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

Abstract

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.

Novel quinoxaline 1,4-di-N-oxide derivatives as new potential antichagasic agents

“…A similar explanation could be given for the rationale involved in the replacement of the ketone at C-2 [27] of quinoxaline ring by a methyl or an ethyl ester. The ester derivatives improve the biological activity of the corresponding ketone in every case with the exception of when the substituents in C-3, C-6 and C-7 are CF 3 , F and F respectively.…”

“…[18,27,32] However, the mechanism of action through which these derivatives carry out their activity is unclear. In previous studies, an inhibition of mitochondrial dehydrogenases was demonstrated and it was also observed that benzofuroxan derivatives containing N-oxide cause a mitochondrial membrane depolarization in T. cruzi.…”

“…In previous studies, an inhibition of mitochondrial dehydrogenases was demonstrated and it was also observed that benzofuroxan derivatives containing N-oxide cause a mitochondrial membrane depolarization in T. cruzi. [27,33,34] In order to shed some light on this subject, a study was conducted which involved the measuring of the reduction potentials of the N-oxide groups in different synthesized derivatives and selected analogues. This experiment allowed us to conduct a study regarding the relationship between structure, N-oxides potential reduction and anti-T. cruzi activity.…”

“…This Table 5 shows the in vitro activity results of 19 quinoxaline 1,4-di-N-oxide derivatives, previously evaluated by our research group [27]. With respect to position C-3 of the quinoxaline ring, the introduction of the trifluoromethyl group is decisive in the in vitro biological activity shown by the derivatives with with-drawing substituents in C-6 and C-7; this is clearly observed upon comparing the activity of the new derivatives with the activity shown by the analogs with a methyl group or phenyl group in C-3 (A,L vs 13, E vs 1, D vs 4, O vs 11 and N vs 12, Tables 2 and 5).…”

“…[16][17][18][19][20][21][22][23][24][25][26] The evaluation of several libraries of compounds led us to find a series with high in vitro activity against T. cruzi. [27] This finding allowed us to establish structural features for maintaining high in vitro activity against the parasite (Scheme 1).…”