Bioactive oxadiazolo-benzodiazepines: synthesis, α amylase inhibition, antioxidant activity, molecular docking and DFT calculation.

AIM: This study aimed to design, synthesize, and biologically evaluate new oxadiazolo-benzodiazepine derivatives integrating two pharmacologically relevant scaffolds, and to investigate their antidiabetic and antioxidant potential supported by computational studies.

MATERIALS &

METHODS

Two 1,2,4-oxadiazolo-1,5-benzodiazepines were synthesized via a regio- and chemoselective 1,3-dipolar cycloaddition between a 1,5-benzodiazepine and an in situ generated nitrile oxide. The compounds were fully characterized by 1H, 13C Nuclear Magnetic Resonance (NMR) and High-Resolution Mass Spectrometry (HRMS). In vitro antioxidant activity was evaluated using 1,1-diphenyl-2-picrylhydrazy (DPPH) and 2,2-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging assays, while antidiabetic potential was assessed through α-amylase inhibition. Density functional theory (DFT) calculations (B3LYP/def2-TZVP), molecular docking against α-amylase and oxidative stress-related enzymes, and in silico ADME analysis were performed to support experimental findings.

RESULTS AND

CONCLUSIONS

Both diastereoisomers 3 and 4 demonstrated superior activity compared to standard drugs. Compound 3 showed potent α-amylase inhibition IC50 = 22.78 µM) compared to Acarbose IC50 = 123 µM). For antioxidant activity, compounds 4 and 3 exhibited strong DPPH scavenging IC50 = 68.16 and 79.50 μM, respectively), outperforming ascorbic acid. Docking studies confirmed favorable binding interactions within the active sites of target enzymes. The synthesized oxadiazolo-benzodiazepines represent promising multifunctional antidiabetic and antioxidant candidates, warranting further pharmacological investigation.