Design, Synthesis, and Evaluation of Novel Anti-Trypanosomal Compounds.

Human African trypanosomiasis (HAT) is a deadly neglected tropical disease caused by the protozoan parasite . During the course of screening a collection of diverse nitrogenous heterocycles, we discovered two novel compounds that contain the tetracyclic core of the alkaloids, were potent inhibitors of proliferation and methionyl-tRNA synthetase (MetRS) activity. Inspired by these key findings, we prepared several novel series of hydroxyalkyl δ-lactam, δ-lactam, and piperidine analogs and tested their anti-trypanosomal activity. A number of inhibitors are more potent against than these initial hits with one hydroxyalkyl δ-lactam derivative being 25-fold more effective in our assay. Surprisingly, most of these active compounds failed to inhibit MetRS. This work underscores the importance of verifying, irrespective of close structural similarities, that new compounds designed from a lead with a known biological target engage the putative binding site.