TY - JOUR
T1 - Amino-Substituted 3-Aryl- And 3-Heteroarylquinolines as Potential Antileishmanial Agents
AU - Hammill, Jared T.
AU - Sviripa, Vitaliy M.
AU - Kril, Liliia M.
AU - Ortiz, Diana
AU - Fargo, Corinne M.
AU - Kim, Ho Shin
AU - Chen, Yizhe
AU - Rector, Jonah
AU - Rice, Amy L.
AU - Domagalska, Malgorzata A.
AU - Begley, Kristin L.
AU - Liu, Chunming
AU - Rangnekar, Vivek M.
AU - Dujardin, Jean Claude
AU - Watt, David S.
AU - Landfear, Scott M.
AU - Guy, R. Kiplin
N1 - Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society.
PY - 2021/8/26
Y1 - 2021/8/26
N2 - 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.
AB - 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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U2 - 10.1021/acs.jmedchem.1c00813
DO - 10.1021/acs.jmedchem.1c00813
M3 - Article
C2 - 34355566
AN - SCOPUS:85113826716
SN - 0022-2623
VL - 64
SP - 12152
EP - 12162
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 16
ER -