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.