We sought to identify a potent and selective antitrypanosomal agent through modulation of the mechanism of action of a 2-arylquinazoline scaffold as an antitrypanosomal agent via chemical functionalization at the 4-position. We wished to use the: (i) susceptibility of trypanosomatids towards nitric oxide (NO) and reactive oxygen species (ROS); (ii) capacity of the 4-substituted quinazoline system to act as an antifolate agent. Three quinazolin-based moieties that differed from each other by having at the 4-position key pharmacophores targeting the induction of NO and ROS production were evaluated in vitro against Leishmania infantum and Trypanosoma cruzi parasites and their modes of action were explored. Replacement of an oxygen moiety at the 4-position of the antifolate 2-arylquinazolin-4(3H)one by hydrazinyl and 5-nitrofuryl-hydrazinyl pharmacophores enhanced antitrypanosomatid activity significantly due to promotion of an additional mechanism beyond the antifolate response such as NO or ROS production, respectively. Among the three types of chemical functionalization, the 5-nitrofuryl-hydrazinyl moiety generated the most potent compounds. Compound 3b was a potential candidate thanks to its sub-micromolar response against the promastigotes/amastigotes of L. infantum and epimastigote of T. cruzi, moderate toxicity on macrophages (J774.1), good selectivity index (∼15.1-17.6) and, importantly, non-mutagenic effects. 2-Arylquinazoline could be an attractive platform to design new anti-trypanosomatid agents with the use of key pharmacophores.
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