3-Trifluoromethylquinoxaline N,N′-Dioxides as Anti-Trypanosomatid Agents. Identification of Optimal Anti-T. cruzi Agents and Mechanism of Action Studies

• Published in: Journal of medicinal chemistry Vol. 54; no. 10; pp. 3624 - 3636
• Main Authors: Benitez, Diego, Cabrera, Mauricio, Hernández, Paola, Boiani, Lucía, Lavaggi, María L, Di Maio, Rossanna, Yaluff, Gloria, Serna, Elva, Torres, Susana, Ferreira, María E, Vera de Bilbao, Ninfa, Torres, Enrique, Pérez-Silanes, Silvia, Solano, Beatriz, Moreno, Elsa, Aldana, Ignacio, López de Ceráin, Adela, Cerecetto, Hugo, González, Mercedes, Monge, Antonio
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.05.2011; Amer Chemical Soc
• Subjects: Animals; Chemistry, Medicinal; Chemistry, Pharmaceutical - methods; Cyclic N-Oxides - chemistry; Drug Design; Electrons; Humans; Inhibitory Concentration 50; Life Sciences & Biomedicine; Mice; Models, Chemical; Mutagenicity Tests; Parasitemia - drug therapy; Pharmacology & Pharmacy; Quinoxalines - chemical synthesis; Quinoxalines - chemistry; Quinoxalines - pharmacology; Science & Technology; Toxicity Tests; Trypanocidal Agents - pharmacology; Trypanosoma cruzi - metabolism; MYCOBACTERIUM-TUBERCULOSIS; ANTIMYCOBACTERIAL ACTIVITY; H-1-NMR; STRAINS; POTENTIAL ANTITRYPANOSOMAL DRUGS; GROWTH; BIOLOGICAL EVALUATION; INHIBITORS; N-OXIDE DERIVATIVES; 1,4-DI-N-OXIDE DERIVATIVES
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm2002469

For a fourth approach of quinoxaline N,N′-dioxides as anti-trypanosomatid agents against T. cruzi and Leishmania, we found extremely active derivatives. The present study allows us to state the correct requirements for obtaining optimal in vitro anti-T. cruzi activity. Derivatives possessing electron-withdrawing substituents in the 2-, 3-, 6-, and 7-positions were the most active compounds. With regard to these features and taking into account their mammal cytotoxicity, some trifluoromethylquinoxaline N,N′-dioxides have been proposed as candidates for further clinical studies. Consequently, mutagenicity and in vivo analyses were performed with the most promising derivatives. In addition, with regard to the mechanism of action studies, it was demonstrated that mitochondrial dehydrogenases are involved in the anti-T. cruzi activity of the most active derivatives.