The synthesis and evaluation of triazolopyrimidines as anti-tubercular agents

被引：43

作者：

Zuniga, Edison S. ^{[1
]}

Korkegian, Aaron ^{[1
]}

Mullen, Steven ^{[1
]}

Hembre, Erik J. ^{[2
]}

Ornstein, Paul L. ^{[3
]}

Cortez, Guillermo ^{[2
]}

Biswas, Kallolmay ^{[4
]}

Kumar, Naresh ^{[4
]}

Cramer, Jeffrey ^{[2
]}

Masquelin, Thierry ^{[2
]}

Hipskind, Philip A. ^{[2
]}

Odingo, Joshua ^{[1
]}

Parish, Tanya ^{[1
]}

机构：

[1] Infect Dis Res Inst, TB Discovery Res, 1616 Eastlake Ave East, Seattle, WA 98102 USA

[2] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA

[3] Roosevelt Univ, Coll Pharm, Schaumburg, IL 60173 USA

[4] Jubilant Chemsys Ltd, B-34,Sect 58, Noida 201301, India

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2017年 / 25卷 / 15期

基金：

比尔及梅琳达.盖茨基金会;

关键词：

Tuberculosis; Mycobacterium tuberculosis; Anti-tubercular activity; Triazolopyrimidines; FALCIPARUM DIHYDROOROTATE DEHYDROGENASE; ANTIMALARIAL ACTIVITY; LEAD OPTIMIZATION; INHIBITORS; DISCOVERY;

D O I：

10.1016/j.bmc.2017.05.030

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

We identified a di-substituted triazolopyrimidine with anti-tubercular activity against Mycobacterium tuberculosis. Three segments of the scaffold were examined rationally to establish a structure-activity relationship with the goal of improving potency and maintaining good physicochemical properties. A number of compounds displayed sub-micromolar activity against Mycobacterium tuberculosis with no cytotoxicity against eukaryotic cells. Non-substituted aromatic rings at C5 and a two-carbon chain connecting a terminal aromatic at C7 were preferred features; the presence of NH at C7 and a lack of substituent at C2 were essential for potency. We identified compounds with acceptable metabolic stability in rodent and human liver microsomes. Our findings suggest that the easily-synthesized triazolopyrimidines are a promising class of potent anti-tubercular agents and warrant further investigation in our search for new drugs to fight tuberculosis. (C) 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

引用

页码：3922 / 3946

页数：25

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