Synthesis, biological evaluation, and molecular docking study of chromen‐linked hydrazine carbothioamides as potent α‐glucosidase inhibitors

• Published in: Drug development research 2023-08, Vol.84 (5), p.962-974
• Main Authors: Basri, Rabia, Ullah, Saeed, Halim, Sobia Ahsan, Alharthy, Rima D., Rauf, Umair, Khan, Ajmal, Hussain, Javid, Al‐Ghafri, Ahmed, Al‐Harrasi, Ahmed, Shafiq, Zahid
• Format: Article
• Language: English
• Subjects: carbothioamide; Chemical synthesis; chromene; Diabetes mellitus; Glucosidase; Hydrazine; Hydrazines; Inhibitors; Molecular docking; NMR; Nuclear magnetic resonance; Pharmacokinetics; Residues; Substitutes; thiosemicarbazones; α‐glucosidase inhibition
• ISSN: 0272-4391; 1098-2299
• DOI: 10.1002/ddr.22065

Inhibiting α‐glucosidase is a reliable method for reducing blood sugar levels in diabetic individuals. Several novel chromen‐linked hydrazine carbothioamide (3a–r) were designed and synthesized by condensation of chromone‐3‐carbaldehyde with a variety of substituted thiosemicarbazides. The structures of these new analogues were elucidated through various advanced spectroscopic techniques (1H NMR, 13C NMR, and ESI‐MS). The resulted compounds were screened for α‐glucosidase inhibitory potential and all the compounds (3a–r) exhibited potent inhibition of α‐glucosidase with IC50 values ranging 0.29–53.70 µM. Among them compounds 3c, 3f, 3h, and 3r displayed the highest α‐glucosidase inhibitor capability with IC50 values of 1.50, 1.28, 1.08, and 0.29 µM, respectively. Structure–activity relationship showed that different substituted groups are responsible for the variation in the α‐glucosidase inhibition. The kinetics studies of the most active inhibitor (3r) were performed, to investigate the mode of inhibition and dissociation constants (Ki), that indicated a competitive inhibitor with Ki value of 1.47 ± 0.31 µM. Furthermore, molecular docking studies was performed to reveal the possible interactions, such as H‐bonding, or π–π stacking, with the key residues of α‐glucosidase. Docking analysis revealed the importance of hydrazine carbothioamide moiety of compounds in the attachment of ligands with the crucial residues of α‐glucosidase. The estimated pharmacokinetic, physicochemical, and drug likeness properties of compounds 3a–r reflects that these molecules have acceptable range of these properties.