1.4 Diastereomers, Enantiomers and Bioactivity. TMC207: A New Candidate for the Treatment of Tuberculosis

The tuberculosis (TB) epidemic represents a major global health threat killing about two millions people per year. Despite the increased interest in the last two decades, TB still remains a neglected disease. The authors discovered and optimized at Johnson & Johnson Pharmaceutical Research & Development (J&J-PRD) a novel class of antimycobacterial agents called the diarylquinolines (DARQ), specifically inhibiting mycobacterial ATP synthase and highly active against both drug-susceptible and multi drug-resistant strains of Mycobacterium tuberculosis. The observed structure–activity relationship (SAR) within the DARQ family led to the selection of TMC207, currently in Phase IIb clinical trials for multidrug-resistant tuberculosis (MDR-TB). This chapter provides an overview of investigated synthetic routes, the determination of the absolute configuration of TMC207 and efforts to elucidate the molecular determinants of the ATP synthase inhibition.