Indolyl Linked Meta‐Substituted Benzylidenes as Novel Ligands: Synthesis, Biological Evaluation, and Molecular Docking Studies

Abstract

Synthesis of indolyl linked benzylidene based meta‐substituted phenyl containing thiazolidinediones (4a–b), rhodanine (5a–b), and 1,3‐dicarbonyl based acyclic analogs of isoxazolidinediones (6a–7b) in an effort to develop novel α‐glucosidase inhibitors in the management of hyperglycemia for the treatment of type 2 diabetes is reported. The structure of all the novel synthesized compounds was confirmed through the spectral studies (LC–MS, 1H‐NMR, 13C‐NMR, and FTIR). Comparative evaluation of these compounds revealed that the compound 5b showed maximum inhibitory potential against α‐amylase and α‐glucosidase giving an IC50 value of 0.28 ± 0.01 μM. Furthermore, binding affinities in terms of G score values and hydrogen bond interactions between all the synthesized compounds and the AA residues in the active site of the protein (PDB code: 3TOP) to that of Acarbose (standard drug) were explored with the help of molecular docking studies. Compound 5b was considered as promising candidate of this series.

Recent Developments in the Synthesis of N‐Heterocyclic Compounds as α‐Amylase Inhibitors via In‐Vitro and In‐Silico Analysis: Future Drugs for Treating Diabetes

“…N-4-chlorobenzylindolyl based compounds have enhanced inhibitory activity. [19] Taha and his group (2019) prepared nineteen bisindolylmethanesulfonamide analogues by a very efficient and practical method. [47,48] The designed products 46 were synthesized by reacting equimolar amounts of 45 with aryl sulphonyl chloride in the presence of pyridine as depicted by scheme 14.…”

“…Structure activity studies demonstrated that presence of chlorine atom and H‐bonding have a major impact on the activity of these compounds. N‐4‐chlorobenzylindolyl based compounds have enhanced inhibitory activity [19] …”

“…The mechanism of amylase response is depicted in figure 1. There are numerous natural and manmade substances known to block pancreatic amylase enzymes [19] . According to structural studies and inhibitory assays, the majority of the substances listed above have the ability to reduce the activity of the pancreatic amylase enzyme.…”

“…There are numerous natural and manmade substances known to block pancreatic amylase enzymes. [19] According to structural studies and inhibitory assays, the majority of the substances listed above have the ability to reduce the activity of the pancreatic amylase enzyme. These chemicals share the same glucose ring structure as acarbose (a possible amylase inhibitor).…”

Rhodanine‐Incorporated Indole Derivatives as Pharmacologically Vital Hybrids

“…Furthermore, combining indole and rhodanine rings in a single molecule enhances the activity. [28] Horishny et al synthesized a series of (Z)-2-(5-((1H-indol-3yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid derivatives 93-103 using classical methods of organic synthesis (Figure 15). Synthesized compounds were evaluated for their antimicrobial activity against eight Gram-positive and Gramnegative bacterial species.…”