Vinyl sulfone-based inhibitors of trypanosomal cysteine protease rhodesain with improved antitrypanosomal activities

Bioorg Med Chem Lett. 2020 Jul 15;30(14):127217. doi: 10.1016/j.bmcl.2020.127217.

Huaisheng Zhang ¹, Jasmine Collins ¹, Rogers Nyamwihura ¹, Olamide Crown ², Oluwatomi Ajayi ¹, Ifedayo Victor Ogungbe ³

Affiliations

1 Department of Chemistry, Physics, and Atmospheric Sciences, Jackson State University, Jackson, MS 39217, USA.
2 Department of Chemistry, Physics, and Atmospheric Sciences, Jackson State University, Jackson, MS 39217, USA; Department of Biochemistry, Federal University of Technology, Akure, Nigeria.
3 Department of Chemistry, Physics, and Atmospheric Sciences, Jackson State University, Jackson, MS 39217, USA. Electronic address: [email protected].

PMID: 32527539 DOI: 10.1016/j.bmcl.2020.127217

Abstract

The number of reported cases of Human African Trypanosmiasis (HAT), caused by kinetoplastid protozoan parasite Trypanosoma brucei, is declining in sub-Saharan Africa. Historically, such declines are generally followed by periods of higher incidence, and one of the lingering public health challenges of HAT is that its drug development pipeline is historically sparse. As a continuation of our work on new antitrypanosomal agents, we found that partially saturated quinoline-based vinyl sulfone compounds selectively inhibit the growth of T. brucei but displayed relatively weak inhibitory activity towards T. brucei's cysteine protease rhodesain. While two nitroaromatic analogues of the quinoline-based vinyl sulfone compounds displayed potent inhibition of T. brucei and rhodesain. The quinoline derivatives and the nitroaromatic-based compounds discovered in this work can serve as leads for ADME-based optimization and pre-clinical investigations.

Keywords

Covalent inhibitors; Cysteine protease; Nitroaromatic; Rhodesain; Trypanosomes.

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