Design, synthesis, in silico, and in vitro evaluation of novel benzyloxybenzene substituted (S)‐α‐amino amide derivatives as cholinesterases and monoaminoxidases inhibitor

Abstract

In this study, a series of novel benzyloxybenzene substituted (S)‐α‐amino acid methyl esters and their amide derivatives were synthesized and evaluated for their inhibitory actions against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), monoamine oxidase A (MAO‐A), and monoamine oxidase B (MAO‐B). The synthetic strategy was based on starting from benzyl bromide (5) and 4‐hydroxybenzaldehyde (6). The reaction of 5 and 6 in the presence of K2CO3 gave benzyloxybenzaldehyde 7. Benzyloxybenzene substituted (S)‐α‐amino acid methyl esters 11, 12, 13, (±)‐19, and (±)‐20 were obtained from the reaction of L‐amino acid methyl esters with benzyloxybenzaldehyde (7) followed by in situ reduction with NaBH4. The reaction of (S)‐11, (S)‐12, 13, (±)‐19, and (±)‐20 with excess ammonia gave amides (S)‐14, (S)‐15, 16, (±)‐21, and (±)‐22. The in vitro inhibitory activities of compounds against MAO‐A, MAO‐B, AChE, and BChE were investigated. Within the α‐amino acid methyl ester series, 13 (21.32 ± 0.338 µM) showed selectivity by inhibiting the MAO‐B better than MAO‐A. 13 emerged as the most active member of this series, exhibiting a 12‐fold selectivity for MAO‐B. 14 (4.501 ± 0.295 µM) demonstrated a pronounced selectivity for MAO‐A over MAO‐B, with a selectivity ratio of 110‐fold. In addition, it was determined that compound 15 (95.65 ± 3.09 µM) had high selectivity for BChE inhibition. 21 was demonstrated the most potent inhibition (18.36 ± 1.36 µM) against AChE.