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

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.