Synthesis and evaluation against Leishmania amazonensis of novel pyrazolo[3,4-d]pyridazinone-N-acylhydrazone-(bi)thiophene hybrids.
A new series of pyrazolo[3,4-d]pyridazin-7-one derivatives were synthesised and evaluated for their in vitro antileishmanial activity against Leishmania amazonensis promastigote and axenic amastigote forms. The results showed that the pyrazolo[3,4-d]-pyridazin-7-one-N-acylhydrazone-(bi)thiophene hybrids 5b, 6b and 6d exhibit better antileishmanial activity with IC5084.96, 3.63 and 10.79 μM, against the promastigote form and IC5032.71, 2.32 and >100 μM against the axenic amastigote form, respectively. The active compounds had their cytotoxicity tested against macrophages and fibroblast cells with a higher selectivity index than 10 for compounds 6b and 6d. Molecular docking studies were performed for all active compounds using the enzyme trypanothione reductase (TR) to investigate a possible action mechanism. The results suggested that active compounds had interactions with the residues of amino acids Gly 13, Thr 51, Thr 160, Gly 161, Tyr 198, Arg 287, Asp 327, Thr 335, which may inhibit the enzyme TR.
Departamento de Química, Universidade Estadual de Maringá (UEM), 87020-900, Maringá, PR, Brazil.
Andrey P
AP
Jacomini
Departamento de Química, Universidade Estadual de Maringá (UEM), 87020-900, Maringá, PR, Brazil.
Michael J V
MJV
Silva
Departamento de Química, Universidade Estadual de Maringá (UEM), 87020-900, Maringá, PR, Brazil.
Raí G M
RGM
Silva
Departamento de Química, Universidade Estadual de Maringá (UEM), 87020-900, Maringá, PR, Brazil.
Davana S
DS
Gonçalves
Programa de Pós-Graduação em Ciências Biológicas, Universidade Estadual de Maringá (UEM), 87020-900, Maringá, PR, Brazil.
Hélito
H
Volpato
Departamento de Química, Universidade Estadual de Maringá (UEM), 87020-900, Maringá, PR, Brazil.
Ernani A
EA
Basso
Departamento de Farmácia, Universidade Federal do Pampa (UNIPAMPA), 97500-970, Uruguaiana, RS, Brazil.
Fávero R
FR
Paula
Programa de Pós-Graduação em Ciências Biológicas, Universidade Estadual de Maringá (UEM), 87020-900, Maringá, PR, Brazil.
Celso V
CV
Nakamura
Departamento de Química, Universidade Estadual de Maringá (UEM), 87020-900, Maringá, PR, Brazil.
Maria Helena
MH
Sarragiotto
Departamento de Química, Universidade Estadual de Maringá (UEM), 87020-900, Maringá, PR, Brazil. Electronic address: farosa@uem.br.
Fernanda A
FA
Rosa
D000818:Animals; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D020128:Inhibitory Concentration 50; D007894:Leishmania mexicana / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D062105:Molecular Docking Simulation; D009247:NADH, NADPH Oxidoreductases / Q000737:chemistry / Q000378:metabolism; D021261:Parasitic Sensitivity Tests; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D013876:Thiophenes; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase
Antileishmanial activity; N-acylhydrazone; Pyrazolo-pyridazinone; Thiophene; Trypanothione reductase