ABSTRACT
A series of bezofuran appended 1,5-benzothiazepine compounds 7a-v was designed, synthesized and evaluated as cholinesterase inhibitors. The biological assay experiments showed that most of the compounds displayed a clearly selective inhibition for butyrylcholinesterase (BChE), while a weak or no effect towards acetylcholinesterase (AChE) was detected. All analogs exhibited varied BChE inhibitory activity with IC50 value ranging between 1.0⯱â¯0.01 and 72⯱â¯2.8⯵M when compared with the standard donepezil (IC50, 2.63⯱â¯0.28⯵M). Among the synthesized derivatives, compounds 7l, 7m and 7k exhibited the highest BChE inhibition with IC50 values of 1.0, 1.0 and 1.8⯵M, respectively. The results from a Lineweaver-Burk plot indicated a mixed-type inhibition for compound 7l with BChE. In addition, docking studies confirmed the results obtained through in vitro experiments and showed that most potent compounds bind to both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of BChE active site. The synthesized compounds were also evaluated for their in vitro antibacterial and antifungal activities. The results indicated that the compounds possessed a broad spectrum of activity against the tested microorganisms and showed high activity against both gram positive and gram negative bacteria and fungi.
Subject(s)
Anti-Infective Agents/chemical synthesis , Benzofurans/chemistry , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/chemical synthesis , Drug Design , Thiazepines/chemistry , Acetylcholinesterase/chemistry , Acetylcholinesterase/metabolism , Anti-Infective Agents/pharmacology , Binding Sites , Butyrylcholinesterase/chemistry , Catalytic Domain , Cholinesterase Inhibitors/pharmacology , Fungi/drug effects , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Inhibitory Concentration 50 , Kinetics , Molecular Docking Simulation , Structure-Activity Relationship , Thiazepines/pharmacologyABSTRACT
A series of benzofuran-based chalconoids 6a-v were designed and synthesized as new potential AChE inhibitors. The in vitro assay of synthesized compounds 6a-v showed that most compounds had significant anti-AChE activity at micromolar or sub-micromolar levels. Among the tested compounds, 3-pyridinium derivative 6m bearing N-(2-bromobenzyl) moiety and 7-methoxy substituent on the benzofuran ring exhibited superior activity. This compound with IC50 value of 0.027 µM was as potent as standard drug donepezil.
Subject(s)
Acetylcholinesterase/metabolism , Benzofurans/chemistry , Chalcones/chemistry , Chalcones/pharmacology , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Pyridinium Compounds/chemistry , Animals , Chalcones/chemical synthesis , Cholinesterase Inhibitors/chemical synthesis , Dose-Response Relationship, Drug , Electrophorus , Molecular Structure , Pyridinium Compounds/chemical synthesis , Pyridinium Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
Cerium(III) nitrate hexahydrate efficiently catalyzes the three-component Biginelli reaction under solvent-free conditions of an aldehyde, a beta-keto ester or beta-diketone and urea or thiourea to afford the corresponding 3,4-dihydropyrimidin-2(1H)-ones or -thiones in excellent yields.
