Designing oxazole-linked sulfonamides with optimal structural features for enhanced antidiabetic efficacy: A quantitative approach

• This study presents synthesis of oxazole based sulfonamide derivatives with anti-diabetic potential. • These derivatives were subjected to molecular docking study to gain insight into the binding interactions with target enzymes. • These derivatives were also investigated for their pharmacokinetic properties through ADME analysis to study their drug likeness attributes. • Enzyme kinetics study was also conducted to investigate the enzyme inhibition and rate of reaction. • DFT calculations also explored reactivity of the potent compounds. A series of novel 14 oxazole based sulfonamide derivatives were synthesized via a multistep process which involves the linkage of substituted oxazole moiety and sulfonamide group. The structures of these compounds were elucidated using HREI-MS, 13 CNMR and 1 HNMR techniques. The synthesized compounds were evaluated for their inhibitory activities against α-amylase and α-glucosidase, which play a crucial role in glucose metabolism which leads to hyperglycemia (Diabetes Mellitus). Compound 5, 6, 7 and 12 exhibited potent activity, with IC 50 values ranging from 7.30 ± 0.20 to 19.10 ± 0.20 µM and 7.70 ± 0.40 to 19.70 ± 0.10 µM, respectively. This biological potency was comparable to or better than those of acarbose, a well-known inhibitor of α-amylase and α-glucosiadse. A structure activity relationship study revealed that the nature and patterns of substituents on the phenyl ring significantly disrupt the inhibitory activities of the compounds. To elucidate the inhibitory kinetics of the synthesized compounds, a comprehensive enzyme kinetics assay was conducted. Additional molecular docking and DFT helps to gain insight into the binding interactions, molecular orbitals formation, electrostatic potential distribution and reactivity indices of potent compounds. ADMET studies were conducted to evaluate the drug-like properties of the lead compounds. The results of these studies provide valuable insights in to the potential of these compounds as therapeutic agents for the treatment of Diabetes Mellitus.