Recent Medicinal Chemistry Studies against Neurodegenerative Diseases

Neurodegenerative diseases include Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Huntington's disease. These diseases involve different aspects of reward processing (primary rewards, secondary rewards, reward-based learning, and reward-based decision-making). About 70% of the population with age of 65 years or more are affected by these progressive neurodegenerative disorders of the central nervous system and are characterized by gradual loss of cognitive function, progressive memory loss, disorientation, language impairment, abnormal behavior, personality changes, etc. Medicinal Chemistry studies include current developments in rational drug design, synthetic chemistry, bioorganic chemistry, high-throughput screening, combinatorial chemistry, compound diversity measurements, drug absorption, drug distribution, metabolism, new and emerging drug targets, natural products, pharmacogenomics, and structure-activity relationships. This thematic issue reported medicinal chemistry studies of different methodologies applied in order to optimize the search for new drugs for the cure and treatment of neurodegenerative diseases [1-10].

Alzheimer's and Parkinson's diseases are neurodegenerative disorders that affect a great number of people around the world, seriously compromising the quality of life of individuals due to motor and cognitive damage. In these diseases, pharmacological treatment is used only to alleviate symptoms. This emphasizes the need to discover alternative molecules for use in prevention. Using Molecular Docking, our review entitled Computational Studies Applied to Linalool and Citronellal Derivatives Against Alzheimer and Parkinson Disorders: A Review with Experimental Approach aimed to evaluate the anti-Alzheimer and anti-Parkinson activity of linalool and citronellal, as well as their derivatives. Before performing Molecular Docking simulations, the compounds' pharmacokinetic characteristics were evaluated. The compounds studied presented a high probability of modulatory activity against the disease targets under study and are potential candidates for future drugs.

Phytochemicals or natural products have been studied extensively for their potential in the treatment of neurodegenerative diseases (NDs) like Parkinson’s disease, Alzheimer’s disease, etc. The targeting pathway must prevent cell death and should restore the damaged neurons. In the treatment of NDs and related diseases, natural products are playing the role of neuroprotective agents. This review of Dr. Mittal et al., entitled Natural products-based drugs: Potential drug targets against neurological degeneration, targeted the therapeutic potential of various phytochemicals which shows their neuroprotective action. Traditional herbs and formulations which are used in Indian ayurvedic system are rich sources of antioxidant, anti-amyloidogenic, neuroprotective and anti-inflammatory compounds. They promote quality of life by improving cognitive memory and rejuvenating brain functioning through neurogenesis. A rich knowledge base of traditional herbal plants (Turmeric, Gingko, Ashwagandha, Shankhpushpi, Giloy, Gotu kola, Garlic, Tulsi, Ginger, and Cinnamon) combined with modern science could suggest new functional leads for Alzheimer's drug discovery. In the article entitled Herbal therapeutics for Alzheimer's disease: Ancient Indian medicine system from the modern viewpoint, Ayurveda, the ancient Indian herbal medicine system, based clinical and experimental evidence have been reviewed for treating Alzheimer’s disease (AD) and improving brain functioning. The article of Dr. Kushwah and co-workers presented a modern perspective of the herbs available in the ancient Indian Medicine system as well as their possible mechanisms of action for AD treatment. Main objective here was to provide a systematic review of herbal drugs that are easily accessible and have the potential for the treatment of AD.

According to the Aβ hypothesis, progressive buildup of extracellular and intracellular Aβ aggregates has a significant contribution to the AD-linked neurodegeneration process. Since Aβ plays an important role in the etiology of AD, therefore Aβ-linked pathways are mainly targeted in order to develop 30 potential AD therapies. Accumulation of Aβ plaques in the brains of AD individuals is an important hallmark of AD. These plaques are mainly composed of Aβ (a peptide of 39-42 amino acids) aggregates produced via the proteolytic cleavage of amyloid precursor protein. It has been confirmed by numerous studies that Aβ are ordered oligomers which play a role as a cause instead of an AD product. It has been confirmed by various animal and in vitro studies that polyphenols (PPHs) exhibited neuroprotective potentials in multiple Aβ-induced toxicity models, which further suggest that analogs or molecules containing similar chemical structures might be regarded as effective therapeutic agents for the AD treatment. The review Unveiling the Potential of Polyphenols as Anti-Amyloid Molecules in Alzheimer’s Disease summarized the roles of Aβ in AD pathogenesis, the Aβ aggregation pathway, types of PPHs, and distribution of PPHs in dietary sources. Furthermore, Dr. Khabir et al. focused on the potential of food-derived PPHs as putative anti-amyloid drugs.The rapid increase in AD has led to a concomitant increase in the research work directed toward the discovery of a lucrative cure for AD. The neuropathology of AD comprises the deficiency in the availability of neurotransmitters and important neurotrophic factors in the brain, extracellular beta-amyloid plaque depositions, and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. Current pharmaceutical interventions utilizing synthetic drugs have manifested resistance and toxicity problems. This has led to the quest for new pharmacotherapeutic candidates naturally prevalent in phytochemicals. In the review Current naturopathy to combat Alzheimer’s disease, Dr. Chakrovorty and colleagues aim to provide an elaborative description of promising phyto component entities having activities against various potential AD targets. Therefore, naturopathy may combine with synthetic chemotherapeutics to longer the survival of the patients.

Huntington’s disease (HD) is a rare and fatal neurodegenerative disorder with no disease modifying therapeutics. HD is characterized by extensive neuronal loss and is caused by the inherited expansion of the huntingtin (HTT) gene that encodes a toxic mutant HTT (mHTT) a protein having expanded polyglutamine (polyQ) residues. Current HD therapeutics only offer symptomatic relief. In fact, Food and Drug Administration (FDA) approved two synthetic small-molecule VMAT2 inhibitors, tetrabenazine (1) and deutetrabenazine (2), for managing HD chorea and various others in clinical trials. Therefore, the landscape of drug discovery programs for HD is evolving to discover disease-modifying HD therapeutics. Likewise, numerous natural products are being evaluated at different stages of clinical development and have shown the potential to ameliorate HD pathology. The inherent anti-inflammatory and antioxidant properties of natural products mitigate the mHTT-induced oxidative stress and neuroinflammation, improve mitochondrial functions, and augment the anti-apoptotic and pro-autophagic mechanisms for increased survival of neurons in HD. In the review the emerging landscape of natural small-molecule therapeutics for Huntington’s disease, Dr. Bhat et al. discussed HD pathogenesis. They summarized the anti-HD clinical and pre-clinical natural products, focusing on their therapeutic effects and neuroprotective mechanism/s.

We, the Guest-Editors would like to express our gratitude to the many authors who contributed to this special issue, reporting their investigations into the various aspects involved in Recent Medicinal Chemistry studies against neurodegenerative diseases.