QSAR-driven Design Synthesis and Discovery of Potent Chalcone Derivatives with Antitubercular Activity

摘要

New anti-tuberculosis (anti-TB) drugs are urgently needed to battle drug-resistant Mycobacterium tuberculosis strains and to shorten the current 6–12-month treatment regimen. In this work, we have continued the efforts to develop chalcone-based anti-TB compounds by using an in silico design and QSAR-driven approach. Initially, we developed SAR rules and binary QSAR models using literature data for targeted design of new chalcone-like compounds with anti-TB activity. Using these models, we prioritized 33 compounds for synthesis and biological evaluation. As a result, 10 chalcones-like compounds (>4, 8, 9, 11, 13, 17–20, and >23) were found to exhibit nanomolar activity against replicating micobacteria, low micromolar activity against nonreplicating bacteria, and nanomolar and micromolar against rifampin (RMP) and isoniazid (INH) monoresistant strains (rRMP and rINH) (<1 µM and <10 µM, respectively). The series also show low activity against commensal bacteria and generally show good selectivity toward M. tuberculosis, with very low cytotoxicity against Vero cells (SI = 11–545). Our results suggest that our designed chalcone-like compounds, due to their high potency and selectivity, are promising anti-TB agents.