The synthesis and evaluation of (E)-styrylisatin analogues as inhibitors of monoamine oxidase B

摘要: Monoamine oxidase B (MAO-B) inhibitors are currently clinically used in the symptomatic treatment of Parkinson's disease (PD) and may also possess neuroprotective activity. The irreversible MAO-B inhibitor, (R)-deprenyl, is commonly PD treatment, usually combination with levodopa during dopamine replacement therapy. In contrast reversible inhibition, enzyme recovery after inhibition involves de novo synthesis. relatively quick return activity makes potent safer more desirable. Both isatin caffeine small molecules that have been reported to inhibit MAO-B. Isatin a good endogenous inhibitor (K, = 3 uM) whereas weak (Kj 650 urn). inhibitory potency improved by substitution at C-8 ring styryl side-chain. Addition an electron withdrawing substituent C-3 phenyl produced structures exceptional potency, for example (£)-8-(3-chlorostyryl)caffeine (CSC) 0.1 uM). this study we investigated whether lead compound, isatin, C-5 C-6 will similarly enhance isatin's potency. Preliminary computer modelling proposed (£)-5-styrylisatin (£)-6-styrylisatin analogues, as well into active site recombinant supported hypothesis increased these analogues. sidechain seems be stabilised entrance cavity binding, while moiety located substrate-binding where it involved hydrogen bonding. This duel binding mode similar caffeines thought facilitate caffeines. After successful synthesis compounds were evaluated vitro baboon liver Inhibitory styrylisatin analogues determined spectro photo metric method. potencies all expressed terms concentration compound necessary 50% (IC50 value). Reversibility was confirmed time-dependent showed (E)-styrylisatin independent time period which analogue incubated enzyme. results side-chain on resulted exceptionally potent. For example, (£)-5iv (3-chlorostyryl)isatin 20.7 nM) found 430 times than 8.6 Also, (E)-5-styrylisatin IC50 value 41.7 nM, approximately 210 isatin. moderate, inhibition. has 436.8 nM. electronic lipophilic properties seem important compounds. study, synthesised particular (£)-5-(3chlorostyryl)isatin, potential novel inhibitors. Synthesis evaluatin extensive series styryiisatin would enable Hansch-type structure-activity relationship could identify optimal physicochemical