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

Abstract

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.

Exploration of the Detailed Structure–Activity Relationships of Isatin and Their Isomers As Monoamine Oxidase Inhibitors

“…The Ile199 side chain was seen along the boundary of the active center, which correlates to the open conformer, in the enzyme complex with compound 76 , whereas the stated residue side chain moved forward toward the catalytically active cavity in the selegiline-bound state. In conclusion, from this literature, we learn that these 3-imino indolin-2-one compounds maybe good inhibitors, provided they showed good drug profiling based on the in silico analysis as well as the MTT assay …”

“…Ahmadi et al. 63 created 3-imino indolin-2-one compounds ( Figure 22 a) and tested them biologically for their inhibitory profiles of MAOs. Recently, the synthesis of 3-imino indolin-2-one compounds was performed using reflux circumstances with a wide range of solvents.…”

“…In conclusion, from this literature, we learn that these 3-imino indolin-2-one compounds maybe good inhibitors, provided they showed good drug profiling based on the in silico analysis as well as the MTT assay. 63 …”

“…Ahmadi et al . created 3-imino indolin-2-one compounds (Figure a) and tested them biologically for their inhibitory profiles of MAOs.…”

“…Based on these findings, it was determined that p-alkyl and hydrogen-bonding interactions are responsible for the majority of the powerful drug inhibition of MAO-B. Ahmadi et al 63 created 3-imino indolin-2-one compounds (Figure 22a) and tested them biologically for their inhibitory profiles of MAOs. Recently, the synthesis of 3-imino indolin-2one compounds was performed using reflux circumstances with a wide range of solvents.…”