Biological activity of esters of quinoxaline-7-carboxylate 1,4-di-N-oxide against E. histolytica and their analysis as potential thioredoxin reductase inhibitors

SOTO-SÁNCHEZ, JACQUELINE; MARCHAT, LAURENCE A.; ARIAS, DIEGO G.; CARO-GÓMEZ, LUIS A.; RIVERA, GILDARDO; RAMÍREZ MORENO, ESTHER; PAZ-GONZÁLEZ, ALMA D.; MOO-PUC, ROSA

PARASITOLOGY RESEARCH

SPRINGER

Lugar: Berlin; Año: 2020 vol. 119 p. 695 - 711

0932-0113

Amoebiasis is caused by the protozoan Entamoeba histolytica thataffects millions of people, throughout the world. The standard treatment ismetronidazole, however, this drug causes several side effects, and is alsomutagenic and carcinogenic. Therefore, the search for therapeutic alternativesis necessary. Quinoxaline 1,4-di-N-oxides (QdNOs) derivatives have beenshown to exhibit activity against different protozoan. In the present study,was evaluated the effects of esters of quinoxaline-7-carboxylate 1,4-di-N-oxide(7-carboxylate QdNOs) derivatives on E. histolytica proliferation,morphology, ultrastructure and oxidative stress, also their potential as E.histolytica thioredoxin reductase (EhTrxR) inhibitors was analyzed. Invitro tests showed that 12 compounds from n-propyl and isopropyl series,were more active (IC50= 0.331 to 3.56 μM) than metronidazole (IC50=4.5 μM). Thecompounds with better biological activity have a bulky, trifluoromethyl andisopropyl group at R1-, R2- and R3-position, respectively. The main alterationsfound in trophozoites treated with some of these compounds included changes inchromatin, cell granularity, redistribution of vacuoles with cellular debrisand an increase in reactive oxygen species. Interestingly, docking studies suggestedthat 7-carboxylate QdNOs derivatives could interact with amino acid residues ofthe NADPH-binding domain and/or the redox-active site of EhTrxR. Enzymatic assaysdemonstrated that selected 7-carboxylate QdNOs inhibits EhTrxR disulfide reductaseactivity, and diaphorase activity shows that these compounds could act as electronacceptor substrates for the enzyme. Taken together, these data indicate that amongthe mechanisms involved in the antiamoebic effect of the 7-carboxylate QdNOs derivativesstudied, is the induction of oxidative stress and the inhibition of EhTrxR activity.