Computational Evaluation of Azinane-Amide-Coupled Triazoles Enabled by an Alkali Metal Reagent as Anti-Enzymatic...

A new electrophile was synthesized and merged with 1,2,4-triazole and piperidine to avail the aimed library of compounds, 10a _i‑v and 10b _i‑v . Various 4-(substituted)-benzenesulfonyl chlorides (1 _i‑v ) were treated with ethyl piperidin-4-carboxylate (2a) and ethyl piperidin-3-carboxylate (2b) to acquire 3a _i‑v and 3b _i‑v esters bearing a sulfamoyl moiety. These esters were converted to different 1,2,4-triazoles 6a _i‑v and 6b _i‑v through the formation of carbohydrazides and thiosemicarbazides as intermediates. A new electrophile, compound 9, was synthesized by reaction of bromoacetyl bromide (7) with an aromatic amine (8) under basic conditions. This electrophile was treated with 6a _i‑v and 6b _i‑v to avail the aimed library of compounds, 10a _i‑v and 10b _i‑v . The structural confirmation of all of the synthesized compounds was performed through 1D NMR data. The whole library of synthesized compounds was evaluated for their pharmacological potential against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), alpha glucosidase, and urease enzymes. Compound 10a _iii showed better % inhibition (63.37 ± 1.25) against the AChE enzyme, while 10b _i showed better % inhibition (72.38 ± 1.21) against the BChE enzyme as compared to the reference standards, Eserine and Pyridostigmine. 10b _v showed best activity against the alpha-glucosidase enzyme with 64.7 ± 1.84% inhibition and the best activity against the urease enzyme was presented by compound 10b _iii with the present inhibition potential of 49.3 ± 1.5. The best biofilm inhibition activity was shown by compound 10b _ii with a % inhibition of 84.03141361 against bacterium, Escherichia coli. Molecular docking was performed to check the active sites of enzymes giving different values of binding affinity. The physicochemical properties and bioactivity values of synthesized compounds rendered them as active drugs. DFT was performed to study the electronic characteristics including molecular electrostatic potential (MEP), structural optimization, and HOMO-LUMO energy gap to evaluate reactivity or stability of the synthesized compounds. Furthermore, full insight evaluation may lead us to find the best antienzymatic drug candidates in the future.