ABSTRACT
The catalytic potential of pyridine-2-carboxlic acid has been evaluated for efficient, green and solvent free synthesis of 2,4,5-trisubstituted imidazole derivatives 3a-3m. The compounds 3a-3m were synthesized by one pot condensation reaction of substituted aromatic aldehydes, benzil, and ammonium acetate in good to excellent yields (74-96 %). To explore the potential of these compounds against Alzheimer's disease, their inhibitory activities against acetylcholinesterase (AChE) were evaluated. In this series of compounds, compound 3m, bearing one ethoxy and a hydroxy group on the phenyl ring on 2,4,5-trisubstituted imidazoles, proved to be a potent AChE inhibitor (102.56±0.14). Structure-activity relationship (SAR) of these compounds was developed. Molecular dockings were carried out for the compounds 3m, 3e, 3k, 3c, 3a, 3d, 3j, and 3f in order to further investigate the binding mechanism. The inhibitor molecule was molecularly docked with acetylcholinesterase to further study its binding mechanism. The amino group of the compound 3m forms an H-bond with the oxygen atom of the residue (i. e., THR121) which has a bond length of 3.051â Å.
Subject(s)
Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/pharmacology , Imidazoles/pharmacology , Neuroprotective Agents/pharmacology , Alzheimer Disease/metabolism , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Molecular Docking Simulation , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Structure-Activity RelationshipABSTRACT
Eluding the involvement of solvents in organic synthesis and introducing environment friendly procedures can control environmental problems. A facile and an efficient solvent free mechanochemical method (grinding) is achieved to synthesize novel bis-biphenyl substituted thiazolidinones using non-toxic and cheap N-acetyl glycine (NAG). Organocatalytic condensation of a series of Schiff's bases bearing different substituents with thioglycolic acid produces a variety of thiazolidinones derivatives in good to excellent yield. In vitro inhibition studies against mushroom tyrosinase of these thiazolidinone analogues revealed that many of them possessed good to excellent tyrosinase inhibition at low micro-molar concentrations. In particular, six compounds exhibited potent inhibitory potential with IC50 values ranging from 0.61 ± 0.31 to 21.61 ± 0.11 µM as compared with that of standard kojic acid (IC50 6.04 ± 0.11 µM). Further molecular docking studies revealed that the thiazolidinones moiety plays a key role in the inhibition mechanism by well fitting into the enzyme bounding pocket.
Subject(s)
Agaricus/enzymology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Monophenol Monooxygenase/antagonists & inhibitors , Thiazolidines/chemistry , Thiazolidines/pharmacology , Catalysis , Enzyme Inhibitors/chemical synthesis , Glycine/analogs & derivatives , Glycine/chemistry , Green Chemistry Technology/methods , Molecular Docking Simulation , Monophenol Monooxygenase/metabolism , Structure-Activity Relationship , Thiazolidines/chemical synthesisABSTRACT
A mild and efficient method for the radical addition of α-aryl-ß,ß-difluoroenol silyl with arene diazonium tetrafluoroborates at room temperature has been disclosed, which involves an innate radical long chain cycle, so only a small amount (0.05 mol%) of photocatalyst and a short light exposure time are required as radical initiators. A proposed mechanism for the transformation is also illustrated based on the results of control experiments and quantum calculations. A variety of α-aryl-α,α-difluoroketones were formed in moderate to high yields, and can be easily further transformed into various difluoromethylarenes under basic conditions.
