Metal-free synthesis of functionalized tacrine derivatives and their evaluation for acetyl/butyrylcholinesterase and α-glucosidase inhibition

• Published in: Organic & biomolecular chemistry Vol. 22; no. 4; pp. 79 - 84
• Main Authors: Shirisha, Thangellapally, Majhi, Subir, Divakar, Kalivarathan, Kashinath, Dhurke
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 24.01.2024; Royal Society of Chemistry
• Subjects: Acarbose; Acetylcholinesterase; Acetylcholinesterase - metabolism; Aldehydes; alpha-Glucosidases; Aniline; Biodegradation; Bonding; Butyrylcholinesterase - metabolism; Catalysts; Chemistry; Chemistry, Organic; Cholinesterase Inhibitors - chemistry; Condensates; Glucosidase; Molecular Docking Simulation; Physical Sciences; Science & Technology; Solvents; Structure-Activity Relationship; Substitution reactions; Tacrine; Tacrine - chemistry; Tartaric acid; Urea; α-Glucosidase; DESIGN; ACID; MULTIFUNCTIONAL AGENTS; ALZHEIMERS-DISEASE; ANTIOXIDANT; DRUGS; DEEP EUTECTIC SOLVENTS; ACETYLCHOLINESTERASE INHIBITORS; HYBRIDS
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/d3ob01760e

A mild and greener protocol was developed for C-C (C(sp 3 )−H functionalization) and C-N bond formation to synthesize functionalized tacrine derivatives using a biodegradable and reusable deep eutectic solvent [(DES) formed from N , N ′-dimethyl urea and l -(+)-tartaric acid in a 3 : 1 ratio at 80 °C]. The condensation of 9-chloro-1,2,3,4-tetrahydroacridines with a variety of aromatic aldehydes gave unsaturated compounds via C(sp 3 )−H functionalization (at the C-4 position) with good yields. The substituted N -aryl tacrine derivatives were obtained from the condensed products of 9-chloro-1,2,3,4-tetrahydroacridine with substituted anilines via the nucleophilic substitution reaction (SN 2 type) in the DES with good yields. This is the first example of C4-functionalized tacrine derivatives, highlighting the dual capacity of the DES to serve as both a catalyst and a solvent for facilitating C-N bond formation on acridine. The generated compounds were evaluated for acetyl/butyrylcholinesterase (AChE/BChE) and α-glucosidase inhibitory activity. It was found that the majority of the compounds reported here were significantly more potent inhibitors than the standard inhibitor tacrine (AChE IC 50 = 203.51 nM; BChE IC 50 = 204.01 nM). Among the compounds screened, 8m was found to be more potent with IC 50 = 125.06 nM and 119.68 nM towards AChE and BChE inhibition respectively. The α-glucosidase inhibitory activity of the compounds was tested using acarbose as a standard drug (IC 50 = 23 100 nM) and compound 8j was found to be active with IC 50 = 19 400 nM. The synthesis, in vitro activity, docking and molecular dynamics of tacrine derivatives were studied for AChE, BChE and α-glucosidase inhibition. It was found that many of the reported compounds here showed better activity than standard drugs.