CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Online First

Parkinson's disease is a neurodegenerative condition characterized by slow movement (bradykinesia), tremors, and muscle stiffness. These symptoms occur due to the degeneration of dopamine-producing neurons in the substantia nigra region of the brain, leading to reduced dopamine levels. The development of Parkinson's Disease (PD) involves a combination of genetic and environmental factors. PD is associated with abnormal regulation of the monoamine oxidase (MAO) enzyme. Monoamine oxidase inhibitors (MAOIs) are an important class of drugs used to treat PD and other neurological disorders. In the early stages of PD, monotherapy with MAO-B inhibitors has been shown to be both safe and effective. These inhibitors are also commonly used as adjuncts in long-term disease management, as they can improve both motor and non-motor symptoms, reduce “OFF” periods, and potentially slow disease progression. However, current MAO-B inhibitors come with side effects like dizziness, nausea, vomiting, light-headedness, and fainting. Therefore, accelerating the development of new MAO-B inhibitors with fewer side effects is crucial. This review explores natural compounds that may inhibit monoamine oxidase B (MAO-B), focusing on key findings from the past seven years. It highlights the most effective heterocyclic compounds against MAO-B, including thiazolyl hydrazone, pyridoxine-resveratrol, pyridazine, isoxazole, oxadiazole, benzothiazole, benzoxazole, coumarin, caffeine, pyrazoline, piperazine, piperidine, pyrrolidine, and morpholine derivatives. The review covers in vitro, in silico, and in vivo data, along with the structure-activity relationship of these compounds. These findings offer valuable insights for the development of more effective MAO-B inhibitors and advancements in Parkinson's disease research.

Parkinson’s disease is considered an advancing neurodegenerative disorder with unknown causes, and its association with some risk factors, including aging, family history, and exposure to chemicals, makes it the second most common occurring neurodegenerative disorder throughout the world with increasing prevalence. Parkinson’s disease is associated with slow movement, rigidity, tremors, imbalance, depression, anxiety, cognitive impairment, orthostasis, hyperhidrosis, sleep disorders, pain, and sensory disturbances. In recent decades, there has been a rise in research on the development of effective and potential therapies for the treatment of Parkinson’s disease. An important target for neuroprotection is Monoamine Oxidases (MAO), which hydrolyze neurotransmitters like dopamine and produce very reactive free radicals as a by-product. Aging and neurodegenerative illnesses cause overexpression in the brain, which exacerbates neuronal loss. The treatment of Parkinson's disease with MAO inhibitors has shown promising outcomes. Herein, we reported characteristic features of Parkinson’s disease, various treatment strategies, and the SAR of potential drugs that can be explored further as lead for the development of newer molecules with improved pharmacological profiles.

Alzheimer's Disease (AD) is a serious neurodegenerative condition that predominantly impacts the cholinergic neurons of the entorhinal cortex and hippocampal regions, playing a critical role in learning, navigation, and brain processing. This paper aims to discuss the three main hypotheses of Alzheimer's disease, focusing on neurotoxicity and neurodegeneration caused by mitochondrial dysfunction and ROS production, particularly analyzing the susceptibility differences between genders. Our comprehensive review focuses on significant findings from the past five years, particularly on Cholinesterase (ChE) and BACE-1 inhibitors. Researchers have conducted a detailed analysis of in vitro, in silico, and in vivo data, incorporating extensive Structure-Activity Relationship (SAR) studies. The reviewed papers have been sourced from platforms, such as Google Scholar, Semantic Scholar, and ClinicalTrials.gov, and have been selected based on their AChE and BACE-1 inhibitory activity and structural motif similarity. The review identifies the most effective compounds targeting ChE and BACE-1, highlighting acridine, dihydropyridine, and thiazole-coumarin hybrids for ChE inhibition, and oxadiazole, benzofuran, and dihydropyrimidinone for BACE-1 inhibition. This demonstrates a diverse array of potent heterocyclic hybrids. The review presents a varied compilation of scaffolds showing promise in treating Alzheimer's disease, highlighting the potential of specific compounds against ChE and BACE-1. Given the critical insights derived from our analysis, we posit that this compilation will substantially contribute to the ongoing efforts to combat neurodegeneration and prolong dementia, underscoring the importance of continuous research in this domain.