Synthesis of indole derivatives as Alzheimer inhibitors and their molecular docking study

Abstract

Acetylcholinesterase prevails in the healthy brain, with butyrylcholinesterase reflected to play a minor role in regulating brain acetylcholine (ACh) levels. However, BuChE activity gradually increases in patients with (AD), while AChE activity remains unaffected or decays. Both enzymes therefore represent legitimate therapeutic targets for ameliorating the cholinergic deficit considered to be responsible for the declines in cognitive, behavioural, and global functioning characteristic of AD. Current study described the synthesis of indole-based sulfonamide derivatives (1-23) and their biological activity. Synthesis of these scaffolds were achieved by mixing chloro-substituted indole bearing amine group with various substituted benzene sulfonyl chloride in pyridine, under refluxed condition to obtained desired products. All products were then evaluated for AchE and BuchE inhibitory potential compare with positive Donepezil as standard drug for both AchE and BchE having IC₅₀ = 0.016 ± 0.12 and 0.30 ± 0.010 μM respectively. In this regard analog 9 was found potent having IC₅₀ value 0.15 ± 0.050 μM and 0.20 ± 0.10 for both AchE and BuChE respectively. All other derivatives also found with better potential. All compounds were characterized by various techniques such as ¹H, ¹³C-NMR and HREI-MS. In addition, biological activity was maintained to explore the bioactive nature of scaffolds and their protein-ligand interaction (PLI) was checked through molecular docking study.

Communicated by Ramaswamy H. Sarma

Keywords:

• Alzheimer’s inhibitors
• indole analogs
• SAR
• molecular docking

Acknowledgment

Authors would like to thank Institute for Research and Medical Consultations (IRMC) at Imam Abdulrahman Bin Faisal University (IAU) for the laboratory facilities and for initiating the Mawhiba Research Enrichment Program-2021 (IAU-IRMC-MAWHIBA-2021) with our long-term collaborator, ‘Mawhiba’, promoting the young talent within the kingdom.

Disclosure statement

No potential conflict of interest was reported by the authors.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

We are highly thankful to King Abdulaziz and His Companions Foundation for Giftedness and Creativity for providing financial support via research agreement with IRMC, IAU.