Design, Synthesis and Inhibitory Activities of 8-(Substituted styrol-formamido)phenyl-xanthine Derivatives on Monoamine Oxidase B

Abstract

The design and synthesis of two series of 8-(substituted styrol-formamido)phenyl-xanthine derivatives are described. Their in vitro monoamine oxidase B (MAO-B) inhibition were tested and the effect of substituents on the N-7, phenyl and the substituted positions are discussed. It was observed that compound 9b displayed significant MAO-B inhibition activity and selectivity, fluorine substitution plays a key role in the selectivity of MAO-B inhibition, and the styrol-formamido group at position-3′ may enhance the activity and selectivity of 8-phenyl-xanthine analogues. These results suggest that such compounds may be utilized for the development of new candidate MAO-B inhibitors for treatment of Parkinson's disease.Key words xanthine derivative; monoamine oxidase B inhibition activity; substituent effect Parkinson's disease (PD) is a neurodegenerative disorder characterized pathologically by a marked loss of dopaminergic nigrostriatal neurons and clinically by disabling movement disorders.1) Currently, the therapy of PD is largely focused on dopamine replacement strategies with the dopamine precursor levodopa and dopamine agonist drugs. Although these strategies are highly effective in controlling the disease at the early stages, drug-related complications are associated with long-term treatment. The inadequacies of dopamine replacement therapy have prompted the research of alternative drug targets. 2-5)Monoamine oxidase (MAO) is an integral protein of the outer mitochondrial membrane, and exist in two forms, namely, monoamine oxidase A (MAO-A) and MAO-B. MAO-A preferentially deaminates aromatic monoamines such as the neurotransmitters serotonin (5-HT), noradrenaline (NA), andadrenaline (A); MAO-B is one of the most important key enzymes in metabolic pathways in vivo and plays mainly three roles: firstly, MAO-B decomposes dopamine into 3,4-dihydroxyphenyl acetic acid and homovanillic acid, meanwhile producing the neurotoxic H 2 O 2 . Secondly, MAO-B inactivates p-phenylethylamine which has the ability to stimulate secrection and reuptake function of dopamine. Thirdly, in the precence of MAO-B, catalyzed oxidation of 1-methyl-4-phenyl-1,2,3,6-terahydropyridine (MPTP) to intermediate 1-methyl-4-phenyl-2,3-dihydropyridin-1-ium (MPDP + ) and then to 1-methyl-4-phenylpyridin-1-ium (MPP + )with neurotoxicity occurs. Together these suggest that inhibiting the action of MAO-B can not only reduce the degradation of dopamine and reuptake, improving the concentration of dopamine in the brain, but also lower levels of H 2 O 2 , and MPP + to enhance neuroprotective properties. [6][7][8][9][10][11][12] Recently, xanthine and its derivatives were reported to produce little or no inhibition of MAO-B. In the last decade, when introducing phenyl at position-8, 8-phenyl xanthine exhibited MAO-B inhibition activity in vitro with a inhibition constant (K i ) value of 86.2 μM.2) Petzer et al. found a series of 8-styryl xanthine analogues exhibiting more powerful inhibition of MAO-B than 8-phenyl xanthine analogues (CSC K i =100 nM; KW6...

Cinnamamide Derivatives for Central and Peripheral Nervous System Disorders—A Review of Structure–Activity Relationships

“…Their activity resultsi nraising dopamine levels but also inhibition of the production of neurotoxic hydrogen peroxidea nd 1methyl-4-phenylpyridin-1-ium. [61] Designing as caffold containingb oth moieties resulted in ag roup of cinnamamide compoundse xhibiting activity of MAO-B inhibitors.…”

“…Designing as caffold containingb oth moieties resulted in ag roup of cinnamamide compoundse xhibiting activity of MAO-B inhibitors. [61]…”

“…Localization of the styrol-formamide group (cinnamoyl moiety) in position 3o ft he phenyl substituent of xanthine might be preferential for both selectivity and inhibitory properties over substitution in position4.7 -N-Methylation of xanthine seemed to have no impact on the evaluated properties. [61]…”

“…Activity of cinnamamides 23-25 active against monoamine oxidase B( MAO-B) [61]. AE 1.45[a] %Inhibition was determined in mice brain homogenates using kynuramined ihydrobromide as as ubstrate, the concentration of 4-hydroxyquinolinew as measured at at estc ompoundc oncentration of 1nm;d ata are the mean AE SEM of at least three independent experiments.…”

Synthesis and Evaluation of Phenylxanthine Derivatives as Potential Dual A2AR Antagonists/MAO-B Inhibitors for Parkinson’s Disease

“…In our previous studies [ 12 , 13 ], we have reported that a group of PX derivatives are potent inhibitors of monoamine oxidase B (MAO-B) which are known to possess antiparkinsonian properties [ 14 , 15 ]. Since xanthine derivatives such as caffeine, CSC and istradefylline ( Figure 1 ) have the ability to block A2AR, we speculated that PX derivatives ( Figure 2 ) might also have similar ability.…”