Uncovering the Unusual Inhibition Mechanism of a Trypanosome Alternative Oxidase Inhibitor Displaying Broad-Spectrum Activity against African Animal Trypanosomes

  • J Med Chem. 2025 Jun 4. doi: 10.1021/acs.jmedchem.5c00631.
Godwin U Ebiloma  1  2 ,  Emmanuel O Balogun  3  4  5 ,  Natsumi Arai  2 ,  Momoka Otani  2 ,  Cecilia Baldassarri  6 ,  Amani Alhejely  7 ,  Eduardo Cueto-Díaz  8 ,  Harry P De Koning  9 ,  Christophe Dardonville  8 ,  Tomoo Shiba  2
Affiliations
  • 1. School of Science, Engineering & Environment, University of Salford, Manchester M5 4NT, United Kingdom.
  • 2. Graduate School of Science and Technology, Department of Applied Biology, Kyoto Institute of Technology, Kyoto 606-8585, Japan.
  • 3. Department of Biochemistry, Ahmadu Bello University, Zaria 2222, Nigeria.
  • 4. Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
  • 5. Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.
  • 6. Medicinal Chemistry Unit, School of Pharmacy, Chemistry Interdisciplinary Project (ChIP), University of Camerino, Via Madonna delle Carceri, 62032 Camerino, Italy.
  • 7. Biology Department, Darb University College, Jazan University, Jazan 82817-2820, Saudi Arabia.
  • 8. Instituto de Química Médica, IQM-CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain.
  • 9. School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G43 2DX, United Kingdom.
PMID: 40464345 DOI: 10.1021/acs.jmedchem.5c00631
Abstract

The glucose-dependent respiration of bloodstream forms of the Parasite Trypanosoma brucei depends on an unusual and essential mitochondrial electron-transport system, consisting of glycerol-3-phosphate dehydrogenase and the trypanosome alternative oxidase (TAO). We report here the discovery of an allosteric inhibitor of TAO that displays highly potent activity (EC50 values in the range 1-20 nM) against the important veterinary pathogens T. b. brucei, Trypanosoma evansi, Trypanosoma equiperdum, and Trypanosoma congolense, i.e., >5-fold greater potency than the standard drugs. The methylene-linked 2-methyl-4-hydroxybenzoate 2-pyridinyldiphenylphosphonium derivative (1) was the best inhibitor of recombinant TAO (IC50 = 1.3 nM) via a noncompetitive/allosteric mechanism (Ki = 3.46 nM). Remarkably, X-ray crystallography showed that 1 was bound to a site of TAO ∼25 Å from the catalytic pocket. Although 1 demonstrated good safety toward mammalian cells in vitro (selectivity index >2300), it did not fully clear parasitemia in experimental Animals, attributable to a high hepatic clearance.

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