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Nitroarenes as Antitubercular Agents: Stereoelectronic Modulation to Mitigate Mutagenicity
Author(s) -
Landge Sudhir,
Ramachandran Vasanthi,
Kumar Anupriya,
Neres João,
Murugan Kannan,
Sadler Claire,
Fellows Mick D.,
Humnabadkar Vaishali,
Vachaspati Prakash,
Raichurkar Anandkumar,
Sharma Sreevalli,
Ravishankar Sudha,
Guptha Supreeth,
Sambandamurthy Vasan K.,
Balganesh Tanjore S.,
Ugarkar Bheemarao G.,
Balasubramanian V.,
Bandodkar Balachandra S.,
Panda Manoranjan
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500462
Subject(s) - chemistry , mycobacterium tuberculosis , stereochemistry , nitro , enzyme , combinatorial chemistry , mode of action , biochemistry , tuberculosis , organic chemistry , medicine , alkyl , pathology
Nitroarenes are less preferred in drug discovery due to their potential to be mutagenic. However, several nitroarenes were shown to be promising antitubercular agents with specific modes of action, namely, nitroimidazoles and benzothiazinones. The nitro group in these compounds is activated through different mechanisms, both enzymatic and non‐enzymatic, in mycobacteria prior to binding to the target of interest. From a whole‐cell screening program, we identified a novel lead nitrobenzothiazole (BT) series that acts by inhibition of decaprenylphosphoryl‐β‐ d ‐ribose 2′‐epimerase (DprE1) of Mycobacterium tuberculosis ( Mtb ). The lead was found to be mutagenic to start with. Our efforts to mitigate mutagenicity resulted in the identification of 6‐methyl‐7‐nitro‐5‐(trifluoromethyl)‐1,3‐benzothiazoles (cBTs), a novel class of antitubercular agents that are non‐mutagenic and exhibit an improved safety profile. The methyl group ortho to the nitro group decreases the electron affinity of the series, and is hence responsible for the non‐mutagenic nature of these compounds. Additionally, the co‐crystal structure of cBT in complex with Mtb DprE1 established the mode of binding. This investigation led to a new non‐mutagenic antitubercular agent and demonstrates that the mutagenic nature of nitroarenes can be solved by modulation of stereoelectronic properties.