Development of a New Class of Monoamine Oxidase-B Inhibitors by Fine-Tuning the Halogens on the Acylhydrazones.

A total of 14 acyl hydrazine derivatives (ACH1-ACH14) were developed and examined for their ability to block monoamine oxidase (MAO). Thirteen analogues showed stronger inhibition potency against MAO-B than MAO-A. With a half-maximum inhibitory concentration of 0.14 µM, ACH10 demonstrated the strongest inhibitory activity against MAO-B, followed by ACH14, ACH13, ACH8, and ACH3 (IC50 = 0.15, 0.18, 0.20, and 0.22 µM, respectively). Structure-activity relationships suggested that the inhibition effect on MAO-B resulted from the combination of halogen substituents of the A- and/or B-rings. This series concluded that when -F was substituted to the B-ring, MAO-B inhibitory activities were high, except for ACH6. In the inhibition kinetics study, the compounds ACH10 and ACH14 were identified as competitive inhibitors, with Ki values of 0.097 ± 0.0021 and 0.10 ± 0.038 µM, respectively. In a reversibility experiment using the dialysis methods, ACH10 and ACH14 showed effective recoveries of MAO-B inhibition as much as lazabemide, a reversible reference. These experiments proposed that ACH10 and ACH14 were efficient, reversible competitive MAO-B inhibitors. In addition, the lead molecules showed good blood-brain barrier permeation with the PAMPA method. The molecular docking and molecular dynamics simulation study confirmed that the hit compound ACH10 can form a stable protein-ligand complex by forming a hydrogen bond with the NH atom in the hydrazide group of the compound.

Flavonoid and Chalcone Scaffolds as Inhibitors of BACE1: Recent Updates.

Flavonoids and chalcones are two major classes of chemical moieties that have a vast background of pharmacological activities. Chalcone is a subclass of flavonoids whose therapeutic potential has been implicated due to an array of bioactivities. A lot of research works have shown interest in investigating the neuroprotective effect of these molecules, and have revealed them to be much more potent molecules that can be used to treat neurodegenerative disorders. Beta-site APP cleaving enzyme (BACE1), which is majorly found in the brain, is one of the reasons behind the development of Alzheimer's disease (AD). Flavonoids and chalcones have proven clinical data that they inhibit the production of Aß plaques that are involved in the progression of AD. In this article, we have provided a detailed chronological review of the research work on the BACE1 inhibiting potency of both flavonoids and chalcones. Almost all the flavonoids and chalcones mentioned in this article have shown very good in vitro and in vivo BACE1 inhibiting activity. The docking studies and the structural importance of some BACE1-inhibiting flavonoids, as well as chalcones, are also mentioned here.