Rational design of nitrofuran derivatives: Synthesis and valuation as inhibitors of Trypanosoma cruzi trypanothione reductase.
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 IC50value in the range of Nfx, but compound 13 exhibited an improved effect with an IC50of 1.0 ± 0.1 μM 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 as the major pivotal thiol. The three compounds behaved as better inhibitors of trypanothione reductase than Nfx (Ki values of 118 μM, 61 μM and 68 μM for 8, 12 and 13, respectively, compared with 245 μM 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.
Instituto de Agrobiotecnología del Litoral (CONICET-UNL), Argentina; Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Argentina.
D G
DG
Arias
Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Argentina.
F E
FE
Herrera
Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Argentina.
A S
AS
Garay
Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Argentina.
D
D
Rodrigues
Instituto de Química Rosario (CONICET) - FCByF- Universidad Nacional de Rosario, Argentina.
P S
PS
Forastieri
Instituto de Química Rosario (CONICET) - FCByF- Universidad Nacional de Rosario, Argentina.
L E
LE
Luna
Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Argentina.
M D L M
MD
Bürgi
Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Argentina.
C
C
Prieto
Instituto de Agrobiotecnología del Litoral (CONICET-UNL), Argentina; Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Argentina.
A A
AA
Iglesias
Instituto de Química Rosario (CONICET) - FCByF- Universidad Nacional de Rosario, Argentina.
R M
RM
Cravero
Instituto de Agrobiotecnología del Litoral (CONICET-UNL), Argentina; Facultad Regional Santa Fe, Universidad Tecnológica Nacional (UTN), Argentina. Electronic address: saguerrero@santafe-conicet.gov.ar.
S A
SA
Guerrero
D014355:Chagas Disease / Q000188:drug therapy / Q000469:parasitology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D062105:Molecular Docking Simulation; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009581:Nitrofurans / Q000737:chemistry* / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology*
D004791:Enzyme Inhibitors; D009581:Nitrofurans; D014344:Trypanocidal Agents; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase
Nifurtimox; Nitroheterocycle drugs; Trypanosoma cruzi; Trypanothione