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. Epub 2021 Aug 6.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Female
  • Leishmania / drug effects
  • Leishmaniasis, Cutaneous / drug therapy*
  • Mice
  • Mice, Inbred BALB C
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Quinolines / chemical synthesis
  • Quinolines / metabolism
  • Quinolines / pharmacokinetics
  • Quinolines / therapeutic use*
  • Structure-Activity Relationship
  • Trypanocidal Agents / chemical synthesis
  • Trypanocidal Agents / metabolism
  • Trypanocidal Agents / pharmacokinetics
  • Trypanocidal Agents / therapeutic use*

Substances

  • Quinolines
  • Trypanocidal Agents