Monoamine oxidases (MAOs; EC 1.4.3.4) are mitochondrial bound flavoenzymes which catalyse the oxidative degradation of amines, including several neurotransmitters, producing an iminium ion that spontaneously hydrolyses to the corresponding aldehyde and ammonium ion. In humans two different isoforms have been observed that differ for substrate specifities and tissue distribution. Physiological and pathological roles of hMAO-A and hMAO-B have been extensively studied. These enzymes play a fundamental role in monoaminergic neurotransmissions regulation controlling the amounts of dopamine (DA), adrenaline (A) and noradrenaline (NA) inside the synaptic cleft. Since an altered activity of the enzymes leads to a reduction of neurotransmitters level in the brain, inhibitors able to selectively act against one of them have been developed and proposed for several neurodegenerative pathologies (Parkinson¿s disease, Alzheimer disease, ecc.).
The efforts of the last years have been focused on the discovery of selective and reversible inhibitors for hMAO-B, higher expressed in the central nervous system than hMAO-A.
Based on our previous experience about hMAOs, we designed and synthesised novel putative inhibitors of hMAO-B, endowed with N-arylbenzofuran-2-carboxamide and N¿-arylbenzofuran-2-carbohydrazide structures. The proposed synthesis of these compounds appears to be quite simple, with three steps, resulting in a save-time process. All the derivatives will be characterized by means NMR and IR spectroscopy and melting point determination. At the end, they will be evaluated for their hMAO-A and hMAO-B inhibitory activity.
The project here presented has the scope to widen the knowledge about the inhibitory activity of benzofuran-based molecules against human monoamine oxidases (hMAOs), FAD-dependent enzymes involved in the oxidative deamination of endogenous and exogenous amines including several neurotransmitters. These enzymes are located to the outer mitochondrial membrane and play a fundamental physiological role in monoaminergic neurotransmissions regulation by controlling the amounts of dopamine (DA), adrenaline (A) and noradrenaline (NA) inside the synaptic cleft.
The two human isoforms of hMAO (hMAO-A and B) differ for distribution, substrate specificity as well as sensibility to inhibitors. They have a pivotal role in key physiological processes taking place in the central nervous system; so, the altered activity of these enzyme is involved in the pathogenesis of various psychiatric and neurological disorders. In order to modulate this altered activity, inhibitors able to selectively act against one of the two isoforms have been developed and proposed for different pathologies of the CNS. The selectivity is an important issue because, the use of non-selective MAO-inhibitors has limitations for the high prevalence of hMAO-A in the gastrointestinal tract where it is mainly involved in the metabolism of an exogenous monoamine, p-tyramine, which can behave as a peripheral adrenergic agonist causing dangerous hypertensive crisis: the so called cheese-effect.
So, the efforts of the last years have been focused on the discovery of selective and reversible inhibitors for hMAO-B, highly expressed in neurodegenerative diseases. Indeed, selective hMAO-B inhibitors are generally proposed as an option for the early therapy of Parkinson¿s disease (PD), alone or in combination with the prodrug levodopa, reducing the metabolic degradation of dopamine. In addition to the enhancement of the dopaminergic neurotransmission, hMAO-B inhibitors reduce the production of hydrogen peroxide (the by-product of MAO-catalysed deamination of neurotransmitters) which exerts oxidative stress on neurons. This can result in a neuroprotective and neurorestorative effects.
The proposed compounds possess some features that make them attractive. In particular, they could be endowed with low-nanomolar and selective activity against the hMAO-B isoform; furthermore, the synthesis to obtain these compounds is quite simple, with only 3 steps, resulting in a save-time process. Besides, using software freely available on-line (molinspiration), the two most simple compounds (N-Phenyl-1-benzofuran-2-carboxamide and N'-Phenyl-1-benzofuran-2-carbohydrazide) of the proposed series have been evaluated for their physic-chemical properties. The results exhibited good ¿drug-like¿ properties, underling the potential of these compounds for their ability to cross the blood brain barrier (BBB) and to be able to effectively act in the CNS.