Trimethoxylated Halogenated Chalcones as Dual Inhibitors of MAO-B and BACE-1 for the Treatment of Neurodegenerative Disorders

Abstract

Six halogenated trimethoxy chalcone derivatives (CH1–CH6) were synthesized and spectrally characterized. The compounds were further evaluated for their inhibitory potential against monoamine oxidases (MAOs) and β-secretase (BACE-1). Six compounds inhibited MAO-B more effectively than MAO-A, and the 2′,3′,4′-methoxy moiety in CH4–CH6 was more effective for MAO-B inhibition than the 2′,4′,6′-methoxy moiety in CH1–CH3. Compound CH5 most potently inhibited MAO-B, with an IC50 value of 0.46 µM, followed by CH4 (IC50 = 0.84 µM). In 2′,3′,4′-methoxy derivatives (CH4-CH6), the order of inhibition was –Br in CH5 > -Cl in CH4 > -F in CH6 at the para-position in ring B of chalcone. CH4 and CH5 were selective for MAO-B, with selectivity index (SI) values of 15.1 and 31.3, respectively, over MAO-A. CH4 and CH5 moderately inhibited BACE-1 with IC50 values of 13.6 and 19.8 µM, respectively. When CH4 and CH5 were assessed for their cell viability studies on the normal African Green Monkey kidney cell line (VERO) using MTT assays, it was noted that both compounds were found to be safe, and only a slightly toxic effect was observed in concentrations above 200 µg/mL. CH4 and CH5 decreased reactive oxygen species (ROS) levels of VERO cells treated with H2O2, indicating both compounds retained protective effects on the cells by antioxidant activities. All compounds showed high blood brain barrier permeabilities analyzed by a parallel artificial membrane permeability assay (PAMPA). Molecular docking and ADME prediction of the lead compounds provided more insights into the rationale behind the binding and the CNS drug likeness. From non-test mutagenicity and cardiotoxicity studies, CH4 and CH5 were non-mutagenic and non-/weak-cardiotoxic. These results suggest that CH4 and CH5 could be considered candidates for the cure of neurological dysfunctions.

Chalcone Scaffolds Exhibiting Acetylcholinesterase Enzyme Inhibition: Mechanistic and Computational Investigations

“…Chalcones have been regarded as a privileged scaffold due to their extraordinary features of smaller molecular size, convenient and cost-effective synthesis, and flexibility for modifications [ 41 , 42 ]. The lipophilicity of the corresponding compounds can be altered and modulated to allow it to cross the blood–brain barrier (BBB) and be effective for neurological disorders, including AD [ 43 , 44 , 45 ]. The critical capabilities of chalcone scaffold led to vast investigations resulting in the identification of several derivatives showing promising anticancer, anti-infection, anti-ulcer, anti-inflammatory, and anti-neurodegenerative diseases [ 46 , 47 , 48 , 49 ].…”

Selected Class of Enamides Bearing Nitro Functionality as Dual-Acting with Highly Selective Monoamine Oxidase-B and BACE1 Inhibitors

“…Recently, our group developed some trimethoxy halogenated chalcones as dual-acting MAO-B and BACE1 inhibitors that exhibited activities in the range of 0.84 to 4.17 µM and 13.6 to 19.8 µM, respectively [ 35 ]. In another study, phytochemicals from Rauwolfia serpentina roots were evaluated for their MTDL efficiencies, while indole alkaloids (reserpine and ajmalicine) were evaluated as potential agents for MAO-B and BACE1 inhibition with dose-dependent activities [ 36 ].…”

The Emerging Role of Topical Ocular Drugs to Target the Posterior Eye

“…Besides the formulations mentioned above, many other forms of nanomedicines, including nanoemulsion [ 121 ], quantum dot [ 122 ], solid–lipid nanoparticle [ 123 ], and so on, have been investigated as topical ocular drug carriers and demonstrate beneficial efficacy. As an example, dexamethasone carried by soluble nanoparticle (drug name OCS-01) developed by Oculis is now in a phase III clinical trial for DME.…”