Antileishmanial activity of quinazoline derivatives: Synthesis, docking screens, molecular dynamic simulations and electrochemical studies

• Published in: European journal of medicinal chemistry 2015-03, Vol.92, p.314-331
• Main Authors: Mendoza-Martínez, Cesar, Galindo-Sevilla, Norma, Correa-Basurto, José, Ugalde-Saldivar, Victor Manuel, Rodríguez-Delgado, Rosa Georgina, Hernández-Pineda, Jessica, Padierna-Mota, Cecilia, Flores-Alamo, Marcos, Hernández-Luis, Francisco
• Format: Article
• Language: English
• Subjects: Animals; Antiprotozoal Agents - chemical synthesis; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - pharmacology; Antiprotozoan activity; Dose-Response Relationship, Drug; Electrochemical Techniques; Leishmania mexicana; Leishmania mexicana - cytology; Leishmania mexicana - drug effects; Macrophages - drug effects; Mice; Mice, Inbred BALB C; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Parasitic Sensitivity Tests; Quinazoline; Solubility; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2014.12.051

A series of quinazoline-2,4,6-triamine were synthesized and evaluated in vitro against Leishmania mexicana. Among them, N6-(ferrocenmethyl)quinazolin-2,4,6-triamine (H2) showed activity on promastigotes and intracellular amastigotes, as well as low cytotoxicity in mammalian cells. Docking and electrochemical studies showed the importance of both the ferrocene and the heterocyclic nucleus to the observed activity. H2 is readily oxidized electrochemically, indicating that the mechanism of action probably involves redox reactions. [Display omitted] •A quinazoline derivative (H2) as antileishmanial agent with low cytotoxicity was found.•H2 is active against promastigote and amastigote form of Leishmania mexicana.•H2 begins its antiparasitic action in less than 1 h, probably by oxidative mechanism.•H2 probably has a dual mechanism: oxidative stress inductor and DHFR inhibitors.