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

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 K 2 CO 3 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 NaBH 4 . 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.