Synthesis of novel indazole derivatives as inhibitors of diabetics II along with molecular docking and simulation study

• Published in: JOURNAL OF MOLECULAR STRUCTURE
• Main Authors: Al-Nasser, Fatema; Taha, Muhammad; Rahim, Fazal; Adalat, Bushra; Chigurupati, Sridevi; Nawaz, Muhammad; Ajmal, Amar; Wadood, Abdul; Uddin, Nizam; Khan, Khalid Mohammed; Shah, Syed Adnan Ali; Felemban, Shatha Ghazi; Venugopal, Vijayan
• Format: Article
• Language: English
• Published: ELSEVIER 2025
• Subjects: Chemistry
• Online Access: https://www-webofscience-com.uitm.idm.oclc.org/wos/woscc/full-record/WOS:001344553300001
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2024.140394

In the light of the pharmacological significance of the indazole and 1, 3, 4-thiadiazole scaffold, hybrid analogs of indazole and 1, 3, 4-thiadiazole (1-14) were synthesized, identified using HREI-MS, 1H, and 13CNMR, and their capability for inhibition of alpha-amylase and alpha-glucosidase enzymes was evaluated. Generally, most of the synthesized derivatives of the series exhibited good inhibition activity in comparison to the reference drug acarbose with IC50 value of 10.30 f 0.20 for alpha-amylase, and 9.80 f 0.20 for alpha-glucosidase. Amongst the synthesized derivatives, fluoro substituted analog 10 appeared to be the most potent inhibitor having IC50 value of 9.90 f 0.30 for alpha-amylase and 9.20 f 0.30 for alpha-glucosidase. A structure activity relationship (SAR) for the series was established based on electronic effects and the positions of various groups on the phenyl ring. To comprehend the chemicals' binding interactions, molecular docking along with simulation study were also carried out. Compound 10 was ranked top in the series based on docking score and interactions with receptors. Compound 10 establish more H-bond contacts with the active site's residue of alpha-amylase and alpha-glucosidase as compared to all other compounds. Furthermore, 10 was found to be highly stable throughout 50 ns MD simulation. As compared to the control drug, 10 revealed high stability with both alpha-amylase and alpha-glucosidase enzymes during molecular dynamics simulation.