Discovery of a quinoline-based phenyl sulfone derivative as an antitrypanosomal agent

Abstract

A series of natural products-based phenyl sulfone derivative and their property-based analogues were investigated as potential growth inhibitors of Trypanosoma brucei. Trypanosoma brucei is a kinetoplastid protozoan parasite that causes trypanosomiasis. In this work, we found that nopol- and quinoline-based phenyl sulfone derivative were the most active and selective for T. brucei, and they were not reactive towards the active thiol of T. brucei's cysteine protease rhodesain. A thiol reactive variant of the quinoline-based phenyl sulfone was subsequently investigated and found to be a moderate inhibitor of rhodesain. The quinoline-based compound that is not reactive towards rhodesain can serve a template for phenotypic-based lead discovery while its thiol-active congener can serve as template for structure-based investigation of new antitrypanosomal agents.

Keywords: Cysteine protease; Natural products; Quinoline; Trypanosoma brucei.

Figure 1

Pseudo-first order inhibition plots for compound 27.

Figure 2

a. The superposition of docked compound 27 (Yellow) and D1R (Blue) at the active site of rhodesain; b. The interaction plot of compound 27 with active site residues.

Scheme 1

Synthesis of target compounds 5–25.

Scheme 2

Synthesis of target compound 27.