Antileishmanial activity of a series of N²,N⁴-disubstituted quinazoline-2,4-diamines

Kurt S Van Horn, Xiaohua Zhu, Trupti Pandharkar, Sihyung Yang, Brian Vesely, Manu Vanaerschot, Jean-Claude Dujardin, Suman Rijal, Dennis E Kyle, Michael Zhuo Wang, Karl A Werbovetz, Roman Manetsch

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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.

Original languageEnglish
JournalJ Med Chem
Issue number12
Pages (from-to)5141-56
Number of pages16
Publication statusPublished - 2014


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