<i>Mycobacterium tuberculosis</i> PptT Inhibitors Based on Heterocyclic Replacements of Amidinoureas
Samantha Ottavi, Kelin Li, Jackson G. Cacioppo, Andrew J. Perkowski, Remya Ramesh, Ben Gold, Yan Ling, Julia Roberts, A.D. Singh, David Zhang, John Mosior, Laurent Goullieux, Christine Roubert, Eric Bacqué, James C. Sacchettini, Carl Nathan, Jeffrey Aubé
Abstract
4′-Phosphopantetheinyl transferase (PptT) is an essential enzyme for Mycobacterium tuberculosis ( Mtb ) survival and virulence and therefore an attractive target for a tuberculosis therapeutic. In this work, two modeling-informed approaches toward the isosteric replacement of the amidinourea moiety present in the previously reported PptT inhibitor AU 8918 are reported. Although a designed 3,5-diamino imidazole unexpectedly adopted an undesired tautomeric form and was inactive, replacement of the amidinourea moiety afforded a series of active PptT inhibitors containing 2,6-diaminopyridine scaffolds.