Design, synthesis, biological evaluation and docking studies of new 3-(4,5-dihydro-1 H -pyrazol/isoxazol-5-yl)-2-phenyl-1 H -indole derivatives as potent antioxidants and 15-lipoxygenase inhibitors

摘要

Abstract New candidates of 3-(4,5-dihydro-1 H -pyrazol/isoxazol-5-yl)-2-phenyl-1 H -indole derivatives (4–7) were designed combining the pyrazoline/isoxazoline heterocycles and 2-phenylindole to explore its potential as 15-lipoxygenase (15-LOX) inhibitors. The design of the new derivatives was based on utilizing the antioxidant properties of pyrazoline, 2-phenylindole and the good 15-LOX inhibition properties of indolylpyrazoline. The derivatives were synthesized adopting simple and laboratory friendly reaction conditions to give the target compounds in quantitative yields. The resulting indolylpyrazolines/isoxazolines were evaluated as antioxidants against 2,2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO) and superoxide dismutase (SOD); indolylpyrazoline (4b) was the most potent antioxidant against SOD assay (IC 50 ?=?1.78?μM) to be superior to ascorbic by 2 folds. Consistently, (4b) was the most potent inhibitor when tested against Soybean 15-LOX (IC 50 ?=?3.84?μM) excelling quercetin as standard inhibitor by 1.8 folds. Some of the new derivatives were docked into the active binding site of human 15-LOX (PDB entry 4NRE) emphasizing the most potent derivative (4b) and the least potent one (4c) . Docking solutions of compounds (4b) , (4c) , (5b) and (6c) revealed that (4b) was the only compound that got stabilized into the catalytic pocket of enzyme by π-cation interaction with the catalytic Fe + and formation of one hydrogen bond with Ile 676 amino acid. Other derivatives including the least potent one variably got stabilized into the active binding pocket by π-cation interaction with the catalytic Fe + but failed to form hydrogen bond with Ile 676. For the future optimization of the generated inhibitors, (i) antioxidant activity against SOD, (ii) the inhibitor stabilization by π-cation interaction with the catalytic Fe +3 and (iii) formation of hydrogen bond with Ile 676 should be regarded. Graphical abstract Display Omitted Highlights ? New indolylpyrazolines were designed on structural basis to target 15-LOX isoenzyme. ? The new derivatives are a hybrid scaffold combines the antioxidants 2-phenylindole and pyrazoline heterocycles. ? Indolylpyrazoline is a good 15-LOX inhibitor; converted to potent inhibitor via the newly designed hybrid. ? Antioxidant and 15-LOX inhibition assays of the new indolylpyrazolines highlighted 4b as superior inhibitor. ? SOD antioxidant assay is the regarded assay for future development of the generated 15-LOX inhibitors.