Structural engineering, BSA binding and computational analysis of isonipacotate based enzyme inhibitors containing...

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Enzyme Inhibition

Background:

• Challenges in activating C-C, C-S, and C-N double bonds are long-standing in synthetic chemistry.
• Development of novel compounds targeting C-N, N-N, and C-S bonds within fused ring systems is crucial for therapeutic advancements.

Purpose of the Study:

• To synthesize novel piperidine-based 1,2,4-triazole analogues.
• To evaluate the synthesized analogues for inhibitory potential against key enzymes including acetylcholinesterase (AChE), butyrylcholinesterase (BChE), 15-lipoxygenase (15-LOX), and α-Glucosidase.
• To confirm in vitro findings through molecular docking and bovine serum albumin (BSA) binding studies.

Main Methods:

• Metal-free synthesis of piperidine-based 1,2,4-triazole analogues (7a-j) using conventional and microwave-assisted techniques.
• Structural characterization of synthesized compounds using proton and carbon NMR, and IR spectroscopy.
• In vitro screening of analogues against AChE, BChE, 15-LOX, and α-Glucosidase, followed by molecular docking and BSA binding assays.

Main Results:

• Microwave-assisted synthesis yielded targeted molecules (7a-j) with significantly higher yields (87-95%) compared to conventional methods (59-72%).
• Compounds 7h, 7c, and 7i exhibited potent inhibition against AChE, with IC50 values in the micromolar range.
• Analogues 7i and 7e demonstrated significant activity against 15-LOX, outperforming the standard quercetin, while many analogues showed excellent inhibition against α-Glucosidase, surpassing acarbose.

Conclusions:

• The synthesized piperidine-based 1,2,4-triazole analogues represent promising lead compounds for the development of novel therapeutic agents.
• Compounds 7h, 7c, and 7i are identified as potential cholinesterase inhibitors, and compound 7i as a potential 15-LOX inhibitor.
• Further in vivo investigations are warranted to explore the therapeutic potential of these derivatives as inhibitors of therapeutically important enzymes.