N2,N4-disubstituted quinazoline-2,4-diamines were found to display activity against Leishmania donovani and L. amazonensis. SAR studies suggested the most potent activities were obtained with quinazoline-2,4-diamine scaffolds bearing N2-benzyl-N4-alkyl/phenyl or N2-isopropyl-N4-furfuryl substituent combination. Substitution of the benzenoid ring has been identified to play a secondary role for efficacy with improved selectivity indices. Assessment of key physicochemical properties confirmed that the aqueous solubility, distribution coefficient, and passive transcellular permeability were in acceptable ranges. Subsequently, three selected lead compounds were tested in an in vivo murine visceral leishmaniasis model. While two compounds did not have activity translate from in vitro to in vivo, the third quinazoline reduced parasitemia by 37% when 15 mg/kg/day were given via the intraperitoneal route for five consecutive days. Therefore, we think that the observed potencies of frontrunner compounds in conjunction with favorable physicochemical and pharmacokinetic properties make N2,N4-disubstituted quinazoline-2,4-diamines a suitable platform for the future development of antileishmanial agents.

Development of 2,4-diaminoquinazolines with in vivo antileishmanial activity

245th National Meeting (2013)

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