title: Antileishmanial activity of a series of N²,N⁴-disubstituted quinazoline-2,4-diamines.
abstract: 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.
authors.affiliation: Department of Chemistry, University of South Florida , 4202 East Fowler Avenue, CHE 205, Tampa, Florida 33620, United States.
authors.forename: Kurt S
authors.initials: KS
authors.lastname: Van Horn
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Zhu
authors.forename: Trupti
authors.initials: T
authors.lastname: Pandharkar
authors.forename: Sihyung
authors.initials: S
authors.lastname: Yang
authors.forename: Brian
authors.initials: B
authors.lastname: Vesely
authors.forename: Manu
authors.initials: M
authors.lastname: Vanaerschot
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Dujardin
authors.forename: Suman
authors.initials: S
authors.lastname: Rijal
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Kyle
authors.forename: Michael Zhuo
authors.initials: MZ
authors.lastname: Wang
authors.forename: Karl A
authors.initials: KA
authors.lastname: Werbovetz
authors.forename: Roman
authors.initials: R
authors.lastname: Manetsch
mesh_terms: D000818:Animals; D000965:Antimony / Q000494:pharmacology; D002460:Cell Line; D003959:Diamines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D004351:Drug Resistance; D007891:Leishmania / Q000187:drug effects*; D007893:Leishmania donovani / Q000187:drug effects / Q000302:isolation & purification; D007894:Leishmania mexicana / Q000187:drug effects; D007898:Leishmaniasis, Visceral / Q000188:drug therapy; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology; D008297:Male; D008807:Mice, Inbred BALB C; D011799:Quinazolines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D003959:Diamines; D011799:Quinazolines; D014344:Trypanocidal Agents; D000965:Antimony