Toxicity-Driven Drug Optimization in Novel Antitubercular Agents

The project focuses on safer, more effective antitubercular agents from the template compound K2653 which has shown promise against tuberculosis (TB), however with notable toxicity issues. Facing the escalating challenge of drug-resistant TB, the approach applied in this project encompasses in-depth structure-activity-toxicity relationship analyses for new derivatives to maintain or enhance their efficacy while minimizing the toxicity. A key focus is on modifying toxicity parameters—specifically targeting its cytotoxicity, cardiotoxicity, and biotransformation, to ensure safety without compromising the anti-TB potency. By preparing over 30 designed compounds against resistant mycobacteria, assessing their mechanism of action and in vivo, and foremostly safety profiles, we seek to identify lead candidates that will bring a significant advancement in TB treatment with no cross-resistance to current drugs. Successful outcomes could significantly impact TB treatment and provide a foundation for a new drug discovery pipeline to be pursued in other fields of drug discovery research. The project aims to improve the toxicity profile of the template hit K2653 while maintaining or enhancing its antitubercular efficacy; to elucidate the structure-activity-toxicity relationship in this novel family of compounds, to determine the in vivo profile and to identify new lead candidates.