Nα‐Aroyl‐N‐Aryl‐Phenylalanine Amides: A Promising Class of Antimycobacterial Agents Targeting the RNA Polymerase

Abstract

Tuberculosis (TB), mainly caused by Mycobacterium tuberculosis, remains the leading cause of death from a bacterium in the world. The global prevalence of clinically relevant infections with opportunistically pathogenic non‐tuberculous mycobacteria (NTM) have also been on the rise. Pharmacological treatment of both TB and NTM infections usually requires prolonged regimens of drug combinations, and is often challenging because of developed or inherent resistance to common antibiotic drugs. Medicinal chemistry efforts are thus needed to improve treatment options and therapeutic outcomes. Nα‐aroyl‐N‐aryl‐phenylalanine amides (AAPs) have been identified as potent antimycobacterial agents that target the RNA polymerase with a low probability of cross resistance to rifamycins, the clinically most important class of antibiotics known to inhibit the bacterial RNA polymerase. In this review, we describe recent developments in the field of AAPs, including synthesis, structural characterization, in vitro microbiological profiling, structure‐activity relationships, physicochemical properties, pharmacokinetics and early cytotoxicity assessment.