Identification of a Series Containing a Pentafluorophenyl Moiety That Targets Pks13 to Inhibit Growth of Mycobacterium tuberculosis

Abstract

Although not currently in the infectious disease spotlight, there is still a pressing need for new agents to treat tuberculosis caused by Mycobacterium tuberculosis. As there is an ever-increasing amount of clinical resistance to the current drugs, ideally new drugs would be found against novel targets to circumvent pre-existing resistance. A phenotypic growth screen identified a novel singleton, 1, as an inhibitor of M. tuberculosis growth. Mechanism-of-action studies determined that 1 targeted Pks13, an essential enzyme in cell wall biosynthesis that, as of yet, has not been targeted by agents in the clinic. The reactive nature of the pentafluorophenyl warhead meant that the molecule was inherently metabolically unstable. A medicinal chemistry optimization program is described that resulted in the identification of a compound that was reactive enough to still inhibit Pks13 and M. tuberculosis growth while being metabolically stable enough to explore in vivo.