ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

Design, synthesis and biological evaluation of novel piperic acid and benzylpiperazine hybrid molecules for improvement of memory impairment via cholinesterase inhibitory activity

Jitendra Kumar, Gauri Shankar, Sunil Kumar, Gourav Singh, T. A. Gajendra, Sanskriti Rai, Upesh Mandloi, Saripella Srikrishna, Saroj Kumar, Amit Kumar Singh, Pradeep Kumar, Kavindra Nath Tiwari, Sairam Krishnamurthy, Gyan Modi, and Sunil Kumar Mishra

Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, India

E-mail: skmishra.phe@itbhu.ac.in

Received: 14 August 2023  Accepted: 1 May 2024

Abstract:

In this paper, we have developed a series of piperic acid (PA) derivatives to overcome the inherent constraints linked to PA for Alzheimer's disease (AD) management. We have carried out a comprehensive study to investigate the structure–activity relationship (SAR) of PAanalogs to enhance their inhibitory properties towards cholinesterase enzymes. Compound 3m exhibited notable inhibition against butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) among all developed analogs (BChE (µM), 1.03 ± 0.011; AChE (µM), 4.26 ± 0.13 respectively) over PA (AChE% inhibition at 20 µM, 7.14 ± 0.98; BChE% inhibition at 20 µM, 5.87 ± 0.76). Compound 3m  was chosen for further biological investigations based on these encouraging outcomes. 3 m demonstrated a binding affinity for AChE’s peripheral anionic site, indicating its interaction with this specific enzyme region. Additionally, it also possesses favorable permeability across the blood–brain barrier, with a Pe (permeability coefficient) value of 5.79 ± 1.12. The molecular docking investigations unveiled the ability of 3mto intricately engage with AChE and BChE.In cell-based cytotoxicity tests, compound 3m displayed cell-friendly characteristics across different tested concentrations. Notably, 3m exhibited the ability to counteract scopolamine-induced memory impairmentin mice, enhancing both spatial and cognitive memories. These results strongly suggest that 3m can behave as a potential compound for AD management.

Graphical abstract

Keywords: Alzheimer’s disease; Piperic acid; Cholinesterase inhibitors; Antioxidants; Y-maze experiment

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-024-03787-7

Chemical Papers 79 (1) 395–415 (2025)