Introduction
Neurodegenerative disorders (ND); including Parkinson’s1, 2, Alzheimer’s,3, 4 and other
neural diseases;5 have been described to involve the
gradual loss of particular neuronal cell population. Although numerous
investigations have been devoted to the elucidation of the ND
pathologies, their primary causes continue elusive. Some interrelated
crucial aspects on the progression of these disorders are
proteopathy6-8, metal ion
dyshomeostasis9-32, environmental
pollutants,33-47 and neurotransmitter deficiencies. A
chemical phenomenom shared by all these diseases is oxidative stress
(OS). It could be accountable for the dysfunction or death of neuronal
cells that conduces to disease pathogenesis.48-65
OS arises due to unregulated production and consumption of free
radicals, primarily reactive oxygen species
(ROS).66-78 ROS are produced from molecular oxygen in
the mitochondrial respiratory chain. Some partially reduced
O2 intermediates are formed in low amounts, including
the highly reactive hydroxyl radical (•OH) and the
superoxide anion (O2•-), among
others66, 74, 75, 78-84. Neurons are particularly
vulnerable to ROS-induced damage because of their high oxygen
consumption, relatively low antioxidant defense, low regenerative
capacity, and high polyunsaturated fatty acid
content.78, 85-87 Thus, ROS overproduction in brain
tissue imposes a very harmful threat. One possible therapeutic strategy
is to prevent and/or diminish OS using free radical scavengers. In fact,
a variety of neuroprotective drug agents are used because of their
antioxidant capability88-97.
Rasagiline (N-propargyl-1-(R)-aminoindan; Azilect®) is
an anti-Parkinson, selective irreversible monoamine oxidase (MAO-B)
inhibitor drug. It is currently accepted by the US Food and Drug
Administration, and has demonstrated to show neuroprotective and
neurorestorative activities in in vitro and in vivomodels98-114. Rasagiline benefits patients with both
early and late Parkinson’s disease as monotherapy or as an assistant to
levodopa.115-117 From a chemical point of view,
rasagiline is a secondary cyclic benzylamine and indane derivative, in
which the acetylenic group provides hydrophobicity and steric volume.
Rasagiline can act as a hydrogen bond donor, enabling an additional
interaction with monoamine oxidase B enzyme. Youdim et al. reported that
the S-isomer of rasagiline, TVP1022, is thousands times less potent as a
MAO-B inhibitor118-120 than selegiline. Nevertheless,
both compounds present similar molecular mechanisms, suggesting that the
neuroprotective effect of rasagiline is not depending on MAO-B
inhibition, but to some extent is related to the N-propargyl moiety.
Rasagiline is mainly metabolized by hepatic cytochrome P-450. Its major
metabolite, 1-(R)-aminoindan, is a weak reversible MAO-B inhibitor and a
non-amphetamine compound with antioxidant and neuroprotective
capabilities121. 1-(R)-aminoindan has reversed
behavioral asymmetry and restored striatal catecholamine levels and
neurons protection from hydrogen peroxide-induced oxidative stressin vivo models of Parkinson’s disease.122, 1235-hydroxy-1-(R)-aminoindan is the major metabolite of Ladostigil
[(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate], an
anti-Parkinson drug. It in vitro neuroprotective
capabilities are similar to those of 1-(R)-aminoindan. These findings
suggest that 1-(R)-aminoindan and 5-hydroxy-1-(R)-aminoindan contribute
to the overall neuroprotective activity of its parental compounds and
are also neuro-active compounds.124, 125 So, is the
N-propargyl moiety a key feature to design novel derivatives with potent
antioxidant behavior?
Based on the above-discussed information, the aims of this study are:
-To performe a rational search of molecules derived from the rasagiline
framework, using a computer-assisted design protocol.
-To analyze the importance of the rasagiline triple bond and of the
1-(R)-aminoindan moiety in their drug-like behaviour and antioxidant
potential.
-To propose rasagiline derivatives with high probabilities of being
multipurpose antioxidants capable of lowering OS.
To accomplish that, the rasagiline structure was systematically modified
in two different ways: (i) By inserting different functional groups in
all the possible positions of the aromatic ring. (ii) By replacing the
triple bond of rasagiline with a methyl group or a hydrogen atom (Scheme
1).
The reported results are expected to encourage further theoretical and
experimental investigations on these molecules.