ABSTRACT A novel series of β ‐lactam analogues derived from 6‐aminopenicillanic acid (6‐APA) was synthesized and evaluated for their antidiabetic potential through in vitro α‐amylase inhibition, molecular docking, and ADMET studies. Structure–activity analysis revealed that electronic effects and substituent orientation significantly influence activity. Compound 4a (benzaldehyde derivative) showed the highest α‐amylase inhibition (83.71 ± 0.98%), comparable to acarbose (86.61 ± 0.65%), followed by 4d ( para ‐nitro, 82.90 ± 0.19%). Molecular docking studies further demonstrated that 4e , 4f , and 4a exhibited superior binding affinities, with total docking scores of 8.21, 7.93, and 7.81, respectively, surpassing that of acarbose (7.87). ADMET analysis confirmed favorable pharmacokinetic profiles, identifying 4h and 4i as the safest analogues with LD 50 values of 15,000 mg/kg and 2880 mg/kg, respectively. Although the series showed moderate antibacterial activity, all compounds displayed high drug‐likeness scores, with 4a achieving the maximum (0.86). These findings highlight 6‐APA as a privileged scaffold for designing safe and effective nontraditional antidiabetic agents.
Parmar et al. (Sun,) studied this question.