Design, synthesis and biological evaluation of quinazoline derivatives as anti-trypanosomatid and anti-plasmodial agents

César Mendoza-Martínez, José Correa-Basurto, Rocío Nieto-Meneses, Adrián Márquez-Navarro, Rocío Aguilar-Suárez, Miriam Dinora Montero-Cortes, Benjamín Nogueda-Torres, Erick Suárez-Contreras, Norma Galindo-Sevilla, Ángela Rojas-Rojas, Alejandro Rodriguez-Lezama, Francisco Hernández-Luis

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In this paper, the design, synthesis and biological evaluation of a set of quinazoline-2,4,6-triamine derivatives (1-9) as trypanocidal, antileishmanial and antiplasmodial agents are explained. The compounds were rationalized basing on docking studies of the dihydrofolate reductase (DHFR from Trypanosoma cruzi, Leishmania major and Plasmodium vivax) and pteridin reductase (PTR from T. cruzi and L. major) structures. All compounds were in vitro screened against both bloodstream trypomastigotes of T. cruzi (NINOA and INC-5 strains) and promatigotes of Leishmania mexicana (MHOM/BZ/61/M379 strain), and also for cytotoxicity using Vero cell line. Against T. cruzi, three compounds (5, 6 and 8) were the most effective showing a better activity profile than nifurtimox and benznidazole (reference drugs). Against L. mexicana, four compounds (5, 6, 8, and 9) exhibited the highest activity, even than glucantime (reference drug). In the cytotoxicity assay, protozoa were more susceptible than Vero cells. In vivo Plasmodium berghei assay (ANKA strain), the compounds 1, 5, 6 and 8 showed a more comparable activity than chloroquine and pyrimethamine (reference drugs) when they were administrated by the oral route. The antiprotozoal activity of these substances, endowed with redox properties, represented a good starting point for a medicinal chemistry program aiming for chemotherapy of Chagas' disease, leishmaniosis and malaria.

Original languageEnglish
Pages (from-to)296-307
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - 26-May-2015
Externally publishedYes


  • Administration, Oral
  • Animals
  • Antimalarials
  • Antiprotozoal Agents
  • Cercopithecus aethiops
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Design
  • Female
  • Leishmania major
  • Malaria
  • Mice
  • Mice, Inbred Strains
  • Models, Molecular
  • Molecular Structure
  • Parasitic Sensitivity Tests
  • Plasmodium vivax
  • Quinazolines
  • Structure-Activity Relationship
  • Trypanosoma cruzi
  • Vero Cells
  • Journal Article
  • Research Support, Non-U.S. Gov't

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