2. Academic Validation
  3. Discovery of an orally active nitrothiophene-based antitrypanosomal agent

Discovery of an orally active nitrothiophene-based antitrypanosomal agent

  • Eur J Med Chem. 2024 Jan 5:263:115954. doi: 10.1016/j.ejmech.2023.115954.
Oluwatomi Ajayi 1,  Damilohun S Metibemu 2,  Olamide Crown 2,  Olawale S Adeyinka 2,  Marcel Kaiser 3,  Nathalie Shoji 4,  Mariana Silva 5,  Ana Rodriguez 4,  Ifedayo Victor Ogungbe 6
Affiliations

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 Chemistry, The University of Alabama in Huntsville, Huntsville, AL, 35899, USA.
  • 3 Swiss Tropical and Public Health Institute, Kreuzstrasse 2, 4123, Allschwil, Switzerland; University of Basel, 4001, Basel, Switzerland.
  • 4 Department of Microbiology, New York University Grossman School of Medicine, New York, NY, 10010, USA.
  • 5 University of Basel, 4001, Basel, Switzerland.
  • 6 Department of Chemistry, Physics, and Atmospheric Sciences, Jackson State University, Jackson, MS, 39217, USA; Department of Chemistry, The University of Alabama in Huntsville, Huntsville, AL, 35899, USA. Electronic address: [email protected].
PMID: 37984297 DOI: 10.1016/j.ejmech.2023.115954
Abstract

Human African Trypanosomiasis (HAT), caused by Trypanosoma brucei gambiense and rhodesiense, is a parasitic disease endemic to sub-Saharan Africa. Untreated cases of HAT can be severely debilitating and fatal. Although the number of reported cases has decreased progressively over the last decade, the number of effective and easily administered medications is very limited. In this work, we report the antitrypanosomal activity of a series of potent compounds. A subset of molecules in the series are highly selective for trypanosomes and are metabolically stable. One of the compounds, (E)-N-(4-(methylamino)-4-oxobut-2-en-1-yl)-5-nitrothiophene-2-carboxamide (10), selectively inhibited the growth of T. b. brucei, T. b. gambiense and T. b. rhodesiense, have excellent oral bioavailability and was effective in treating acute Infection of HAT in mouse models. Based on its excellent bioavailability, compound 10 and its analogs are candidates for lead optimization and pre-clinical investigations.

Keywords

Cysteine protease; HAT; Inhibitors; Trypanosomes; Vinyl sulfone.

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