2. Academic Validation
  3. Amino-Substituted 3-Aryl- and 3-Heteroarylquinolines as Potential Antileishmanial Agents

Amino-Substituted 3-Aryl- and 3-Heteroarylquinolines as Potential Antileishmanial Agents

  • J Med Chem. 2021 Aug 26;64(16):12152-12162. doi: 10.1021/acs.jmedchem.1c00813.
Jared T Hammill 1,  Vitaliy M Sviripa 1 2 3,  Liliia M Kril 2 4,  Diana Ortiz 5,  Corinne M Fargo 5,  Ho Shin Kim 1,  Yizhe Chen 1,  Jonah Rector 1,  Amy L Rice 1,  Malgorzata A Domagalska 6,  Kristin L Begley 2 4,  Chunming Liu 3 4,  Vivek M Rangnekar 3 7 8,  Jean-Claude Dujardin 6,  David S Watt 1 2 3 4,  Scott M Landfear 5,  R Kiplin Guy 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536-0509 United States.
  • 2 Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536-0596, United States.
  • 3 Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536-0093, United States.
  • 4 Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0509, United States.
  • 5 Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon 97239, United States.
  • 6 Department of Biomedical Sciences, Institute of Tropical Medicine, Nationalestraat, 155, Antwerpen 2000, Belgium.
  • 7 Department of Radiation Medicine, College of Medicine, University of Kentucky, Lexington, Kentucky 40506-9983, United States.
  • 8 Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0305, United States.
PMID: 34355566 DOI: 10.1021/acs.jmedchem.1c00813
Abstract

Leishmaniasis, a disease caused by protozoa of the Leishmania species, afflicts roughly 12 million individuals worldwide. Most existing drugs for leishmaniasis are toxic, expensive, difficult to administer, and subject to drug resistance. We report a new class of antileishmanial leads, the 3-arylquinolines, that potently block proliferation of the intramacrophage amastigote form of Leishmania parasites with good selectivity relative to the host macrophages. Early lead 34 was rapidly acting and possessed good potency against L. mexicana (EC50 = 120 nM), 30-fold selectivity for the Parasite relative to the macrophage (EC50 = 3.7 μM), and also blocked proliferation of Leishmania donovani parasites resistant to antimonial drugs. Finally, another early lead, 27, which exhibited reasonable in vivo tolerability, impaired disease progression during the dosing period in a murine model of cutaneous leishmaniasis. These results suggest that the arylquinolines provide a fruitful departure point for the development of new antileishmanial drugs.

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