Synthesis, Characterization, and Enzyme Inhibition Properties of 1,2,4-Triazole Bearing Azinane Analogues

Abstract

Considering the importance of acetylcholine esterase (AChE, BchE) and α-glucosidase in the treatment of Alzheimer’s disease and diabetes mellitus, the synthesis of novel azinane triazole-based derivatives as effective acetylcholinesterase (AchE), α-glucosidase, urease, lipoxygenase (LOX), and butyrylcholinesterase (BChE) inhibitors is described. Azinane analogue ( 2 ) was merged with 1,2,4-triazole to acquire 1-(4-toluenesulfonyl)-4-(3-mercapto-4-methyl-4 H -1,2,4-triazol-5-yl) piperidine ( 8 ) through a list of intermediates including 1-(4-toluenesulfonyl)-4-(ethoxycarbonyl) piperidine ( 3 ), 1-(4-toluenesulfonyl)-4-(2-hydrazinocarbonyl)piperidine ( 5 ), and 1-(4-toluenesulfonyl)-4-[1-(methyl amino thiocarbonyl)-2-hydrazinocarbonyl]piperidine ( 7 ). The target molecules, 1-(4-toluenesulfonyl)-4-[3-( N -alkyl/phenyl/aryl-2-ethanamoyl thio)-4-methyl-4 H -1,2,4-triazol-5-yl] piperidine ( 12a–o ), were achieved through the reaction of 8 with N -alkyl/phenyl/aryl-2-bromo ethanamides ( 11a–o ) as electrophiles. These electrophiles were accomplished by a benign reaction of alkyl/phenyl/aryl amines ( 9a–o ) and 2-bromo ethanoyl bromide ( 10 ). The spectral study of IR, 1D-NMR, and EI-MS corroborated the synthesized compounds. Methyl phenyl and methyl phenyl-substituted derivatives 12d and 12m with IC 50 = 0.73 ± 0.54; 36.74 ± 1.24; 19.35 ± 1.28; 0.017 ± 0.53; and 0.038 ± 0.50 μM are found to be the most potent AChE, α-glucosidase, urease, and BChE inhibitors. The high inhibition potential of synthesized molecules against AChE, α-glucosidase, urease, and BChEenzymes inferred their role in enzyme inhibition properties.

Triazole derivatives as potential xanthine oxidase inhibitors: Design, enzyme inhibition potential, and docking studies

“…[63] As quoted by Ayse Tan in his research, the triazole derivatives appreciably interacted in the active site of XO with various pi-pi interactions and hydrophobic interactions. It has been seen from the extensive literature survey that the triazole ring with certain modifications has been widely studied for the inhibition of various enzymes such as carbonic anhydrase, [64] XO, [65] urease, [66] acetylcholinesterase, [67] butyrylcholinesterase, [68] cyclooxygenase-2, [69] and 15-lipooxygenase. [70] In 2016, Ailong Shi et al, designed and synthesized a series of 2phenyl-5-methyl-2H-1,2,3-triazole-4-carboxylic acid/carbohydrazide derivatives as potent XO inhibitors for the treatment of gout.…”

Urease Inhibition and Structure‐Activity Relationship Study of Thiazolidinone‐, Triazole‐, and Benzothiazole‐Based Heterocyclic Derivatives: A Focus Review

“…Asif et al [105] . synthesized azinane containing 1,2,4‐triazoles and assessed for their antiurease potential.…”

“…Asif et al [105] synthesized azinane containing 1,2,4-triazoles and assessed for their antiurease potential. Outcomes revealed that only derivatives 43 c, 43 d, 43 i, 43 j, 43 k, and 43 m endured potency against urease enzyme, while compounds 43 d and 43 m displayed effective inhibition; 98.22 and 98.65 %, respectively in comparison to standard thiourea (98.28 % inhibition).…”

An overview of the privileged synthetic heterocycles as urease enzyme inhibitors: Structure–activity relationship

“…Asif et al [ 81 ] synthesized 1,2,4‐triazole bearing azinane hybrids and evaluated them against urease. The SAR study of compound 170a (IC 50 = 14.29 μM) bearing CH 3 in 3‐ and 5‐positions on the phenyl ring is stronger than thiourea (IC 50 = 21.37 μM).…”