1. Optimization of diastereomeric dihydropyridines as antimalarials.
- Author
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Van Horn KS, Zhao Y, Parvatkar PT, Maier J, Mutka T, Lacrue A, Brockmeier F, Ebert D, Wu W, Casandra DR, Namelikonda N, Yacoub J, Sigal M, Knapp S, Floyd D, Waterson D, Burrows JN, Duffy J, DeRisi JL, Kyle DE, Guy RK, and Manetsch R
- Subjects
- Structure-Activity Relationship, Animals, Mice, Stereoisomerism, Parasitic Sensitivity Tests, Molecular Structure, Dose-Response Relationship, Drug, Humans, Antimalarials pharmacology, Antimalarials chemistry, Antimalarials chemical synthesis, Dihydropyridines pharmacology, Dihydropyridines chemistry, Dihydropyridines chemical synthesis, Plasmodium falciparum drug effects
- Abstract
The increase in research funding for the development of antimalarials since 2000 has led to a surge of new chemotypes with potent antimalarial activity. High-throughput screens have delivered several thousand new active compounds in several hundred series, including the 4,7-diphenyl-1,4,5,6,7,8-hexahydroquinolines, hereafter termed dihydropyridines (DHPs). We optimized the DHPs for antimalarial activity. Structure-activity relationship studies focusing on the 2-, 3-, 4-, 6-, and 7-positions of the DHP core led to the identification of compounds potent (EC
50 < 10 nM) against all strains of P. falciparum tested, including the drug-resistant parasite strains K1, W2, and TM90-C2B. Evaluation of efficacy of several compounds in vivo identified two compounds that reduced parasitemia by >75 % in mice 6 days post-exposure following a single 50 mg/kg oral dose. Resistance acquisition experiments with a selected dihydropyridine led to the identification of a single mutation conveying resistance in the gene encoding for Plasmodium falciparum multi-drug resistance protein 1 (PfMDR1). The same dihydropyridine possessed transmission blocking activity. The DHPs have the potential for the development of novel antimalarial drug candidates., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Masson SAS.)- Published
- 2024
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