New amides derived from sclareolide as anticholinesterase agents

A series of 25 amides (15 new) derived from (3aR)-(+)-sclareolide were prepared and subjected to Ellman's assay to determine their efficacies as inhibitors for AChE or BuChE. Five amides (9, 13, 14, 15 and 17) caused inhibition of one of the enzymes greater than 60%; thereby those that inhibited BuChE were more active than positive control galantamine, and they showed better K_i values (1.07 to 8.49). In general, it was found that molecules holding a meta-substituted phenyl group showed a higher percentage of enzymatic inhibition. Molecular modelling calculations indicated the putative interactions of compounds with the amino acids residues of both enzymes AChE and BuChE. The cytotoxicity of compounds 9, 13, 14, 15 and 17 was evaluated against a non-malignant murine embryonic fibroblast cell line (NIH 3T3). Of special note is compound 15, as it presented the second-best K_i value for BuChE (1.71), was not cytotoxic (EC₅₀ > 30 μM). Compound 15 also does not violate Lipinski rules, and showed permeability in the blood brain barrier, indicating that it can be considered a lead for the development of new drugs to treat Alzheimer's disease.