Trypanocidal properties, structure–activity relationship and computational studies of quinoxaline 1,4-di-N-oxide derivatives

Abstract

Two series of pyrazol and propenone quinoxaline derivatives were tested for parasiticidal activity (against amastigotes of Leishmania peruviana and trypomastigotes of Trypanosoma cruzi) and for toxicity against proliferative and non-proliferative cells. The pyrazol series was almost inactive against1,4-dioxide inhibited 50% of Leishmania growth at 8.9 µM with no impact against proliferative kidney cells and low toxicity against Thp-1 and murine macrophages. The compounds of the propenone series were moderately active against T. cruzi. Among them, 2 compounds were particularly interesting: (2E)-1-(7-Fluoro-3-methyl-quinoxalin-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propenone, that showed a selective activity against proliferative cells (cancer and parasites), being inactive against normal murine peritoneal macrophages and (2E)-3-(3,4,5-Trimethoxy-phenyl)-1-(3,6,7-trimethyl-quinoxalin-2-yl)-propenone that was only active against Leishmania and inactive against the other tested cells.Furthermore in silico studies were performed for ADME properties and docking studies, both series of compounds respected the Lipinski's rules and show linear correlation between tripanosomaticidal activities and LogP. Docking studies revealed that compounds of the second series could interact with the poly (ADP-ribose) polymerase protein of Trypanosoma cruzi.3

A Quinoxaline Derivative as a Potent Chemotherapeutic Agent, Alone or in Combination with Benznidazole, against Trypanosoma cruzi

“…[13], [16], [17] In the present study, quinoxaline 4 exhibited strong anti- Trypanosoma cruzi activity against all of the main forms of the parasite, which was even greater than the activity against epimastigotes determined in vitro for benznidazole, the standard drug for treating Chagas’ disease. In a previous study, Estevez [18] synthesized and evaluated the anti- Trypanosoma properties of a library of 11 quinoxaline derivatives, all the compounds exhibits trypanocidal activity but none of the tested compounds presented activity higher than quinoxaline 4 .…”

“…[16]–[17] A library of new quinoxaline derivatives was recently tested against Leishmania peruviana and T. cruzi and showed interesting results. [18].…”

In Vitro and In Vivo Activities of 2,3-Diarylsubstituted Quinoxaline Derivatives against Leishmania amazonensis

“…The antileishmanial activities of the quinoxaline derivatives 4-alkapolynylpyrrolo[1,2-␣]quinoxalines (29,30) and 1,4-di-N-oxide quinoxaline (13,26,31,32) have also been reported. We recently reported the activity of 2,3-disubstituted quinoxaline derivatives against Trypanosoma cruzi and L. amazonensis (33,34).…”

Present status of quinoxaline motifs: Excellent pathfinders in therapeutic medicine

“…Recently, the search for new leishmanicidal compounds showed that quinoxaline could open the way to finding innovative anti-leishmanial drug candidates [179]. The in silico study showed that quinoxaline derivatives, 194 and 195 respected Lipinski's rules and that they confirmed a linear correlation between leishmanicidal activities and LogP [178]. Antiproliferative activities of quinoxaline N,N-dioxide derivatives 196 and 197 against Tulahuen 2 strain were reported to have percentage of growth inhibition (PGI) value of 100% [180] while tricyclic N-oxide 198 was effective at PGI value of 36% [181].…”

“…Leishmaniasis is a parasitic disease which appears in visceral, cutaneous and mucocutaneous forms affecting millions of people throughout the world [178]. Recently, the search for new leishmanicidal compounds showed that quinoxaline could open the way to finding innovative anti-leishmanial drug candidates [179].…”