Functionally substituted derivatives of novel thiourea and phenylthiourea as potent aldose reductase, α-amylase, and α-glycosidase inhibitors: in vitro and in silico studies

Abstract

Phenylthiourea was synthesized for the first time with a yield of 75–80% based on thiourea, in the presence of various catalysts, and optimal conditions were identified for some reactions. At the same time, the condensation of their methylene-active molecules and various aldehydes in acidic media caused the synthesis of di-, tetra-, hexahydropyrimidinethiones, which are not known in the literature so far; the role of different catalysts in this process were comparatively studied. Synthesis of heterocyclic compounds containing phenol hydroxyl, mono-, dual-, triple-amine, -thion, and hydroxyl groups in the presence of ionic liquids, CCl₃COOH CF₃COOH, NiCl₂.6H₂O catalysts as well as in the increase of yield percentages showed that the use of environmentally and economically efficient ionic liquids among these catalysts allows to obtain purposeful compounds with the highest yield (95%). The inhibition of α-glycosidase, aldose reductase, and α-amylase enzymes by functionally substituted derivatives of thiourea and phenylthiourea (1a–1f) is then observed. Compound 1d displayed the lowest inhibitory  effect against AR in these series with an IC₅₀ value of 3.25 µM, whereas compound 1c compound displayed the highest inhibitory  effect with an IC₅₀ value of 1.46 µM. The enzymes α-amylase and α-glycosidase were also easily inhibited by these substances. All substances were examined for their capacity to inhibit the α-glycosidase enzyme, with Ki values ranging between 14.321.53 and 29.322.50 µM and IC₅₀ values between 12.23 and 25.22 µM. Additionally, the IC₅₀ values for the effective inhibition profile of the α-amylase, which was determined vary from 1.02 to 7.87 µM.

Graphical abstract

Enzyme inhibitor and docking of it