1,2,5-Oxadiazole N-Oxide Derivatives and Related Compounds as Potential Antitrypanosomal Drugs:  Structure−Activity Relationships

Abstract

The syntheses of a new series of derivatives of 1,2,5-oxadiazole N-oxide, benzo[1,2-c]1,2,5-oxadiazole N-oxide, and quinoxaline di-N-oxide are described. In vitro antitrypanosomal activity of these compounds was tested against epimastigote forms of Trypanosoma cruzi. For the most effective drugs, derivatives IIIe and IIIf, the 50% inhibitory dose (ID50) was determined as well as their cytotoxicity against mammalian fibroblasts. Electrochemical studies and ESR spectroscopy show that the highest activities observed are associated with the facile monoelectronation of the N-oxide moiety. Lipophilic-hydrophilic balance of the compounds could also play an important role in their effectiveness as antichagasic drugs.

Electrochemical Reduction Using Glassy Carbon Electrode in Aqueous Medium of a Potential Anti-Chagas Drug: NFOH

“…Some new nitroheterocyclic compounds have been proposed as candidate drugs for Chagas' disease chemotherapy, [3][4][5][6] some of which have a trypanocidal action due to their ability to be reduced by flavoproteins generating the nitro radical anion or forming the superoxide and hydrogen peroxide. Consequently, the electron transfer from the radical to the molecular oxygen causes direct or indirect cellular damage, the former by reaction with various biological macromolecules and the latter by generation of the highly reactive hydroxyl radical.…”

“…Consequently, the electron transfer from the radical to the molecular oxygen causes direct or indirect cellular damage, the former by reaction with various biological macromolecules and the latter by generation of the highly reactive hydroxyl radical. 3,4 The biological action of nitrofurazone ͑NF͒ has been reported on T. cruzi through trypanothione reductase inhibition, an enzyme found in the parasite rather than in the host. 5,7 It is generally accepted that the nitro radical anion and hydroxylamine derivative are the main species responsible for some nitroheterocyclic compounds' cytotoxic action.…”

Synthesis, biological evaluation and bioavailability prediction of novel furoxan derivatives as leishmanicidal compounds

“…The compounds 1, 2a, 2b, 5, 6, 10 and 13 were synthesized according to a previously described methodology [4][5][6][7][8][9]. of aminoguanidine hydrochloride (45mg; 0,4mmol) and 3mL of ethanol was stirred at room temperature for 2 to 3h and monitored by TLC (100% ethyl acetate).…”

Quimioterapia da doença de Chagas: estado da arte e perspectivas no desenvolvimento de novos fármacos

“…O processo de planejamento tinha como objetivo a geração de compostos mais seletivos frente ao parasita, explorando as qualidades biorredutíveis superiores do grupo N-óxido em relação àquelas dos fármacos 3 e 4 (Figura 1). 67 Com base nisso foi planejada uma nova série de derivados N-óxido-benzimidazóis não tautomerizáveis e a atividade in vitro foi determinada contra a forma epimastigota de T. cruzi. 70 Com o intuito de aumentar a diversidade química e melhorar algumas propriedades físico-químicas desta classe de compostos, as estratégias de ciclização de o-nitro-anilinas e de reação de derivados de benzofuroxanos com 2-bromoacetato, iodeto de pentila e nitroalcanos foram empregadas com sucesso.…”