Design and development of novel p-aminobenzoic acid derivatives as potential cholinesterase inhibitors for the treatment of Alzheimer's disease

Sushant K Shrivastava; Saurabh K Sinha; Pavan Srivastava; Prabhash N Tripathi; Piyoosh Sharma; Manish K Tripathi; Avanish Tripathi; Priyanka K Choubey; Digambar K Waiker; Lalit M Aggarwal; Manish Dixit; Subhash C Kheruka; Sanjay Gambhir; Sharmila Shankar; Rakesh K Srivastava

doi:10.1016/j.bioorg.2018.10.009

Design and development of novel p-aminobenzoic acid derivatives as potential cholinesterase inhibitors for the treatment of Alzheimer's disease

Bioorg Chem. 2019 Feb:82:211-223. doi: 10.1016/j.bioorg.2018.10.009. Epub 2018 Oct 9.

Authors

Affiliations

¹ Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi 221005, U.P., India. Electronic address: skshrivastava.phe@iitbhu.ac.in.
² Department of Pharmaceutical Sciences, Mohanlal Sukhadia University, Udaipur 313001, Rajasthan, India.
³ Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi 221005, U.P., India.
⁴ Department of Radiotherapy & Radiation Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP 221 005, India.
⁵ Department of Nuclear Medicine, SGPGIMS, Raebareli Road, Lucknow 226014, UP, India.
⁶ Department of Genetics, Louisiana State University Health Sciences Center, 1700 Tulane Avenue, New Orleans, LA 70112, USA.
⁷ Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, 1700 Tulane Avenue, New Orleans, LA 70112, USA.

PMID: 30326403
DOI: 10.1016/j.bioorg.2018.10.009

Abstract

Based on the quantitative structure-activity relationship (QSAR), some novel p-aminobenzoic acid derivatives as promising cholinesterase enzyme inhibitors were designed, synthesized, characterized and evaluated to enhance learning and memory. The in vitro enzyme kinetic study of the synthesized compounds revealed the type of inhibition on the respective acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The in vivo studies of the synthesized compounds exhibited significant reversal of cognitive deficits in the animal models of amnesia as compared to standard drug donepezil. Further, the ex vivo studies in the specific brain regions like the hippocampus, hypothalamus, and prefrontal cortex regions also exhibited AChE inhibition comparable to standard donepezil. The in silico molecular docking and dynamics simulations studies of the most potent compound 22 revealed the consensual interactions at the active site pocket of the AChE.

Keywords: Antiamnesic; Anticholinesterase; Molecular dynamics; Working and reference memory; p-Aminobenzoic acid.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylcholinesterase / chemistry
Acetylcholinesterase / metabolism
Alzheimer Disease / drug therapy*
Animals
Brain / metabolism
Butyrylcholinesterase / chemistry
Butyrylcholinesterase / metabolism
Catalytic Domain
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / therapeutic use*
Cholinesterase Inhibitors / toxicity
Drug Design
Female
Kinetics
Male
Memory / drug effects
Molecular Docking Simulation
Molecular Dynamics Simulation
Molecular Structure
Nootropic Agents / chemical synthesis
Nootropic Agents / chemistry
Nootropic Agents / therapeutic use*
Nootropic Agents / toxicity
Quantitative Structure-Activity Relationship
Rats
Semicarbazones / chemical synthesis
Semicarbazones / chemistry
Semicarbazones / therapeutic use
Semicarbazones / toxicity
para-Aminobenzoates / chemical synthesis
para-Aminobenzoates / chemistry
para-Aminobenzoates / therapeutic use*
para-Aminobenzoates / toxicity

Substances

Cholinesterase Inhibitors
Nootropic Agents
Semicarbazones
para-Aminobenzoates
Acetylcholinesterase
Butyrylcholinesterase