Synthesis, biological evaluation and docking study of 1,3,4-thiadiazole-thiazolidinone hybrids as anti-inflammatory agents with dual inhibition of COX-2 and 15-LOX.
Bioorg Chem
; 80: 461-471, 2018 10.
Article
em En
| MEDLINE
| ID: mdl-29986191
ABSTRACT
Selective inhibition of both cyclooxygenase-2 (COX-2) and 15-lipooxygenase (15-LOX) may provide good strategy for alleviation of inflammatory disorders while minimizing side effects associated with current anti-inflammatory drugs. The present study describes the synthesis, full characterization and biological evaluation of a series of thiadiazole-thiazolidinone hybrids bearing 5-alk/arylidene as dual inhibitors of these enzymes. Our design was based on merging pharmacophores that exhibit portent anti-inflammatory activities in one molecular frame. 5-(4-hydroxyphenyl)-1,3,4-thiadiazol-2-amine (3) was efficiently synthesized, chloroacetylated and cyclized to give the key 4-thiazolidinone (5). Knovenagel condensation of 5 with different aldehydes afforded the final compounds 6a-m, 7, 8 and 9. These compounds were subjected to in vitro COX-1/COX-2, 15-LOX inhibition assays. Compounds (6a, 6f, 6i, 6l, 6m and 9) with promising potency (IC50â¯=â¯70-100â¯nM) and selectivity index (SIâ¯=â¯220-55) were further tested for in vivo anti-inflammatory activity and effect on gastric mucosa. The most promising compound (6l) inhibits COX-2 enzyme at a nanomolar concentration (IC50â¯=â¯70â¯nM, SIâ¯=â¯220) with simultaneous inhibition of 15-LOX (IC50â¯=â¯11⯵M). These results are comparable to the potency and selectivity of the standard drugs of both enzymes; celecoxib (COX-2 IC50â¯=â¯49â¯nM, SIâ¯=â¯308) and zileuton (15-LOX IC50â¯=â¯15⯵M) in one construct. Interestingly three compounds (6a, 6l and 9) exhibited equivalent to or even higher than that of celecoxib in vivo anti-inflammatory activity at 3â¯h interval with good GIT safety profile. Molecular docking study conferred binding sites of these compounds on COX-2 and 15-LOX. Such type of compounds would represent valuable leads for further investigation and derivatization.
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Base de dados:
MEDLINE
Assunto principal:
Inibidores de Lipoxigenase
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Inibidores de Ciclo-Oxigenase 2
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Tiazolidinas
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article