Rational design, synthesis, and in silico evaluation of novel pyridine-based heterocyclic compounds as multifunctional antidiabetic agents: molecular docking and ADMET profiling

Diabetes mellitus continues to pose a major global health challenge, highlighting the urgent need for novel therapeutic agents that target critical enzymatic pathways involved in glucose regulation. Pyridine-based ring systems are extensively employed in drug discovery due to their considerable influence on pharmacological properties, thereby facilitating the development of various broad-spectrum therapeutics. In this context, a new series of pyridine-based heterocyclic compounds was synthesized and structurally characterized using a range of spectroscopic techniques. The synthesized derivatives were assessed for their inhibitory activity against α-amylase, yielding promising results. Notably, compounds 3b and 5 demonstrated the highest inhibition, with IC₅₀ values of 3.36 ± 0.25 µM and 3.21 ± 0.15 µM, respectively, in comparison to the standard drug Acarbose (2.62 ± 0.25 µM). Furthermore, the study was extended to include the assessment of in vitro dipeptidyl peptidase-4 (DPP-4) and peroxisome proliferator-activated receptor gamma (PPAR-γ) activities as additional antidiabetic targets. Interestingly, the most active derivatives 3b and 5 demonstrated significant DPP-4 inhibitory activity, with IC₅₀ values of 3.12 ± 0.5 µMand 3.96 ± 0.42 µM, respectively, comparable to Sitagliptin (3.44 ± 0.42 µM). Additionally, PPAR-γ transactivation assays revealed that 3b and 5 exhibited potent activity with IC₅₀ values of 1.762 ± 0.11 µM and 3.36 ± 0.19 µM, respectively, surpassing the IC₅₀ value of Pioglitazone (4.884 ± 0.29 µM). These findings suggest that both compounds possess insulin-sensitizing and glucose metabolism-enhancing potential. In silico ADMET predictions indicated favorable oral bioavailability, drug likeness, and a favorable positive safety profile. Finally, molecular docking studies have confirmed a good binding affinity and favorable interactions within the active sites of α-amylase, PPAR-γ, and DPP-4, thereby underscoring their potential as multi-target antidiabetic agents. These findings offer significant insights into the rational design of next-generation antidiabetic therapies characterized by multitarget activity. © 2025 Elsevier B.V.