Trisubstituted Imidazoles as Mycobacterium tuberculosis Glutamine Synthetase Inhibitors

Abstract

Mycobacterium tuberculosis glutamine synthetase (MtGS) is a promising target for antituberculosis drug discovery. In a recent high-throughput screening study we identified several classes of MtGS inhibitors targeting the ATP-binding site. We now explore one of these classes, the 2-tert-butyl-4,5-diarylimidazoles, and present the design, synthesis, and X-ray crystallographic studies leading to the identification of MtGS inhibitors with submicromolar IC50 values and promising antituberculosis MIC values.

Antimycobacterial potentials of quercetin and rutin against Mycobacterium tuberculosis H37Rv

“…This enzyme is an essential biocatalyst involved in the cell wall biosynthesis of M. tuberculosis (Villaume et al 2017). Furthermore, it also regulates the ammonia levels within infected host cells and so helps the pathogen in the inhibition of the phagosome acidification and phagosome-lysosome fusion (Gising et al 2012). It also has been reported that quercetin inhibits 74.40% of mycobacteria proteasomes with IC 50 71.29 µM, whereas rutin did not inhibit (Zheng et al 2014).…”

Hybrid imidazole (benzimidazole)/pyridine (quinoline) derivatives and evaluation of their anticancer and antimycobacterial activity

“…One of the strategies widely used in cancer and TB therapy is targeting DNA with small molecules, imidazole/benzimidazole, and pyridine/quinoline derivatives being leading structures in this respect [anticancer [5][6][7][8][9][10] , anti-TB [11][12][13][14][15] ]. In previously research work, we successfully identify azaheterocycles derivatives (imidazole/benzimidazole and pyridine/quinoline included) with anticancer 9,10,[16][17][18][19] and anti-TB [15][16][17][20][21][22][23] activity.…”

Nickel-Catalyzed Hiyama-type Decarboxylative Coupling of Propiolic Acids and Organosilanes

“…22 3-(Naphthalen-1-yl)propiolic acid (1h) (392 mg, 2.0mmol) and triethoxyphenylsilane (2a) 5, 133.4, 131.9, 130.6, 128.9, 128.6, 128.6, 128.5, 126.9, 126.6, 126.4, 125.5, 123.6, 121.1, 94.6, 87.8; MS (EI) m/z: 228 (M + ). 23 3-(6-Methoxynaphthalen-2-yl)propiolic acid (1i) (452mg, 2.0mmol) and triethoxyphenylsilane (2a) (721 mg, 3.0mmol) afforded 2-methoxy-6-(phenylethynyl)naphthalene (3i)(424mg, 1.64mmol, 82 % yield) as white solid,m.p.167 -168 °C; 1 H NMR (500 MHz, CDCl 3 ) δ 7.98 (m, 1H), 7.71 (t, J = 8. 3 Hz,2H),3H),3H),7.17 (dd,J = 8.8,2.5 Hz,1H), 7.12 (d, J = 2.6 Hz, 1H); 13 C{ 1 H} NMR (126 MHz, CDCl 3 ) δ 158.…”