A Library of Thiazolidin‐4‐one Derivatives as Protein Tyrosine Phosphatase 1B (PTP1B) Inhibitors: An Attempt To Discover Novel Antidiabetic Agents

Abstract

Protein tyrosine phosphatase 1B (PTP1B) is an important target for the treatment of diabetes. A series of thiazolidin‐4‐one derivatives 8–22 was designed, synthesized and investigated as PTP1B inhibitors. The new molecules inhibited PTP1B with IC50 values in the micromolar range. 5‐(Furan‐2‐ylmethylene)‐2‐(4‐nitrophenylimino)thiazolidin‐4‐one (17) exhibited potency with a competitive type of enzyme inhibition. structure–activity relationship studies revealed various structural facets important for the potency of these analogues. The findings revealed a requirement for a nitro group‐including hydrophobic heteroaryl ring for PTP1B inhibition. Molecular docking studies afforded good correlation with experimental results. H‐bonding and π–π interactions were responsible for optimal binding and effective stabilization of virtual protein‐ligand complexes. Furthermore, in‐silico pharmacokinetic properties of test compounds predicted their drug‐like characteristics for potential oral use as antidiabetic agents.Additionally, a binding site model demonstrating crucial pharmacophoric characteristics influencing potency and binding affinity of inhibitors has been proposed, which can be employed in the design of future potential PTP1B inhibitors.

Thiazole Ring—A Biologically Active Scaffold

“…Patel et al [164] reported the synthesis of three series of thiazolidin-4-one derivatives and evaluation of their PTP1B inhibitory activity. Among all compounds, 111a-f (Figure 46) exhibited potent inhibitory activity with an IC50 values < 10 μM with compound 111e being the best competitive PTP1B inhibitor with an IC50 value of 5.88 ± Hidalgo-Figueroa et al [161] designed and synthesized two thiazolidine-2,4dione/benzazole derivatives (108a, 108b) as PTP1B inhibitors (Figure 43).…”

Recent advances in the development of allosteric protein tyrosine phosphatase inhibitors for drug discovery

“…Most of the earlier drug discovery efforts were primarily focused on designing a generation of potent, selective, bioavailable PTP-based active-site inhibitors (pTyr mimetic). [20][21][22] However, several challenges emerged during targeting active-site of PTPs including the catalytic pTyr binding site is highly conserved among all PTPs superfamily, suggesting the difficulty to develop active-site targeted inhibitor for one isoform without inhibiting the activity of closely related isoforms, which in turn leads to off-target cellular effects. In addition, the active site is cationic in nature to facilitate the interaction with the negatively charged in pTyr site.…”

A comprehensive review on the antidiabetic attributes of thiazolidine‐4‐ones: Synthetic strategies and structure–activity relationships

“…[83] Therefore, inhibitors of PTPs such as thiazolidine-4-ones are expected to have potential therapeutic value. [84] This fact has been validated by several researchers like 3. [89][90][91] This reduction of glucose to sorbitol is generally nonsignificant under the euglycemic condition that occurs at the cost of NADPH leading to decreased glutathione levels, resulting in oxidative stress.…”