2. Academic Validation
  3. Optimization of diastereomeric dihydropyridines as antimalarials

Optimization of diastereomeric dihydropyridines as antimalarials

  • Eur J Med Chem. 2024 Sep 5:275:116599. doi: 10.1016/j.ejmech.2024.116599.
Kurt S Van Horn 1,  Yingzhao Zhao 2,  Prakash T Parvatkar 2,  Julie Maier 3,  Tina Mutka 4,  Alexis Lacrue 4,  Fabian Brockmeier 2,  Daniel Ebert 5,  Wesley Wu 5,  Debora R Casandra 4,  Niranjan Namelikonda 6,  Jeanine Yacoub 6,  Martina Sigal 3,  Spencer Knapp 7,  David Floyd 7,  David Waterson 8,  Jeremy N Burrows 8,  James Duffy 8,  Joseph L DeRisi 9,  Dennis E Kyle 10,  R Kiplin Guy 11,  Roman Manetsch 12
Affiliations

Affiliations

  • 1 Department of Chemistry, University of South Florida, 4202 E. Fowler Avenue, Tampa, FL, 33620, United States; Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, MA, 02115, United States. Electronic address: [email protected].
  • 2 Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, MA, 02115, United States.
  • 3 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, United States.
  • 4 Department of Global Health, College of Public Health, University of South Florida, 3720 Spectrum Boulevard, Tampa, FL, 33612, United States.
  • 5 Department of Biochemistry and Biophysics, University of California, San Francisco, CA, 94158, United States.
  • 6 Department of Chemistry, University of South Florida, 4202 E. Fowler Avenue, Tampa, FL, 33620, United States.
  • 7 Department of Chemistry and Chemical Biology, Rutgers - The State University of New Jersey, 610 Taylor Road, Piscataway, NJ, 08854, United States.
  • 8 Medicines for Malaria Venture, 20, Route de Pré-Bois, P.O. Box 1826, 1215, Geneva, 15, Switzerland.
  • 9 Department of Biochemistry and Biophysics, University of California, San Francisco, CA, 94158, United States; Howard Hughes Medical Institute, Chevy Chase, MD, 20815, United States.
  • 10 Department of Global Health, College of Public Health, University of South Florida, 3720 Spectrum Boulevard, Tampa, FL, 33612, United States; Center for Tropical & Emerging Global Diseases, University of Georgia, Athens, GA, 30602, United States.
  • 11 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, United States; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, 40506, United States.
  • 12 Department of Chemistry, University of South Florida, 4202 E. Fowler Avenue, Tampa, FL, 33620, United States; Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, MA, 02115, United States; Department of Pharmaceutical Sciences, Northeastern University, 360 Huntington Avenue, Boston, MA, 02115, United States. Electronic address: [email protected].
PMID: 38909569 DOI: 10.1016/j.ejmech.2024.116599
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.

Keywords

Antimalarial; Cytotoxicity; Dihydropyridine; Drug resistance; Hantzsch condensation; Plasmodium.

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