Discovery of novel N-methyl carbazole tethered rhodanine derivatives as direct inhibitors of Mycobacterium tuberculosis InhA

被引：23

作者：

Shaikh, Mahamadhanif S. ^{[1
]}

Kanhed, Ashish M. ^{[1
]}

Chandrasekaran, Balakumar ^{[1
]}

Palkar, Mahesh B. ^{[1
]}

Agrawar, Nikhil ^{[1
]}

Lherbet, Christian ^{[2
,3
]}

Hampannavar, Girish A. ^{[1
]}

Karpoormath, Rajshekhar ^{[1
]}

机构：

[1] Univ KwaZulu Natal UKZN, Coll Hlth Sci, Discipline Pharmaceut Sci, ZA-4001 Durban, South Africa

[2] Univ Paul Sabatier Toulouse III, UMR CNRS 5068, Lab SPCMIB, 118 Route Narbonne, F-31062 Toulouse 9, France

[3] Univ Paul Sabatier Toulouse III, CNRS, ITAV USR3505, Toulouse, France

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2019年 / 29卷 / 16期

基金：

新加坡国家研究基金会;

关键词：

Tuberculosis; InhA inhibitor; Carbazole; Hybridization; GLIDE; Molecular dynamics; DESIGN; SCAFFOLD; DRUGS;

D O I：

10.1016/j.bmcl.2019.06.015

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

InhA (Enoyl-ACP reductase) plays a crucial role in the biosynthetic pathway of cell wall synthesis in Mycobacterium tuberculosis (Mtb). Isoniazid (INH) is an important first-line drug, which inhibits InhA. The rapid increase in resistance to INH and currently marketed drugs as well as emergence of MDR-TB and XDR-TB has complicated the diagnosis and treatment of Mtb with ever increasing threat to human kind. Herein, we report novel N-methyl carbazole derivatives as potential anti-TB compounds acting directly via InhA inhibition. All the synthesized final compounds were screened against Mtb virulent cell line H(37)Rv and investigated the InhA enzyme inhibition. Interestingly, compound 9e displayed promising inhibition (91%) at 50 mu M concentration and IC50 of 2.82 mu M against InhA. To understand the ligand receptor interaction between compound 9e and InhA, molecular docking and molecular dynamics experiments were performed. The computational results were in agreement with the observed experimental data. Further, the cytotoxicity studies on mammalian cells revealed that all the compounds were safe.

引用

页码：2338 / 2344

页数：7

共 43 条

[1] Binding of 12-Crown-4 with Alzheimer's Aβ40 and Aβ42 Monomers and Its Effect on Their Conformation: Insight from Molecular Dynamics Simulations [J].