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Discovery of trypanocidal coumarins with dual inhibition of both the glycerol kinase and alternative oxidase of Trypanosoma brucei brucei
journal contribution
posted on 2023-06-09, 20:20 authored by Emmanuel Oluwadare Balogun, Daniel Ken Inaoka, Tomoo Shiba, Chiaki Tsuge, Benjamin May, Tomohiro Sato, Yasutoshi Kido, Takeshi Nara, Takashi Aoki, Teruki Honma, Akiko Tanaka, Masayuki Inoue, Shigeru Matsuoka, Paul A M Michels, Yoh-Ichi Watanabe, Anthony Moore, Shigeharu Harada, Kiyoshi KitaAfrican trypanosomiasis, sleeping sickness in humans or nagana in animals, is a potentially fatal neglected tropical disease and a threat to 65 million human lives and 100 million small and large livestock animals in sub-Saharan Africa. Available treatments for this devastating disease are few and have limited efficacy, prompting the search for new drug candidates. Simultaneous inhibition of the trypanosomalglycerolkinase(TGK) andtrypanosomalalternative oxidase (TAO) is considered a validated strategy toward the development of new drugs. Our goal is to develop a TGK-specific inhibitor for coadministration with ascofuranone (AF), the most potent TAO inhibitor. Here, we report on the identification of novel compounds with inhibitory potency against TGK. Importantly, one of these compounds (compound 17) and its derivatives (17a and 17b) killed trypanosomes even in the absence of AF. Inhibition kinetics revealed that derivative 17b is a mixed-type and competitive inhibitor for TGK and TAO, respectively. Structural data revealed the molecular basis of this dual inhibitory action, which, in our opinion, will aid in the successful development of a promising drug to treat trypanosomiasis. Although the EC50 of compound 17b against trypanosome cells was 1.77 mM, it had no effect on cultured human cells, even at 50 mM.
History
Publication status
- Published
File Version
- Accepted version
Journal
FASEB JournalISSN
0892-6638Publisher
Federation of American Society of Experimental BiologyExternal DOI
Issue
11Volume
33Page range
13002-13013Department affiliated with
- Biochemistry Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2020-01-23First Compliant Deposit (FCD) Date
2020-01-24Usage metrics
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