Design, synthesis and biological activity of pyrazinamide derivatives for anti-Mycobacterium tuberculosis

Shanbin Yang,Shiyang Zhou,Gangliang Huang

doi:10.1080/14756366.2017.1367774

Shanbin Yang, Shiyang Zhou + Show 1 more

Open Access

https://doi.org/10.1080/14756366.2017.1367774

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Abstract

A total of 11 pyrazinamide derivatives were designed and synthesised using pyrazinamide as the lead compound, which was optimised by structural modification with alkyl chains, six-membered rings, and bioisosterism, respectively. The target compounds were synthesised using pyrazinecarboxylic acid as the starting material by acylation, amidation, and alkylation, respectively. Their structures were confirmed by 1H NMR, 13C NMR, HRESIMS, and elemental analysis, respectively. The bioactivities of derivatives were assayed using bacteriostatic experiment and minimum inhibitory concentration experiment. It was showed that the derivatives had good inhibitory effect on Mycobacterium tuberculosis. The biological activity of derivative 1f was the best among all compounds, its antibacterial activity was 99.6%, and the minimum inhibitory concentration was 8.0 µg/mL.

Highlights

Tuberculosis (TB) is a common and fatal chronic infectious disease, and it is easy to occur in young people
The pyrazinamide derivatives for anti-Mycobacterium tuberculosis bacilli were designed using the pyrazinamide as lead compound, which was modified with the alkyl chains/six-member rings and bioisosterism
Using pyrazinecarboxylic acid as the starting material, the pyrazinamide derivatives were synthesised by acylation, amidation, and

Summary

Introduction

Tuberculosis (TB) is a common and fatal chronic infectious disease, and it is easy to occur in young people. Pyrazinamide has good inhibitory effect on M. tuberculosis at pH 5–5.5, and the inhibition of bacteria is the strongest. When pyrazinamide gets into M. tuberculosis bacteria in vivo, the pyrazinoic acid metabolite achieves the bacteriostatic effect. A general method for all titled derivatives 1a–1k N-(1-bromine methyl) pyrazine formamide (21.60 g, 0.10 mol) was put into 250 mL round-bottomed flask, and 21.5 mL (0.20 mol) sixmembered ring compound and 100 mL toluene were added. N-(2-(piperidin-1-yl)ethyl)pyrazine-2-carboxamide (1d): white crystal; yield 84.0%; m.p. 185–187 C; 1H NMR (CDCl3, 300 MHz): d 1⁄4 9.96 (1H, s, pyrazine-H), 9.10 (1H, dd, J 1⁄4 7.6 Hz, pyrazine-H), 8.89 (1H, dd, J 1⁄4 7.6 Hz, pyrazine-H), 8.81 (1H, s, –NH–), 3.36 (2H, s, J 1⁄4 5.8 Hz, N–CH2–), 2.46 (2H, s, –CH2–), 2.42 (4H, m, –CH2–), 1.49 (4H, m, –CH2–), 1.37 (2H, m, –CH2–); 13C NMR (CDCl3, 75 MHz): d 1⁄4 160.7 (C1⁄4O), 146.6, 145.0, 144.7, 144.6 (pyrazine-C), 57.2 (CH2, N–CH2), 56.8, 54.0, 25.9, 24.5 (CH2, CH2–CH2); HRESIMS m/z (pos): 234.1481 C12H18N4O Vaccination was added into the incubator with 5% CO2 at 36 C for 24 h, and the growth differences of n/med Tuberculosis bacili were observed

Results and discussion

N CH2 1 N NH 1NS 2 N CH2 2 N NH 2NO 2NS 3 N CH2 3 N NH 3NO 3NS

Conclusion