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

Rima D Alharthy; Sana Khalid; Shamool Fatima; Saeed Ullah; Ajmal Khan; Suraj N Mali; Rahul D Jawarkar; Sanjay S Dhabarde; Hamdy Kashtoh; Parham Taslimi; Ahmed Al-Harrasi; Zahid Shafiq; Nader M Boshta

doi:10.1002/ardp.202400140

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

Arch Pharm (Weinheim). 2024 Aug;357(8):e2400140. doi: 10.1002/ardp.202400140. Epub 2024 Apr 30.

Authors

Affiliations

¹ Department of Chemistry, Science & Arts College, Rabigh Branch, King Abdulaziz University, Rabigh, Saudi Arabia.
² Institute of Chemical Sciences, Bahauddin Zakariya University, Multan, Pakistan.
³ Department of Chemistry, Quaid-i-Azam University, Islamabad, Pakistan.
⁴ Natural and Medical Sciences Research Centre, University of Nizwa, Nizwa, Sultanate of Oman.
⁵ Department of Pharmaceutical Science and Technology, Birla Institute of Technology, Mesra, India.
⁶ Department of Medicinal Chemistry and Drug Discovery, Dr. Rajendra Gode Institute of Pharmacy, Amravati, India.
⁷ Department of Chemistry, K. V. Pendharkar College, Thane, India.
⁸ Department of Biotechnology, Yeungnam University, Gyeongsan, Gyeongbuk, Republic of Korea.
⁹ Department of Biotechnology, Faculty of Science, Bartin University, Bartin, Turkey.
¹⁰ Chemistry Department, Faculty of Science, Menoufia University, Shebin El-Koam, Egypt.

PMID: 38687119
DOI: 10.1002/ardp.202400140

Abstract

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.

Keywords: antidiabetic; chromone; molecular dynamic simulations; thiosemicarbazone; α‐glucosidase.

MeSH terms

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 Dynamics Simulation
Molecular Structure
Structure-Activity Relationship
Thiosemicarbazones* / chemical synthesis
Thiosemicarbazones* / chemistry
Thiosemicarbazones* / pharmacology
alpha-Glucosidases* / metabolism

Substances

Glycoside Hydrolase Inhibitors
Hypoglycemic Agents
Chromones
alpha-Glucosidases
Thiosemicarbazones