Nitroarenes as Antitubercular Agents: Stereoelectronic Modulation to Mitigate Mutagenicity

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Antimicrobial Agents

Background:

• Nitroarenes are often avoided in drug discovery due to mutagenicity concerns.
• However, certain nitroarenes like nitroimidazoles and benzothiazinones show promise as antitubercular agents.
• The nitro group's activation mechanism in mycobacteria is crucial for their efficacy.

Purpose of the Study:

• To identify novel nitrobenzothiazole (BT) derivatives as antitubercular agents.
• To address and mitigate the mutagenicity associated with the lead nitrobenzothiazole series.
• To elucidate the binding mode and mechanism of action of the developed compounds.

Main Methods:

• Whole-cell screening to identify lead antitubercular compounds.
• Chemical modification of lead compounds to reduce mutagenicity.
• Co-crystal structure determination of the novel compounds with Mycobacterium tuberculosis DprE1.
• Assessment of mutagenicity and antitubercular activity.

Main Results:

• A novel lead nitrobenzothiazole (BT) series was identified, inhibiting Mtb DprE1.
• The initial lead compound exhibited mutagenicity.
• Development of 6-methyl-7-nitro-5-(trifluoromethyl)-1,3-benzothiazoles (cBTs), a non-mutagenic class of antitubercular agents.
• Co-crystal structure confirmed cBT binding to Mtb DprE1, revealing the mode of action.

Conclusions:

• A new class of non-mutagenic antitubercular agents, cBTs, was discovered.
• Modulation of stereoelectronic properties, specifically the introduction of a methyl group, resolved the mutagenicity issue.
• This study demonstrates a viable strategy to overcome nitroarene mutagenicity in drug discovery for tuberculosis treatment.