A longer-chain acylated derivative of Dictyostelium differentiation-inducing factor-1 enhances the antimalarial activity against Plasmodium parasites.

Autor: Yoshida N; Department of Tropical Medicine and Parasitology, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan., Kikuchi H; Division of Natural Medicines, Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan., Hirai M; Department of Tropical Medicine and Parasitology, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan., Balikagala B; Department of Tropical Medicine and Parasitology, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan., Anywar DA; Faculty of Medicine, Gulu University, P.O. Box 166, Gulu, Uganda., Taka H; Laboratory of Proteomics and Biomolecular Science, Biomedical Research Core Facilities, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan., Kaga N; Laboratory of Proteomics and Biomolecular Science, Biomedical Research Core Facilities, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan., Miura Y; Laboratory of Proteomics and Biomolecular Science, Biomedical Research Core Facilities, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan., Fukuda N; Department of Tropical Medicine and Parasitology, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan., Odongo-Aginya EI; Faculty of Medicine, Gulu University, P.O. Box 166, Gulu, Uganda., Kubohara Y; Laboratory of Health and Life Science, Graduate School of Health and Sports Science, Juntendo University, Inzai, Chiba 270-1695, Japan. Electronic address: ykuboha@juntendo.ac.jp., Mita T; Department of Tropical Medicine and Parasitology, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Electronic address: tmita@juntendo.ac.jp.
Jazyk: angličtina
Zdroj: Biochemical pharmacology [Biochem Pharmacol] 2024 Jul; Vol. 225, pp. 116243. Date of Electronic Publication: 2024 Apr 30.
DOI: 10.1016/j.bcp.2024.116243
Abstrakt: The spread of malarial parasites resistant to first-line treatments such as artemisinin combination therapies is a global health concern. Differentiation-inducing factor 1 (DIF-1) is a chlorinated alkylphenone (1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl) hexan-1-one) originally found in the cellular slime mould Dictyostelium discoideum. We previously showed that some derivatives of DIF-1, particularly DIF-1(+2) (1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl) octan-1-one), exert potent antimalarial activities. In this study, we synthesised DIF-1(+3) (1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl) nonan-1-one). We then evaluated the effects of DIF-1(+3) in vitro on Plasmodium falciparum and in vivo over 7 days (50-100 mg/kg/day) in a mouse model of Plasmodium berghei. DIF-1(+3) exhibited a half-maximal inhibitory concentration of approximately 20-30 % of DIF-1(+2) in three laboratory strains with a selectivity index > 263, including in strains resistant to chloroquine and artemisinin. Parasite growth and multiplication were almost completely suppressed by treatment with 100 mg/kg DIF-1(+3). The survival time of infected mice was significantly increased (P = 0.006) with no apparent adverse effects. In summary, addition of an acyl group to DIF-1(+2) to prepare DIF-1(+3) substantially enhanced antimalarial activity, even in drug-resistant malaria, indicating the potential of applying DIF-1(+3) for malaria treatment.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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