title: Nitroarenes as Antitubercular Agents: Stereoelectronic Modulation to Mitigate Mutagenicity.
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.
authors.affiliation: iMED Infection, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore, 560024, India.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Landge
authors.affiliation: iMED Infection, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore, 560024, India.
authors.forename: Vasanthi
authors.initials: V
authors.lastname: Ramachandran
authors.affiliation: iMED Infection, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore, 560024, India.
authors.forename: Anupriya
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Global Health Institute, École Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland.
authors.forename: João
authors.initials: J
authors.lastname: Neres
authors.affiliation: iMED Infection, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore, 560024, India.
authors.forename: Kannan
authors.initials: K
authors.lastname: Murugan
authors.affiliation: iMED Safety Assessment, AstraZeneca, Alderley Park, Macclesfield, SK10 4TF, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Sadler
authors.affiliation: iMED Safety Assessment, AstraZeneca, Alderley Park, Macclesfield, SK10 4TF, UK.
authors.forename: Mick D
authors.initials: MD
authors.lastname: Fellows
authors.affiliation: iMED Infection, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore, 560024, India.
authors.forename: Vaishali
authors.initials: V
authors.lastname: Humnabadkar
authors.affiliation: iMED Infection, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore, 560024, India.
authors.forename: Prakash
authors.initials: P
authors.lastname: Vachaspati
authors.affiliation: iMED Infection, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore, 560024, India.
authors.forename: Anandkumar
authors.initials: A
authors.lastname: Raichurkar
authors.affiliation: iMED Infection, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore, 560024, India.
authors.forename: Sreevalli
authors.initials: S
authors.lastname: Sharma
authors.affiliation: iMED Infection, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore, 560024, India.
authors.forename: Sudha
authors.initials: S
authors.lastname: Ravishankar
authors.affiliation: iMED Infection, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore, 560024, India.
authors.forename: Supreeth
authors.initials: S
authors.lastname: Guptha
authors.affiliation: iMED Infection, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore, 560024, India.
authors.forename: Vasan K
authors.initials: VK
authors.lastname: Sambandamurthy
authors.affiliation: iMED Infection, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore, 560024, India.
authors.forename: Tanjore S
authors.initials: TS
authors.lastname: Balganesh
authors.affiliation: iMED Infection, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore, 560024, India.
authors.forename: Bheemarao G
authors.initials: BG
authors.lastname: Ugarkar
authors.affiliation: iMED Infection, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore, 560024, India.
authors.forename: V
authors.initials: V
authors.lastname: Balasubramanian
authors.affiliation: iMED Infection, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore, 560024, India.
authors.forename: Balachandra S
authors.initials: BS
authors.lastname: Bandodkar
authors.affiliation: iMED Infection, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore, 560024, India. manapanda@gmail.com.|Biocon Bristol-Myers Squibb Research Center, Biocon Park, Jigani Link Road, Bangalore, 560099, India. manapanda@gmail.com.
authors.forename: Manoranjan
authors.initials: M
authors.lastname: Panda
mesh_terms: D000995:Antitubercular Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D052160:Benzothiazoles / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009153:Mutagens / Q000737:chemistry*; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009574:Nitro Compounds / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D052160:Benzothiazoles; D009153:Mutagens; D009574:Nitro Compounds
keywords: ab initio calculations; antitubercular agents; density functional theory; electron affinity; mutagenicity; nitroarenes