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

Jared T. Hammill, Vitaliy M. Sviripa, Liliia M. Kril, Diana Ortiz, Corinne M. Fargo, Ho Shin Kim, Yizhe Chen, Jonah Rector, Amy L. Rice, Malgorzata A. Domagalska, Kristin L. Begley, Chunming Liu, Vivek M. Rangnekar, Jean Claude Dujardin, David S. Watt, Scott M. Landfear, R. Kiplin Guy

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)12152-12162
Number of pages11
JournalJournal of Medicinal Chemistry
Volume64
Issue number16
DOIs
StatePublished - Aug 26 2021

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint

Dive into the research topics of 'Amino-Substituted 3-Aryl- And 3-Heteroarylquinolines as Potential Antileishmanial Agents'. Together they form a unique fingerprint.

Cite this