Imino isatin derivatives; synthesis, in silico molecular dynamic study over monoamine oxidase B, ADME prediction, and in vitro cytotoxicity evaluation

The monoamine oxidase B (MAO‐B) depicts an attractive drug target for the development of neuro protective agents toward the treatment of neurodegenerative diseases. The current study involved synthesis, in silico and cytotoxic evaluation of N1‐alkylated‐5‐substituted 3‐imino isatin derivatives with the proposed MAO‐B inhibitory activities. The In silico molecular modeling investigation was performed through the induced fit docking, molecular mechanics‐generalized born surface area, and molecular dynamic method in order to uncover the binding mode interaction and their proposed impact on the active site environment and flexibility. The synthesized compounds were characterized by spectroscopic methods. Compound 3‐Imino‐1‐pentyl indolin‐2‐one (3h) with the highest free binding energy adopts an extended conformation spanning from the flavin ring location to the entrance of the substrate cavity. In this way, Ile199 adopts the “open” conformation so the two separate cavities of MAO‐B active site fused and formed a single‐space, which abled the compound extending to the MAO‐B entrance cavity space. From consideration of the data presented in this paper, we reveal that longer N1‐alkylated‐3‐imino isatin derivative could be proposed as inhibitor that would occupy both cavities of the MAO‐B active site. Furthermore, the mentioned derivatives provided acceptable drug profiling based on in silico ADME calculation and MTT cytotoxicity test evaluation. The current study involved synthesis, in silico and cytotoxic evaluation of N1‐alkylated‐5‐substituted isatin derivatives with proposed monoamine oxidase B (MAO‐B) inhibition activity. Compound 3‐Imino‐1‐pentyl indolin‐2‐one (3h) with the highest free binding energy adopts a favorable conformation at the entrance of the substrate cavity. The synthesized compounds could be proposed as a new reversible MAO‐B inhibitor.