Synthesis of urea and thiourea derivatives of C20-epi-aminosalinomycin and their activity against Trypanosoma brucei

Antoszczak, Michał, Gadsby-Davis, Kieran, Steverding, Dietmar and Huczyński, Adam (2023) Synthesis of urea and thiourea derivatives of C20-epi-aminosalinomycin and their activity against Trypanosoma brucei. European Journal of Medicinal Chemistry, 250. ISSN 0223-5234

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Salinomycin (SAL) is a natural polyether ionophore that exhibits a very broad spectrum of biological effects, ranging from anticancer to antiparasitic activities. Our recent studies have shown that the chemical modification of the SAL biomolecule is a fruitful strategy for generating lead compounds for the development of novel antitrypanosomal agents. As a continuation of our program to develop trypanocidal active lead structures, we synthesized a series of 14 novel urea and thiourea analogs of C20-epi-aminosalinomycin (compound 2b). The trypanocidal and cytotoxic activities of the derivatives were assessed with the mammalian life cycle stage of Trypanosoma brucei and human leukemic HL-60 cells, respectively. The most antitrypanosomal compounds were the two thiourea derivatives 4b (C20-n-butylthiourea) and 4d (C20-phenylthiourea) with 50% growth inhibition (GI50) values of 0.18 and 0.22 μM and selectivity indices of 47 and 41, respectively. As potent SAL derivatives have been shown to induce strong cell swelling in bloodstream forms of T. brucei, the effect of compounds 4b and 4d to increase the cell volume of the parasite was also investigated. Interestingly, both derivatives were capable to induce faster cell swelling in bloodstream-form trypanosomes than the reference compound SAL. These findings support the suggestion that C20-epi-aminosalinomycin derivatives are suitable leads in the rational development of new and improved trypanocidal drugs.

Item Type: Article
Additional Information: Acknowledgments: M.A. wishes to acknowledge the Polish Ministry of Science and Higher Education (MNiSW) for the scholarship for outstanding young scientists in the years 2020–2023 (STYP/15/1665/E-336/2020). Data availability: Data will be made available on request.
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology
Depositing User: LivePure Connector
Date Deposited: 02 Mar 2023 09:33
Last Modified: 29 Jan 2024 03:25
DOI: 10.1016/j.ejmech.2023.115241

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