Synthesis and bio-evaluation of newer dihydropyridines and tetrahydropyridines based glycomimetic azasugars.

This study presents the synthesis and bio-evaluation of new triazolylated dihydropyridine and tetrahydropyridine azasugar scaffolds (F1-14). Azasugar glycomimetics are the synthetic substances that mimic the structural and functional characteristics of natural carbohydrates showcasing promising potential as therapeutic agents for diabetes. The α-glucosidase inhibitory activity of synthesized final compounds were evaluated against the commercially available α-glucosidase enzyme. Majority of the screened compounds displayed excellent inhibition with IC50 values ranging from 2.12 to 75.11 µM, when compared to the standard drug Acarbose. Particularly, compound F5 with IC50 value of 2.12 µM was found to be the most active compound among the series. Further molecular docking studies of selected ligands were performed to investigate the binding interactions with enzyme active sites. Their specific binding patterns have been analysed with the binding sites of Saccharomyces cerevisiae α-glucosidase. These findings suggest these candidates as the potential leads for the anti-diabetic activity.

Design, synthesis and in silico evaluation of newer 1,4-dihydropyridine based amlodipine bio-isosteres as promising antihypertensive agents.

Hypertension remains a major global health concern, prompting ongoing research into innovative therapeutic approaches. This research encompasses the strategic design, synthesis, and computational assessment of a novel series of 1,4-dihydropyridine based scaffolds with the objective of developing promising antihypertensive agents as viable alternatives to the well-established dihydropyridine based drugs such as amlodipine, felodipine, nicardipine, etc. The crystal structure of the lead compound determined using X-ray crystallography offers crucial insights into its 3D-conformation and intermolecular interactions. In silico molecular docking experiments conducted against the calcium channel responsible for blood pressure regulation revealed superior docking scores for all the bioisosteres P1-P14 than the standard amlodipine, indicating their potential for enhanced therapeutic efficacy. Extensive ADMET profiling and structure-activity relationship (SAR) elucidated favourable pharmacokinetic properties and essential structural modifications influencing antihypertensive effectiveness. Specifically, P6-P10, P12 and P14 hybrids were found in accordance with Lipinski rules and exhibited druglikeliness attributes, involving high GI absorption and no BBB permeance. In particular, P7 was found to be crystalline in nature having the highest binding affinity with the concerned calcium channels with excellent ADMET profile. The findings highlight the significance of the presence of triazole tethered aryl/heteroaryl ring in the synthesized hybrids, providing a foundation for further preclinical and clinical translation as antihypertensive medications.