Development of new quinoline-triazole based hybrids: synthesis, nano-encapsulation, DFT calculations, and evaluation...

Currently, the development of effective and safe antidiabetic drugs remains a major challenge in diabetes management. This study reports the design and synthesis of new quinoline-based hybrids, featuring an oxymethylene-linked 1,2,3-triazole core and integrated 1,2,4-triazole pharmacophores, alongside their chitosan-encapsulated derivatives, as prospective multitarget antidiabetic agents. The synthesized compounds were evaluated for their in vitro inhibitory activity against α-amylase and α-glucosidase, as well as for glucose uptake stimulation and their antioxidant potential through NO and DPPH radical scavenging assays. Notably, CNPs 5* and 6* demonstrated significant α-amylase and α-glucosidase inhibitory potencies, surpassing that of the standard drug acarbose. Compound 6* (IC₅₀ = 0.17 µM) exhibited the most potent α-amylase inhibition compared to acarbose (IC₅₀ = 25.08 µM), alongside demonstrating significant NO radical scavenging activity with a potency ∼1.78-fold greater than ascorbic acid. Furthermore, it stimulated glucose uptake at a level ∼1.65-fold higher than Berberine. CNPs 5* (IC₅₀ = 58.21 µM) was identified as the most potent α-glucosidase inhibitor, surpassing acarbose (IC₅₀ = 68.91 µM). To elucidate the electronic properties and stability of the new hybrids, DFT calculations were performed. Subsequently, molecular docking studies were conducted to corroborate the in vitro findings and explore the binding interactions within the active sites of the target enzymes. Finally, ADME profiles of the new hybrids suggest their promising drug-like properties and support further investigation as potential antidiabetic leads.