Parkinson¿s disease (PD) is a neurodegenerative, hereditary/sporadic condition characterized by progressive and debilitating nervous system dysfunction (altered movement and cognitive impairment). The loss of dopaminergic neurons and the deficiency of dopamine, in the nigrostriatal pathway (Substantia Nigra pars compacta) is the main hallmark feature in PD. Current therapeutic management of PD largely involves strategies to optimize the replacement of deficient dopamine, using dopamine agonists and inhibitors of dopamine-metabolizing enzymes (i.e. hMAO-B). But these treatments are unlikely to be curative or effective alone. In this kind of multifactorial pathologies, drugs are strongly required to address the varied pathological aspects focusing a combine pharmacological activity on a single molecular entity. As a matter of this, a promising approach results from multifunctional compounds that display the ability to simultaneously interact with alternative targets. Due to the importance of selective hMAO-B inhibitors and A2A receptor antagonists in the treatment of PD, our aim is to design novel compounds endowed with these dual pharmacological activities. The choice of thiazole derivatives as the scaffold to be studied is corroborated by structure-activity relationships on this topic and data reported in the literature. Each compound will be purified and fully characterized before the biological evaluation by means of spectroscopic methods and elemental analysis to verify purity and stability. The diastereoisomers will be separate using chiral phases on HPLC system.
Human monoamine oxidases (hMAOs) are FAD-dependent enzymes which are involved in the oxidative deamination of endogenous and exogenous primary, secondary and tertiary amines. Located on the outer mitochondrial membrane, hMAOs play a fundamental physiological role in the regulation of monoaminergic neurotransmissions by controlling the amounts of dopamine (DA), adrenaline (A) and noradrenaline (NA) inside the synaptic cleft. In the brain, hMAOs are present in two isoforms, hMAO-A and hMAO-B, which differ in distribution, substrate specificity, and sensibility to inhibitors. Inhibition of hMAOs, in fact, represents the rationale for the treatment of those pathologies in which there is an impairment of synaptic transmission, such as depressive disorders and neurodegenerative diseases.However, one of the main limitations to the use of non-selective MAO-inhibitors is the high prevalence of hMAO-A in the gastrointestinal tract, where it is mainly involved in the metabolism of an exogenous monoamine: p-tyramine. Although p-tyramine cannot cross the blood brain barrier, it can behave as a peripheral adrenergic agonist and cause dangerous hypertensive crisis: the so called cheese-effect. The safety of hMAO-inhibitors has been considerably which are endowed with high therapeutic potential against neurodegenerative disorders like Parkinson¿s and Alzheimer¿s disease, but devoid of unwanted peripheral effects. In fact, hMAO-B is highly expressed in astrocytes around senile plaques and its activity is notably increased in patients with age-related gliosis and Alzheimer's disease. hMAO-B selective inhibition is expected to enhance dopaminergic neurotransmission, which is beneficial for PD, and to reduce the oxidative stress exerted on neurons by hydrogen peroxide, a byproduct of MAO-catalyzed deamination of neurotransmitters, resulting in a neuroprotective and neurorestorative effects. Therefore, there is a considerable interest in obtaining potent and selective MAO inhibitors. Structure-activity relationships (SAR) study:
these relationships will be of great value in guiding the investigators decision-making with regard to the synthesis of new and more effective congeners. Compounds share a common nitrogen-scaffold useful to extrapolate accurate SAR studies by means of slight chemical differences.
Molecular modeling studies: the project will be also improved according to the knowledge of the biological target's three-dimensional structure by means of computational methodologies able to suggest rational modification of the lead compounds.