Open AccessAntileishmanial Activity of a Series of N2,N4-Disubstituted Quinazoline-2,4-diamines
Author(s) -
Kurt S. Van Horn,
Xiaohua Zhu,
Trupti Pandharkar,
Sihyung Yang,
Brian A. Vesely,
Manu Vanaerschot,
JeanClaude Dujardin,
Suman Rijal,
Dennis E. Kyle,
Michael Zhuo Wang,
Karl A. Werbovetz,
Roman Manetsch
Publication year - 2014
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/jm5000408
Subject(s) - quinazoline , chemistry , amastigote , leishmania donovani , diamine , combinatorial chemistry , structure–activity relationship , stereochemistry , in vitro , visceral leishmaniasis , leishmaniasis , leishmania , biochemistry , organic chemistry , immunology , parasite hosting , world wide web , biology , computer science
A series of N(2),N(4)-disubstituted quinazoline-2,4-diamines has been synthesized and tested against Leishmania donovani and L. amazonensis intracellular amastigotes. A structure-activity and structure-property relationship study was conducted in part using the Topliss operational scheme to identify new lead compounds. This study led to the identification of quinazolines with EC50 values in the single digit micromolar or high nanomolar range in addition to favorable physicochemical properties. Quinazoline 23 also displayed efficacy in a murine model of visceral leishmaniasis, reducing liver parasitemia by 37% when given by the intraperitoneal route at 15 mg kg(-1) day(-1) for 5 consecutive days. Their antileishmanial efficacy, ease of synthesis, and favorable physicochemical properties make the N(2),N(4)-disubstituted quinazoline-2,4-diamine compound series a suitable platform for future development of antileishmanial agents.