C 40.11, H 3.37, N 12.76; found C 40.36, H 3.09, N 12.90.
4.1.14 Ethyl 2-((5-(furan-2-carboxamido)- 1,3,4-thiadiazol-2-yl)thio)acetate (5n)
Yield: 79 % (0.25 g). M.p. 171–173 °C. – IR (KBr): ν = 1729, 1660 (C=O) cm–1. – 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ ppm = 1.28 (t, J = 7.2 Hz, 3H), 4.08 (s, SCH2), 4.24 (q, J = 7.2 Hz, 2H), 6.66 (dd, J = 3.6, 1.6 Hz, 1H), 7.58 (dd, J = 3.6, 1.6 Hz, 1H), 7.69 (dd, J = 3.6, 1.6 Hz, 1H), 11.28 (s, 1H, NH). – MS: m/z = 313 [M]+. – C11H11N3O4S2: anal. calcd. C 42.16, H 3.54, N 13.41; found C 42.51, H 3.75, N 13.59.
5 Supporting Information
Experimental details of the biological studies and pictures of the 1H NMR and 13C NMR spectra of 5a–n are available online (DOI: 10.1515/znb-2015-0138).
Acknowledgments
This work was supported by a grant from the vice chancellor for research of pharmaceutical sciences branch, Islamic Azad University. Iran National Science Foundation (INSF) is also gratefully acknowledged.
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