SAR refinement of antileishmanial N(2),N(4)-disubstituted quinazoline-2,4-diamines

Bioorganic & Medicinal Chemistry
Xiaohua ZhuKarl A Werbovetz

Abstract

Visceral leishmaniasis is a neglected parasitic disease that has a high fatality rate in the absence of treatment. New drugs that are inexpensive, orally active, and effective could be useful tools in the fight against this disease. We previously showed that N(2),N(4)-disubstituted quinazoline-2,4-diamines displayed low- to sub-micromolar potency against intracellular Leishmania, and lead compound N(4)-(furan-2-ylmethyl)-N(2)-isopropyl-7-methylquinazoline-2,4-diamine (4) exhibited modest efficacy in an acute murine model of visceral leishmaniasis. In the present work, thirty-one N(2),N(4)-disubstituted quinazoline-2,4-diamines that had not previously been examined for their antileishmanial activity were evaluated for their potency and selectivity against Leishmania donovani, the causative parasite of visceral leishmaniasis. Quinazoline-2,4-diamines with aromatic substituents at both N(2) and N(4) exhibited potent in vitro antileishmanial activity but relatively low selectivity, while compounds substituted with small alkyl groups at either N(2) or N(4) generally showed lower antileishmanial potency but were less toxic to a murine macrophage cell line. Based on their in vitro antileishmanial potency, N(4)-benzyl-N(2)-(4-chloroben...Continue Reading

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Nov 21, 2014·Expert Opinion on Investigational Drugs·Shyam Sundar, Jaya Chakravarty
Dec 1, 2014·The Lancet Global Health·Greg MatlashewskiPiero Olliaro

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Citations

Nov 17, 2015·Journal of Medicinal Chemistry·Charles E MowbrayLouis J Maes
Apr 7, 2016·Bioorganic & Medicinal Chemistry Letters·Xiaohua ZhuKarl A Werbovetz
Oct 25, 2017·Antimicrobial Agents and Chemotherapy·April C JoiceKarl A Werbovetz
Dec 30, 2017·PLoS Neglected Tropical Diseases·Diana OrtizScott M Landfear
Mar 15, 2019·Anti-cancer Agents in Medicinal Chemistry·Ebrahim S MoghadamMohsen Amini
Feb 5, 2021·ACS Infectious Diseases·Ahmed AbdelhameedKarl A Werbovetz
Sep 1, 2021·Journal of Medicinal Chemistry·Elany Barbosa da SilvaRafaela S Ferreira

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