Synthesis and biological evaluation of potential acetylcholinesterase inhibitors based on a benzoxazine core

• Published in: Archiv der Pharmazie (Weinheim) 2018-05, Vol.351 (5), p.e1800024-n/a
• Main Authors: Méndez‐Rojas, Claudio, Quiroz, Gabriel, Faúndez, Mario, Gallardo‐Garrido, Carlos, Pessoa‐Mahana, C. David, Chung, Hery, Gallardo‐Toledo, Eduardo, Saitz‐Barría, Claudio, Araya‐Maturana, Ramiro, Kogan, Marcelo J., Zúñiga‐López, María C., Iturriaga‐Vásquez, Patricio, Valenzuela‐Gutiérrez, Carla, Pessoa‐Mahana, Hernán
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; benzoxazinones; human acetylcholinesterase inhibition; indole
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.201800024

With the purpose of expanding the structural variety of chemical compounds available as pharmacological tools for the treatment of Alzheimer's disease, we synthesized and evaluated a novel series of indole‐benzoxazinones (Family I) and benzoxazine‐arylpiperazine derivatives (Family II) for potential human acetylcholinesterase (hAChE) inhibitory properties. The most active compounds 7a and 7d demonstrated effective inhibitory profiles with Ki values of 20.3 ± 0.9 μM and 20.2 ± 0.9 μM, respectively. Kinetic inhibition assays showed non‐competitive inhibition of AChE by the tested compounds. According to our docking studies, the most active compounds from both series (Families I and II) showed a binding mode similar to donepezil and interact with the same residues. A series of novel indole‐benzoxazinones and benzoxazine‐arylpiperazine derivatives were synthesized and evaluated for their human acetylcholinesterase (hAChE) inhibitory properties. Compounds 7a and 7d demonstrated effective inhibitory profiles with Ki values of 20.3 ± 0.9 and 20.2 ± 0.9 μM, respectively.