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

Leishmaniasis, a disease caused by protozoa of the 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, th...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2021-08, Vol.64 (16), p.12152-12162
Main Authors: Hammill, Jared T, Sviripa, Vitaliy M, Kril, Liliia M, Ortiz, Diana, Fargo, Corinne M, Kim, Ho Shin, Chen, Yizhe, Rector, Jonah, Rice, Amy L, Domagalska, Malgorzata A, Begley, Kristin L, Liu, Chunming, Rangnekar, Vivek M, Dujardin, Jean-Claude, Watt, David S, Landfear, Scott M, Guy, R Kiplin
Format: Article
Language:English
Subjects:
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
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Summary:Leishmaniasis, a disease caused by protozoa of the 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 parasites with good selectivity relative to the host macrophages. Early lead was rapidly acting and possessed good potency against (EC = 120 nM), 30-fold selectivity for the parasite relative to the macrophage (EC = 3.7 μM), and also blocked proliferation of parasites resistant to antimonial drugs. Finally, another early lead, , 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.1c00813