Discovery of trypanocidal coumarins with dual inhibition of both the glycerol kinase and alternative oxidase of Trypanosoma brucei brucei

Abstract

African 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 trypanosomal glycerol kinase (TGK) and trypanosom alalternative 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 μM, it had no effect on cultured human cells, even at 50 μM.—Balogun, E. O., Inaoka, D. K., Shiba, T., Tsuge, C., May, B., Sato, T., Kido, Y., Nara, T., Aoki, T., Honma, T., Tanaka, A., Inoue, M., Matsuoka, S., Michels, P. A. M., Watanabe, Y.‐I., Moore, A. L., Harada, S., Kita, K. Discovery of trypanocidal coumarins with dual inhibition of both the glycerol kinase and alternative oxidase of Trypanosoma brucei brucei. FASEB J. 33, 13002–13013 (2019). http://www.fasebj.org

Biochemical Studies of Mitochondrial Malate: Quinone Oxidoreductase from Toxoplasma gondii

“…Ferulenol is a sesquiterpene prenylated coumarin isolated from Ferula communis [79] that is reported to have antibacterial [80], anti-coagulant [81][82][83], and anti-cancer [84] activities. Several targets of ferulenol have been identified so far, such as vitamin K epoxide reductase of rat [85] and bacteria [86], complex II [79,87], PfMQO [23], Eimeria tenella DHODH [88], TAO, trypanosomal glycerol kinase [34,89,90], and human DHODH [88]. In this study, we showed that ferulenol is also an inhibitor of TgMQO; however, its IC 50 was 14 times higher (0.822 ± 0.151 µM) than that of PfMQO (0.057 µM) (Figure 5a) [23].…”

In-cell structures of conserved supramolecular protein arrays at the mitochondria–cytoskeleton interface in mammalian sperm

“…To fit into our EM densities, it must either be present in In-cell structures of conserved supramolecular protein arrays at the mitochondria-cytoskeleton interface in mammalian sperm multiple copies or form a complex with other proteins. In contrast, GK has an estimated molecular weight of ∼60 kDa and is known to form S-shaped dimers (∼120 kDa) that are conserved from bacteria (60,61) to eukaryotes (62,63).…”

A Review of the Antimalarial, Antitrypanosomal, and Antileishmanial Activities of Natural Compounds Isolated From Nigerian Flora

“…PAINS and PAINS-like, despite a possible nano-or micromolar potency, lack a distinct biological mechanism, exhibit poor SAR or optimisability, and thus have very low prospects for clinical development (Baell, 2015). Thus, it is important to utilize assay techniques that will screen-out PAINS and to carry out structural studies of complexes of hits-target molecules and structure-activity optimization studies of the hits (Baell and Nissink, 2018;Balogun et al, 2019).…”