J Comput Aided Mol Des. 2025 Aug 6;39(1):59. doi: 10.1007/s10822-025-00638-9.ABSTRACTThis study evaluated the antidiabetic efficacy of novel benzothiophenes using in silico, in vitro and in vivo methods. The synthesis of benzo[b]thiophene-2-carbohydrazide, specifically the Schiff base of benzo[b]thiophene (2, 3, 6) and the 1,3,4-oxadiazole adducts (4, 5, and 7) was performed through a cyclization reaction of the corresponding intermediates, compounds 2, 3 and 6. The cyclization was carried out by reacting the hydrazones (2, 3 and 6) with copper triflate (Cu(OTf)₂) as the catalyst and potassium carbonate (K₂CO₃) as a base in polar solvents such as N, N-dimethylformamide (DMF). The identity of these compounds was confirmed through comprehensive spectroscopic characterization, including infrared (IR) spectroscopy, carbon-13 nuclear magnetic resonance (¹³C NMR), proton nuclear magnetic resonance (¹H NMR), and high-resolution mass spectrometry (HRMS). Molecular docking, molecular dynamics simulation (200 ns), density functional theory (B3LYP, 6-31G), ADMET, and in vitro α-amylase inhibitory studies of the synthesized benzothiophenes were conducted. Also, the antihyperglycaemic activity of the top-ranked benzothiophenes was evaluated in glucose-loaded mice. Extensive structural characterization of the synthesized Schiff bases and oxadiazole adducts was performed. The molecular docking studies identified the synthesized compounds as potential α-amylase inhibitors, with binding affinities of -9.0, -8.5, and - 8.1 kcal/mol, respectively. Quantum chemical and ADMET studies further indicated the compounds as promising drug candidates. The in vitro inhibitory studies showed that 4 demonstrated the lowest IC50 value of 0.032 µM compared to 2 (0.035 µM) and acarbose (0.09 µM). Comprehensive toxicity and histological studies of the compounds are recommended for further studies. (2 and 4) elicited good α-amylase inhibitory potential with IC50 values of 0.035 and 0.032 µM.PMID:40767979 | DOI:10.1007/s10822-025-00638-9