Akincioglu_2024_Drug.Dev.Res_85_e22161

In this study, a series of novel benzyloxybenzene substituted (S)-alpha-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)-alpha-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 alpha-amino acid methyl ester series, 13 (21.32 +/- 0.338 microM) 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 microM) 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 microM) had high selectivity for BChE inhibition. 21 was demonstrated the most potent inhibition (18.36 +/- 1.36 microM) against AChE.