Evaluation of pyrimidine/pyrrolidine-sertraline based hybrids as multitarget anti-Alzheimer agents: In-vitro, in-vivo, and computational studies

• Published in: Biomedicine & pharmacotherapy 2023-03, Vol.159, p.114239-114239, Article 114239
• Main Authors: Javed, Muhammad Aamir, Jan, Muhammad Saeed, Shbeer, Abdullah M., Al-Ghorbani, Mohammed, Rauf, Abdur, Wilairatana, Polrat, Mannan, Abdul, Sadiq, Abdul, Farooq, Umar, Rashid, Umer
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase - metabolism; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer’s disease; Behavioral assessment tests; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Humans; Molecular Docking Simulation; MTDL; Neurotransmitter levels; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Sertraline - therapeutic use; Structure-Activity Relationship
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2023.114239

Alzheimer’s disease (AD) is a complex, multifactorial and most prevalent progressive neurodegenerative ailment. Its multifactorial and complex nature causes the lack of disease modifying drugs. Hence, multi-target drug design strategies have been adopted to halt the progression of AD. In current research, we applied multitarget strategy to tackle multifactorial nature of AD. Rational design and synthesis of framework of hybrids containing Pyrimidine/pyrrolidine-sertraline scaffolds were carried out. The synthesized compounds were further evaluated for their in-vitro enzyme inhibition potential against cholinesterases, monoamine oxidases and β-site amyloid precursor protein cleaving enzyme-1 (BACE-1). Compound 19 emerged as an optimal multipotent hybrid with IC50 values of 0.07 µM, 0.09 µM, 0.63 µM, 0.21 µM and 0.73 µM against AChE, BChE, MAO-A, MAO-B and BACE-1 respectively. After in-vivo cytotoxicity and in-vitro PAMPA blood brain barrier permeation assays, a number of widely used behavioral assessment tests were also performed for the evaluation of memory and learning.Determination of biochemical parameters showed low levels of acetylcholinesterase by the treatment with synthesized compounds. Furthermore, levels of neurotransmitters such as serotonin, dopamine and noradrenaline were also analyzed. Increased neurotransmitter levels showed the improved short and long-term memory as well as enhanced learning behavior. Docking studies on the target enzymes showed correlation with the experimental in-vitro enzyme inhibition results. [Display omitted] •Rationally designed pyrimidine/pyrrolidine-sertraline based hybrids were synthesized.•Synthesized compounds were evaluated in-vitro against 5 molecular targets.•Excellent in-vivo behavioral assessment results of synthesized compounds were obtained.•Docking studies on all the 5 targets were performed to explore binding orientations.