Studies On The Design, Synthesis And Neuroprotective Effects Of The Novel Mercaptoethylguanidine Derivatives

Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease, mainly characterized by loss of dopaminergic neurons in the substantial nigra pars compacta. Although the underlying mechanisms in the neurodegenerative processes of PD remain to be elucidated, many studies have suggested the involvement of oxidative stress and mitochondrial dysfunction in the activation of an apoptotic cascade that ultimately results in the loss of dopaminergic neurons. Oxidative stress caused by excessive reactive oxygen species (ROS) production has been shown to lead to cellular dysfunction culminating in cell death. Mercaptoethyl compounds such as:mercaptoethylguanidine (MEG), N-acetylcysteine and glutathione were reported to have neuroprotective effect.Many naturally-occurring compounds have been utilized as sources of leads in drug discovery and efforts also have been made to search compounds with neuroprotective effects. Leonurine was recently reported to significantly reduce6-Hydroxydopamine (6-OHDA)-induced cell death in dopaminergic SH-SY5Y cells and attenuated apomorphine-elicited rotational behavior in6-OHDA-lesioned rats. In this study, taking into account of common structure moieties of Leonurine and MEG, we designed and synthesized eight new mercaptoethylleonurine (MEL) analogues by incorporating the mercaptoethyl group and changing the chain length (R1group) to find new chemical entities which may probably have better neuroprotective activity than Leonurine and MEG. From the data of the neuroprotective activity of MEL, when R1is (CH2)3,10b exhibited the highest neuroprotective activity among all the MEL. Further modification of substitution patterns on the phenyl ring did not achieve any promising analogues.Therefore, we also designed and synthesized eleven new MEG in an attempt to improve their bioavailabilities via changing their physicochemical properties to be more hydrophilic. Similar with MEL, when the side chain length of is3, it exhibited the highest neuroprotective activity among all the MEG. Further SAR study by replacement of hydroxyl group with amino group, compound33k, a bioisosterism of33b, surprisingly turned out to be the most potent analogue at the lowest dose (5μM). Based on the excellent neuroprotective activity,33k was chosen for further study, in which molecular mechanism underlying neuroprotective effects of33k was exerted via Akt and JNK pathway.Furthermore, using combination principles of drug design to maintain the structures of both MEG and Ilomastat which is a kind of MMPI, we designed and synthesized8new ilomastat derivatives. The neuroprotective activity indicated that when the chain length of is3, it showed the higher neuroprotective activity than the compounds which the chain length of is2. The S configuration isobutyl exhibited higher neuroprotective activity than R configuration. The hydroxamic acid showed higher neuroprotective activity than acid.In the study we synthesized27target compounds in which25compounds are new. Their structures were decisively elucidated by spectroscopic analysis.