Synthesis and Neurobehavioral Evaluation of a Potent Multitargeted Inhibitor for the Treatment of Alzheimer's Disease.

Autor: Khan MS; Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia., Khan Z; Department of Pharmacology, ISF College of Pharmacy (An Autonomous College), Moga, 142001, Punjab, India., Jabir NR; Department of Biochemistry, Centre for Research and Development, PRIST University, Vallam, Thanjavur, Tamil Nadu, India., Mehan S; Department of Pharmacology, ISF College of Pharmacy (An Autonomous College), Moga, 142001, Punjab, India. sidh.mehan@gmail.com., Suhail M; King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.; Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia., Zaidi SK; Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia., Zughaibi TA; King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.; Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia., Abid M; Medicinal Chemistry Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi, India. mabid@jmi.ac.in., Tabrez S; King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia. shamstabrez1@gmail.com.; Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia. shamstabrez1@gmail.com.
Jazyk: angličtina
Zdroj: Molecular neurobiology [Mol Neurobiol] 2024 Jul 15. Date of Electronic Publication: 2024 Jul 15.
DOI: 10.1007/s12035-024-04351-w
Abstrakt: Alzheimer's disease (AD) poses a significant health challenge worldwide, affecting millions of individuals, and projected to increase further as the global population ages. Current pharmacological interventions primarily target acetylcholine deficiency and amyloid plaque formation, but offer limited efficacy and are often associated with adverse effects. Given the multifactorial nature of AD, there is a critical need for novel therapeutic approaches that simultaneously target multiple pathological pathways. Targeting key enzymes involved in AD pathophysiology, such as acetylcholinesterase, butyrylcholinesterase, beta-site APP cleaving enzyme 1 (BACE1), and gamma-secretase, is a potential strategy to mitigate disease progression. To this end, our research group has conducted comprehensive in silico screening to identify some lead compounds, including IQ6 (SSZ), capable of simultaneously inhibiting the enzymes mentioned above. Building upon this foundation, we synthesized SSZ, a novel multitargeted ligand/inhibitor to address various pathological mechanisms underlying AD. Chemically, SSZ exhibits pharmacological properties conducive to AD treatment, featuring pyrrolopyridine and N-cyclohexyl groups. Preclinical experimental evaluation of SSZ in AD rat model showed promising results, with notable improvements in behavioral and cognitive parameters. Specifically, SSZ treatment enhanced locomotor activity, ameliorated gait abnormalities, and improved cognitive function compared to untreated AD rats. Furthermore, brain morphological analysis demonstrated the neuroprotective effects of SSZ, attenuating Aβ-induced neuronal damage and preserving brain morphology. Combined treatment of SSZ and conventional drugs (DON and MEM) showed synergistic effects, suggesting a potential therapeutic strategy for AD management. Overall, our study highlights the efficacy of multitargeted ligands like SSZ in combating AD by addressing the complex etiology of the disease. Further research is needed to elucidate the full therapeutic potential of SSZ and the exploration of similar compounds in clinical settings, offering hope for an effective AD treatment in the future.
(© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
Externí odkaz: