Optimization of diastereomeric dihydropyridines as antimalarials

Kurt S. Van Horn, Yingzhao Zhao, Prakash T. Parvatkar, Julie Maier, Tina Mutka, Alexis Lacrue, Fabian Brockmeier, Daniel Ebert, Wesley Wu, Debora R. Casandra, Niranjan Namelikonda, Jeanine Yacoub, Martina Sigal, Spencer Knapp, David Floyd, David Waterson, Jeremy N. Burrows, James Duffy, Joseph L. DeRisi, Dennis E. KyleR. Kiplin Guy, Roman Manetsch

Research output: Contribution to journalArticlepeer-review

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 (EC50 < 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.

Original languageEnglish
Article number116599
JournalEuropean Journal of Medicinal Chemistry
Volume275
DOIs
StatePublished - Sep 5 2024

Bibliographical note

Publisher Copyright:
© 2024

Keywords

  • Antimalarial
  • Cytotoxicity
  • Dihydropyridine
  • Drug resistance
  • Hantzsch condensation
  • Plasmodium

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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