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

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.

尽管目前结核分枝杆菌（Mycobacterium tuberculosis）引发的结核病并未处于传染病领域的关注焦点，但研发新型抗结核治疗药物的需求仍极为迫切。当前临床使用的抗结核药物的耐药性问题日益严峻，理想的新药应靶向全新的药物靶点以规避已存在的耐药性。一项表型生长筛选实验鉴定出一种新型单一活性化合物1，可抑制结核分枝杆菌的生长。作用机制研究表明，该化合物1靶向聚酮合酶13（Pks13）——一种参与细菌细胞壁生物合成的必需酶，目前临床上尚无靶向该酶的治疗药物。五氟苯基弹头基团的反应活性特性使得该分子本身存在代谢稳定性不足的缺陷。本文描述了一项药物化学优化研究项目，最终获得了一款化合物：其反应活性足以抑制聚酮合酶13（Pks13）及结核分枝杆菌的生长，同时代谢稳定性足够支持体内实验探索。