Exploring indole-based Schiff bases as potential dual-action α-amylase inhibitors and anti-inflammatory agents: SAR, pharmacokinetic and in-silico insights

A series of indole-based Schiff base derivatives ( 4a–j ) was computationally evaluated for their dual antidiabetic and anti-inflammatory potential. Molecular docking studies revealed strong binding affinities of compound 4f with SGLT2 and DPP-4, consistent with its in vitro α-amylase inhibition (PI: 71.17 ± 0.77 %; IC 50 : 1.75 ± 0.30 mM), which is comparable to acarbose (PI: 86.48 ± 0.78 %; IC 50 : 0.87 ± 0.20 mM). Compounds 4g and 4j exhibited high affinities towards COX-2 and 15-LOX-2, respectively, with 4g demonstrating notable anti-inflammatory activity (PI: 88.99 ± 0.46 %; IC 50 : 1.64 ± 0.60 mM). Molecular dynamics simulations were performed for 100 ns using the CHARMM force field, confirming stable ligand–protein interactions at the atomic level. SAR analysis indicated that para -nitro substituents enhanced antidiabetic activity, while ortho -hydroxyl groups improved anti-inflammatory potency. SwissADME profiling predicted favorable pharmacokinetics and compliance with Lipinski's rule, except for compounds 4e and 4 f . PAINS alerts were observed for 4g and 4h . Toxicity predictions indicated low toxicity for compounds 4f , 4g , and 4j . Overall, these findings suggest that 4f , 4g , and 4j represent promising candidates for further development as multifunctional therapeutic agents. • An Indole-bearing Schiff's base series (4a-j) has been synthesized. • 4f showed α-amylase inhibition, while 4g showed anti-inflammatory activity. • SAR shows para -NO₂ enhanced, while ortho/para -OH reduces antidiabetic efficacy. • 4f , 4j , and 4g showed strong computational results compared to standard inhibitors. • ADME shows drug-likeness, high GI absorption, and minor PAINS alerts for 4g and 4h .