Development of Halogenated-Chalcones Bearing with Dimethoxy Phenyl Head as Monoamine Oxidase-B Inhibitors.

Two series of dimethoxy-halogenated chalcones (DM1−DM20) were synthesized and tested for their ability to inhibit monoamine oxidase (MAOs). Compound DM2 exhibited the most significant inhibition against MAO-B with an IC50 value of 0.067 µM, followed by compound DM18 (IC50 = 0.118 µM), with selectivity index (SI) values of 93.88 and >338.98, respectively. However, none of the substances successfully inhibited MAO-A. The MAO-B inhibitors DM2 and DM18 were competitive and reversible, with Ki values of 0.032 ± 0.004 and 0.045 ± 0.001 µM, respectively. DM2 was non-toxic below 100 µg/mL in the cytotoxic test using the Vero epithelial cell line by the MTT method. According to molecular docking studies, DM2 and DM18 formed very similar conformations within the MAO-B binding pocket, with the ortho-chlorine and ortho-fluorine aromatic rings sandwiched between F168 and Y326. These conformations were predicted to show better interactions with the targeted MAO-B than MAO-A. In particular, the induced-fit docking of the dimethoxy phenyl ring of DM2 facing the hydrophobic pocket made up of FAD, Y398, and Y435 had an impact on F168 in the docking pocket. Taken together, DM2 and DM18 may be suitable candidates for treating neurodegenerative conditions such as Parkinson's disease.

Halogenated Coumarin-Chalcones as Multifunctional Monoamine Oxidase-B and Butyrylcholinesterase Inhibitors.

A series of halogenated coumarin-chalcones were synthesized, characterized, and their inhibitory activities against monoamine oxidases (MAOs), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and ß-site amyloid precursor protein cleaving enzyme 1 (BACE-1) were evaluated. Compound CC2 most potently inhibited MAO-B with an IC50 value of 0.51 µM, followed by CC1 (IC50 = 0.69 µM), with a selectivity index (SI) of >78.4 and >58.0, respectively, over MAO-A. However, none of the compounds effectively inhibited MAO-A, AChE, and BChE, except for CC2 and CC3 inhibiting BChE with IC50 values of 7.00 (SI > 5.73 over AChE) and 11.8 µM, respectively. CC1 and CC2 were found to be reversible and competitive inhibitors of MAO-B, with K i values of 0.50 ± 0.06 and 0.53 ± 0.04 µM, respectively, and CC2 was also a reversible and competitive inhibitor of BChE, with a K i value of 2.84 ± 0.09 µM. The parallel artificial membrane permeability assay (PAMPA) method showed that lead candidates can cross the blood-brain barrier (BBB). The in vitro toxicity analysis on the Vero cell line (Normal African green monkey kidney epithelial cells) by MTT confirmed that both CC1 and CC2 were nontoxic up to 100 µg/mL, which is almost equivalent to 100 times of their effective concentration used in biological studies. In addition, CC1 and CC2 attenuated H2O2-induced cellular damage via their reactive oxygen species (ROS) scavenging effect. These results suggest that CC1 and CC2 are selective and competitive inhibitors of MAO-B, and that CC2 is a selective and competitive inhibitor of BChE. Molecular docking studies of lead compounds provided the possible type of interactions in the targeted enzymes. Based on the findings, both compounds, CC1 and CC2, can be considered plausible drug candidates against neurodegenerative disorders.

Molecular mechanism of zinc neurotoxicity in Alzheimer's disease.

Zinc (Zn) is an essential trace element for most organisms, including human beings. It plays a crucial role in several physiological processes such as catalytic reaction of enzymes, cellular growth, differentiation and metabolism, intracellular signaling, and modulation of nucleic acid structure. Zn containing above 50 metalloenzymes is responsible for proteins, receptors, and hormones synthesis and has a critical role in neurodevelopment. Zn also regulates excitatory and inhibitory neurotransmitters such as glutamate and GABA and is found in high concentration in the synaptic terminals of hippocampal mossy fibers that maintains cognitive function. It regulates LTP and LTD by regulation of AMPA and NMDA receptors. But an excess or deficiency of Zn becomes neurotoxic or cause impairment in growth or sexual maturation. There is mounting evidence that supports this idea of Zn becoming neurotoxic and being involved in the pathogenesis of AD. Zn dyshomeostasis in AD is an area that needs attention as moderate concentration of Zn is involved in the memory regulation via regulation of amyloid plaque. Dyshomeostasis of Zn is involved in the pathogenesis of diseases like AD, ALS, depression, PD, and schizophrenia.