Diarylthiazole: An Antimycobacterial Scaffold Potentially Targeting PrrB-PrrA Two-Component System

详细信息    查看全文

• 作者：Eknath Bellale ; Maruti Naik ; Varun VB ; Anisha Ambady ; Ashwini Narayan ; Sudha Ravishankar ; Vasanthi Ramachandran ; Parvinder Kaur ; Robert McLaughlin ; James Whiteaker ; Sapna Morayya ; Supreeth Guptha ; Sreevalli Sharma ; Anandkumar Raichurkar ; Disha Awasthy ; Vijayshree Achar ; Prakash Vachaspati ; Balachandra Bandodkar ; Manoranjan Panda ; Monalisa Chatterji
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：August 14, 2014
• 年：2014
• 卷：57
• 期：15
• 页码：6572-6582
• 全文大小：447K
• ISSN：1520-4804

文摘

Diarylthiazole (DAT), a hit from diversity screening, was found to have potent antimycobacterial activity against Mycobacterium tuberculosis (Mtb). In a systematic medicinal chemistry exploration, we demonstrated chemical opportunities to optimize the potency and physicochemical properties. The effort led to more than 10 compounds with submicromolar MICs and desirable physicochemical properties. The potent antimycobacterial activity, in conjunction with low molecular weight, made the series an attractive lead (antibacterial ligand efficiency (ALE) >0.4). The series exhibited excellent bactericidal activity and was active against drug-sensitive and resistant Mtb. Mutational analysis showed that mutations in prrB impart resistance to DAT compounds but not to reference drugs tested. The sensor kinase PrrB belongs to the PrrBA two component system and is potentially the target for DAT. PrrBA is a conserved, essential regulatory mechanism in Mtb and has been shown to have a role in virulence and metabolic adaptation to stress. Hence, DATs provide an opportunity to understand a completely new target system for antimycobacterial drug discovery.