Assembling of phenyl substituted halogens in the C3-position of substituted isatins by mono wave assisted synthesis: development of a new class of monoamine oxidase inhibitors

Abstract

A series of ten chloro- and bromo-substituted isatin derivatives were synthesized and evaluated for their ability to inhibit the monoamine oxidase (MAO) enzymes. All compounds demonstrated more potent inhibition of MAO-A compared to MAO-B. The most potent MAO-A inhibitor was HIB2 (IC₅₀ = 0.037 μM), followed by HIB4 (IC₅₀ = 0.039 μM), while HIB10 (IC₅₀ = 0.125 μM) exhibited the most potent inhibition of MAO-B. HIB2 was identified as a specific MAO inhibitor with a selectivity index of 29 for MAO-A over MAO-B. The enzyme-inhibitor dissociation constants (K_i) for HIB2 and HIB10 were 0.031 μM and 0.036 μM, respectively, for MAO-A and MAO-B. Both HIB2 and HIB10 exhibited competitive and reversible inhibition. An analysis of the ADMET and PAMPA suggested that HIB2 is permeable to the blood–brain barrier (BBB). Molecular docking analysis revealed that HIB2 forms stable hydrogen bonds with Asn181 and Gln215 in the MAO-A ligand–protein complex. Dynamic analysis indicated the stability of HIB2 with MAO-A. These findings suggest that HIB2 is potent reversible MAO-A inhibitor, making this class of compounds potential therapeutic agents for neurological disorders.