Nitroarenes as Antitubercular Agents: Stereoelectronic Modulation to Mitigate Mutagenicity |
| |
| Authors: | Dr. Sudhir Landge Dr. Vasanthi Ramachandran Dr. Anupriya Kumar Dr. João Neres Kannan Murugan Dr. Claire Sadler Dr. Mick D. Fellows Vaishali Humnabadkar Dr. Prakash Vachaspati Dr. Anandkumar Raichurkar Sreevalli Sharma Sudha Ravishankar Supreeth Guptha Dr. Vasan K. Sambandamurthy Dr. Tanjore S. Balganesh Dr. Bheemarao G. Ugarkar Dr. V. Balasubramanian Dr. Balachandra S. Bandodkar Dr. Manoranjan Panda |
| |
| Affiliation: | 1. iMED Infection, AstraZeneca India Pvt. Ltd., Bangalore, India;2. Global Health Institute, école Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland;3. iMED Safety Assessment, AstraZeneca, Macclesfield, UK;4. Biocon Bristol-Myers Squibb Research Center, Biocon Park, Bangalore, India |
| |
| Abstract: | 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. |
| |
| Keywords: | ab initio calculations antitubercular agents density functional theory electron affinity mutagenicity nitroarenes |
|
|
