Synthesis of amantadine clubbed N-aryl amino thiazoles as potent urease, α-amylase & α-glucosidase inhibitors, kinetic and molecular docking studies

Abstract

A series of ten novel compounds were synthesized by incorporating a 1,3 thiazole core into amantadine and their structures were validated using different analytical and spectral methods such as FTIR, EI-MS, ¹H NMR, and ¹³C NMR. The antibacterial and enzyme inhibitory properties of these newly synthesized compounds were evaluated. Remarkably, the compounds exhibited significant antibacterial activity against Escherichia coli and Bacillus subtilis. Additionally, the in vitro inhibitory activities of the synthesized compounds, against α-amylase, α-glucosidase, and urease were investigated. Among the tested compounds, compound 6d demonstrated potent and selective inhibition of α-amylase IC₅₀ = 97.37 ± 1.52 μM, while acarbose was used as positive control and exhibited IC₅₀ = 5.17 ± 0.25 μM. Compound 6d and 6e exhibited prominent inhibition against α-glucosidase IC₅₀ = 38.73 ± 0.80 μM and 41.63 ± 0.26 μM respectively. Furthermore, compound 6d inhibited urease with exceptional efficacy IC₅₀ = 32.76 μM, while positive control thiourea showed more prominent activity having IC₅₀ = 1.334 μM. Molecular docking studies disclosed the binding mechanism and affinity of these new inhibitors within the binding sites of various amino acids. To investigate the association between molecular structural characteristics and inhibitory actions of synthesized derivatives, preliminary structure–activity relationship (SAR) studies were performed. These findings indicated that compounds 6a, 6c, 6d and 6e are potential candidates for hit-to-lead follow-up in the drug-discovery process for treating diabetes and hyperglycemia.