Rational design of nitrofuran derivatives: synthesis optimization, and valuation as inhibitors of Trypanosoma cruzi trypanothione reductase

HERRERA FE; FORASTIERI PS; PRIETO C; ARIAS DG; GUERRERO SA; RODRIGUES DE; GARAY AS; BURGÜI MDLM; LUNA LE; CRAVERO RM; IGLESIAS AA

Santa Fe

Congreso; XXVIII Reunión Anual de la Sociedad Argentina de Protozoología (SAP); 2016

The rational design and synthesis of a series of 5-nitro-2-furoic acid analogues are presented. The trypanocidal activity against epimastigote forms of Trypanosoma cruzi and the toxic effects on human HeLa cells were tested. Between all synthetic compounds, three of thirteen had an IC50 value in the range of Nfx, but compound 13 exhibited an improved effect with an IC50 of 1.0 ± 0.1 uM and a selective index of 70 in its toxicity against HeLa cells.We analyzed the activity of compounds 8, 12 and 13 to interfere in the central redox metabolic pathway in trypanosomatids, which is dependent of reduced trypanothione asthe major pivotal thiol. The three compounds behaved as better inhibitors of trypanothione reductase than Nfx (Ki values of 118 uM, 61 uM and 68 uM for 8, 12 and 13, respectively, compared with 245 uM for Nfx), all following an uncompetitive enzyme inhibition pattern. Docking analysis predicted a binding of inhibitors to the enzyme-substrate complex with binding energy calculated in-silico that supports such molecular interaction.