Discovery of small molecule inhibitors of Mycobacterium tuberculosis ClpC1: SAR studies and antimycobacterial evaluation

The emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) in humans, is a primary reason for treatment failure. Currently, only limited options are available for the management of multi-drug resistant TB, warranting the design of novel anti-TB drugs by exploiting newer targets. One of the caseinolytic protease (Clp) machinery components, an unfoldase known as ClpC1, has emerged as a distinct anti-TB drug target owing to its essential role in the pathogen's survival. The naturally occurring cyclic peptides targeting the Mtb ClpC1, exhibit potent antimycobacterial activity. However, the large, complex, and poor synthetic tractability of these peptides limit their clinical application. Identification of small molecule inhibitors of Mtb ClpC1 will be useful for future drug development. Here, we report the discovery of a bisquinoline chemotype from the screening of a small molecule chemical library against Mtb ClpC1. The hit molecule binds with ClpC1 and exhibits dose-dependent inhibition of its enzymatic activity by direct binding. The in vitro growth of Mtb is inhibited by the hit molecule at a minimum inhibitory concentration of 12.5 mu M. Investigation of the structure-activity relationship by chemical synthesis underlines the requirement of the two quinoline rings, 9/10 carbon linker, and the importance of basic ring nitrogen for its inhibitory activity. To our knowledge, this is the first report on the systematic analysis of small molecule inhibitors of Mtb ClpC1.