ABSTRACT
The 1:1 co-crystal N'-[(2-methyl-phen-yl)methyl-idene]pyridine-4-carbohydrazide-benzoic acid (1/1), C13H11N3O·C7H6O2, formed unexpectedly after autoxidation of benzaldehyde during the slow evaporation process of a solution of isoniazid in benzaldehyde. The original intent of the synthesis was to modify isoniazid with benzaldehyde and crystallize the product in order to improve efficacy against Mycobacteria species, but benzoic acid formed spontaneously and co-crystallized with the intended product, N'-benzyl-idene-pyridine-4-carbohydrazide.
ABSTRACT
Series of 7-aryl- (3a-f), 7-arylvinyl- (3g-k) and 7-(arylethynyl)-5-bromo-3-methylindazoles (4a-f) have been evaluated through enzymatic assay in vitro for inhibitory effect against α-glucosidase activity and for antioxidant potential through the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. Compounds 3a-k and 4a-f showed significant to moderate α-glucosidase inhibition with IC50 values in the range of 0.50-51.51 µM and 0.42-23.71 µM compared with acarbose drug (IC50 = 0.82 µM), respectively. 5-Bromo-3-methyl-7-phenyl-1H-indazole (3a), 5-bromo-3-methyl-7-styryl-1H-indazole (3h) and 5-bromo-3-methyl-7-styryl-1H-indazole (4a) exhibited moderate to significant antigrowth effect against the breast MCF-7 cancer cell line and reduced cytotoxicity against the human embryonic kidney derived Hek293-T cells when compared to doxorubicin as reference standard. Non-covalent (alkyl, π-alkyl and π-π T shaped), electrostatic (π-sulfur and/or π-anion) and hydrogen bonding interactions are predicted to increase interactions with protein residues, thereby enhancing the inhibitory effect of these compounds against α-glucosidase.
Subject(s)
Antioxidants/chemistry , Antioxidants/pharmacology , Glycoside Hydrolase Inhibitors/chemistry , Glycoside Hydrolase Inhibitors/pharmacology , Indazoles/chemistry , Indazoles/pharmacology , Antioxidants/chemical synthesis , Glycoside Hydrolase Inhibitors/chemical synthesis , HEK293 Cells , Halogenation , Humans , Indazoles/chemical synthesis , MCF-7 Cells , Methylation , Molecular Docking Simulation , Structure-Activity Relationship , alpha-Glucosidases/metabolismABSTRACT
A series of 5-oxo-5H-furo[3,2-g]chromene-6-carbaldehydes and their hydrazone derivatives were evaluated as potential multi-target-directed ligands in vitro against cholinesterases, ß-secretase, cyclooxygenase-2, and lipoxygenase-15 (LOX-15), as well as for free radical-scavenging activities. The most active compounds against LOX-15 were also evaluated for activity against the human lipoxygenase-5 (LOX-5). Kinetic studies against AChE, BChE, and ß-secretase (BACE-1) were performed on 2-(3-fluorophenyl)- (3b) and 2-(4-chlorophenyl)-6-[(4-trifluoromethylphenyl)hydrazonomethyl]furo[3,2-h]chromen-5-one (3e) complemented with molecular docking (in silico) to determine plausible protein-ligand interactions on a molecular level. The docking studies revealed hydrogen and/or halogen bonding interactions between the strong electron-withdrawing fluorine atoms of the trifluoromethyl group with several residues of the enzyme targets, which are probably responsible for the observed increased biological activity of these hydrazone derivatives. The two compounds were found to moderately inhibit COX-2 and lipoxygenases (LOX-5 and LOX-15). Compounds 3b and 3e were also evaluated for cytotoxicity against the breast cancer MCF-7 cell line and Hek293-T cells.
