Spirocyclohexadienones as an Uncommon Scaffold for Acetylcholinesterase Inhibitory Activity

Author(s)

Gomes, Ralph C. ^[1] ; Sakata, Renata P. ^[1] ; Almeida, Wanda P. ^{[1, 2]} ; Coelho, Fernando ^[1]

Affiliation

^[1] Univ Estadual Campinas, Lab Sintese Prod Nat & Farmacos, Inst Chem, POB 6154, BR-13083970 Campinas, SP - Brazil

^[2] Univ Estadual Campinas, Fac Pharmaceut Sci, POB 6029, BR-13083871 Campinas, SP - Brazil

• Document type: Journal article
• Source: Medicinal Chemistry; v. 15, n. 4, p. 373-382, 2019.
• Web of Science Citations: 1

Abstract

Background: The most important cause of dementia affecting elderly people is the Alzheimer's disease (AD). Patients affected by this progressive and neurodegenerative disease have severe memory and cognitive function impairments. Some medicines used for treating this disease in the early stages are based on inhibition of acetylcholinesterase. Population aging should contribute to increase the cases of patients suffering from Alzheimer's disease, thus requiring the development of new therapeutic entities for the treatment of this disease. Methods: The objective of this work is to identify new substances that have spatial structural similarity with donepezil, an efficient commercial drug used for the treatment of Alzheimer's disease, and to evaluate the capacity of inhibition of these new substances against the enzyme acetylcholinesterase. Results: Based on a previous results of our group, we prepared a set of 11 spirocyclohexadienones with different substitutions patterns in three steps and overall yield of up to 59%. These compounds were evaluated in vitro against acetylcholinesterase. We found that eight of them are able to inhibit the acetylcholinesterase activity, with IC50 values ranging from 0.12 to 12.67 mu M. Molecular docking study indicated that the spirocyclohexadienone, 9e (IC50 = 0.12 mu M), a mixed-type AChE inhibitor, showed a good interaction at active site of the enzyme, including the cationic (CAS) and the peripheral site (PAS). Conclusion: We described the first study aimed at investigating the biological properties of spirocyclohexadienones as acetylcholinesterase inhibitors. Thus, we have identified an inhibitor, which provided valuable insights for further studies aimed at the discovery of more potent acetylcholinesterase inhibitors. (AU)

• FAPESP's process: 13/10449-5 - Morita-Baylis-Hillman adducts as efficient building blocks for the synthesis of molecules of biological interest
• Grantee: Fernando Antonio Santos Coelho
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/18203-5 - Synthesis of molecular hybrids derived from 4-quinolones as potential drug candidates to treat Alzheimer's Disease
• Grantee: Wanda Pereira Almeida
• Support Opportunities: Regular Research Grants