Development of Halogenated Indole-Based Chalcones as New Class of MAO-Inhibitors

Abstract

The design and synthesis of chalcones based on halogenated indole are the main topics of this investigation. Ten derivatives were synthesized by introducing halogen substitutions (F, Cl, Br) at the aromatic B ring's ortho, meta, and para positions. (I-1 to I-10). These compounds' in vitro inhibitory activity towards monoamine oxidases was subsequently determined. Among them, compound I-2 exhibited potent MAO-A inhibition with an IC50 of 0.823±0.045 μM, while compound I-4, with an IC50 of 0.014 ±0.008 μ, showed excellent MAO-B inhibition implying that MAO-B selectivity is improved by parachloro substitution. To assess Central Nervous System (CNS) drug-likeness, the lead molecules were subjected to PAMPA method. The results showed that compound I-2 displayed significant CNS permeability with a Pe value exceeding 4.0 × 10-6 cm/s. Molecular docking revealed that compounds I-2 and I-4 exhibited unique binding interactions compared with the reference drug safinamide, including π-π stacking with TYR-398 and hydrogen bonding with CYS-171, while retaining a conserved hydrogen bond with GLN-206. In silico pharmacokinetic studies further indicated that I-2 and I-4 possess favorable properties, including effective Blood-Brain Barrier (BBB) penetration. Considering these findings, halogenated indole-based chalcones, particularly compounds I-2 and I-4, present themselves as noteworthy lead candidates for addressing neurodegenerative diseases.