Synthesis of the chromone‐thiosemicarbazone scaffold as promising α‐glucosidase inhibitors: An in vitro and in silico approach toward antidiabetic drug design

• Published in: Archiv der Pharmazie (Weinheim) Vol. 357; no. 8; pp. e2400140 - n/a
• Main Authors: Alharthy, Rima D., Khalid, Sana, Fatima, Shamool, Ullah, Saeed, Khan, Ajmal, Mali, Suraj N., Jawarkar, Rahul D., Dhabarde, Sanjay S., Kashtoh, Hamdy, Taslimi, Parham, Al‐Harrasi, Ahmed, Shafiq, Zahid, Boshta, Nader M.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.08.2024
• Subjects: alpha-Glucosidases - metabolism; antidiabetic; chromone; Chromones - chemical synthesis; Chromones - chemistry; Chromones - pharmacology; Computer Simulation; Diabetes Mellitus, Type 2 - drug therapy; Dose-Response Relationship, Drug; Drug Design; Glycoside Hydrolase Inhibitors - chemical synthesis; Glycoside Hydrolase Inhibitors - chemistry; Glycoside Hydrolase Inhibitors - pharmacology; Humans; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Molecular Docking Simulation; molecular dynamic simulations; Molecular Dynamics Simulation; Molecular Structure; Structure-Activity Relationship; thiosemicarbazone; Thiosemicarbazones - chemical synthesis; Thiosemicarbazones - chemistry; Thiosemicarbazones - pharmacology; α‐glucosidase; thiosemicarbazone; α‐glucosidase; antidiabetic; molecular dynamic simulations; chromone
• ISSN: 0365-6233; 1521-4184; 1521-4184
• DOI: 10.1002/ardp.202400140

Diabetes is a serious metabolic disorder affecting individuals of all age groups and prevails globally due to the failure of previous treatments. This study aims to address the most prevalent form of type 2 diabetes mellitus (T2DM) by reporting on the design, synthesis, and in vitro as well as in silico evaluation of chromone‐based thiosemicarbazones as potential α‐glucosidase inhibitors. In vitro experiments showed that the tested compounds were significantly more potent than the standard acarbose, with the lead compound 3n exhibiting an IC50 value of 0.40 ± 0.02 μM, ~2183‐fold higher than acarbose having an IC50 of 873.34 ± 1.67 μM. A kinetic mechanism analysis demonstrated that compound 3n exhibited reversible inhibition of α‐glucosidase. To gain deeper insights, in silico molecular docking, pharmacokinetics, and molecular dynamics simulations were conducted for the investigation of the interactions, orientation, stability, and conformation of the synthesized compounds within the active pocket of α‐glucosidase. Chromone‐derived thiosemicarbazones were synthesized and explored for their potential as α‐glucosidase inhibitors. Kinetic studies showed the competitive mode of inhibition and molecular docking, and molecular dynamics simulation and 2D‐QSAR model analyses were performed to define the pharmacokinetic properties and mechanism of inhibition.