Current Medicinal Chemistry - Volume 28, Issue 12, 2021

The unmet need for the development of effective drugs to treat Alzheimer's disease has been steadily growing, representing a major challenge in drug discovery. In this context, drug repurposing, namely the identification of novel therapeutic indications for approved or investigational compounds, can be seen as an attractive attempt to obtain new medications reducing both the time and the economic burden usually required for research and development programs. In the last years, several classes of drugs have evidenced promising beneficial effects in neurodegenerative diseases, and for some of them, preliminary clinical trials have been started. This review aims to illustrate some of the most recent examples of drugs reprofiled for Alzheimer’s disease, considering not only the finding of new uses for existing drugs but also the new hypotheses on disease pathogenesis that could promote previously unconsidered therapeutic regimens. Moreover, some examples of structural modifications performed on existing drugs in order to obtain multifunctional compounds will also be described.

Metabolic stress, transduced as an altered cellular redox and energy status, presents as the main culprit in many diseases, including diabetes. However, its role in the pathology of neurological disorders is still not fully elucidated. Metformin, a biguanide compound, is an FDA approved antidiabetic drug generally used for the treatment of type 2 diabetes. The recently described wide spectrum of action executed by this drug suggests a potential therapeutic benefit in a panoply of disorders. Current studies imply that metformin could play a neuroprotective role by reversing hallmarks of brain injury (metabolic dysfunction, neuronal dystrophy and cellular loss), in addition to cognitive and behavioral alterations that accompany the onset of certain brain diseases such as Alzheimer’s disease (AD) and depression. However, the mechanisms by which metformin exerts its protective effect in neurodegenerative disorders are not yet fully elucidated. The aim of this review is to reexamine the mechanisms through which metformin performs its function while concentrating on its effect on reestablishing homeostasis in a metabolically disturbed milieu. We will also highlight the importance of metabolic stress, not only as a component of many neurological disorders, but also as a primary driving force for neural insult. Of interest, we will explore the involvement of metabolic stress in the pathobiology of AD and depression. The derangement in major metabolic pathways, including AMPK, insulin and glucose transporters, will be explored and the potential therapeutic effects of metformin administration on the reversal of brain injury in such metabolism dependent diseases will be exposed.

Andrographolide, the main bioactive component separated from Andrographis paniculata in 1951, has been scrutinized with a modern drug discovery approach for anti-inflammatory properties since 1984. Identification of new uses of existing drugs can be facilitated by searching for evidence linking them to known or yet undiscovered drug targets and human disease states to develop new therapeutic indications.Furthermore, a wide spectrum of biological properties of andrographolide such as anticancer, antibacterial, antiviral, hepatoprotective, antioxidant, anti-malarial, anti-atherosclerosis are also reported. However, poor water solubility and instability limit its clinical application. It becomes crucial to enhance its pharmacological function and find a new treatment option for more diseases. Therefore, this article reviews the major recent developments in andrographolide, including repurposing applications in different diseases and underlying mechanisms, particularly focusing on pharmacological enhancement of andrographolide such as derivatives, chemical modifications with potent biological activity and drug delivery. The repurposing and pharmacological enhancement of andrographolide would not only have exciting therapeutic potential to different diseases to facilitate drug marketing, but also decrease the economic burden on healthcare worldwide.

Edaravone is a potent free-radical scavenger that has been in the market for more than 30 years. It was originally developed in Japan to treat strokes and has been used there since 2001. Aside from its anti-oxidative effects, edaravone demonstrated beneficial effects on proinflammatory responses, nitric oxide production, and apoptotic cell death. Interestingly, edaravone has shown neuroprotective effects in several animal models of diseases other than stroke. In particular, edaravone administration was found to be effective in halting amyotrophic lateral sclerosis (ALS) progression during the early stages. Accordingly, after its success in Phase III clinical studies, edaravone has been approved by the FDA as a treatment for ALS patients. Considering its promises in neurological disorders and its safety in patients, edaravone is a drug of interest that can be repurposed for traumatic brain injury (TBI) treatment. Drug repurposing is a novel approach in drug development that identifies drugs for purposes other than their original indication. This review presents the biochemical properties of edaravone along with its effects on several neurological disorders in the hope that it can be adopted for treating TBI patients.

The last couple of months have witnessed the world in a state of virtual standstill. The SARS-CoV-2 virus has overtaken the globe to economic and social lockdown. Many patients with COVID-19 have compromised immunity, especially in an aged population suffering from Parkinson's disease (PD). Alteration in dopaminergic neurons and deficiency of dopamine in PD patients are the most common symptoms affecting 1% population above the age of 60 years. The compromised immune system and inflammatory manifestation in PD patients make them an easy target. The most common drugs under trial for COVID-19 are remdesivir, favipiravir, chloroquine and hydroxychloroquine, azithromycin along with adjunct drugs like amantadine with some monoclonal antibodies. Presently, clinically US FDA approved drugs in PD include Levodopa, catechol-O-methyl transferase (COMT) inhibitors, (Entacapone and Tolcapone), dopamine agonists (Bromocriptine, Ropinirole, Pramipexole, and Rotigotine), monoamine oxidase B (MAO-B) inhibitors (Selegiline and Rasagiline), amantadine and antimuscarinic drugs. The drugs have established mechanisms of action on PD patients with known pharmacodynamics and pharmacokinetic properties along with dose and adverse effects. Conclusion and relevance of this review focus on the drugs that can be tried on PD patients with SAR CoV-2 infection, in particular, amantadine that has been approved by all the developed countries as a common drug possessing both antiviral properties by downregulation of CTSL, lysosomal pathway disturbance and change in pH necessary to uncoat the viral proteins and anti- Parkinson properties. To deal with the significant prognostic adverse effect of SARS-CoV-2 on PD, the present-day treatment options, clinical presentation and various mechanisms are the need of the hour.

Raynaud's Phenomenon (RP) results from exaggerated cold-induced vasoconstriction. RP patients suffer from vasospastic attacks and compromised digital blood perfusion leading to a triple color change at the level the fingers. Severe RP may cause ulcers and threaten tissue viability. Many drugs have been used to alleviate the symptoms of RP. These include calcium-channel blockers, cGMP-specific phosphodiesterase type 5 inhibitors, prostacyclin analogs, and angiotensin receptor blockers. Despite their variety, these drugs do not treat RP but rather alleviate its symptoms. To date, no drug for RP has been yet approved by the U.S Food and Drugs Administration. Cilostazol is a selective inhibitor of phosphodiesterase-III, originally prescribed to treat intermittent claudication. Owing to its antiplatelet and vasodilating properties, cilostazol is being repurposed as a potential drug for RP. This review focuses on the different lines of action of cilostazol serving to enhance blood perfusion in RP patients.

Nitric oxide (NO), an important endogenous signaling molecule released from vascular endothelial cells and nerves, activates the enzyme soluble guanylate cyclase to catalyze the production of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate. cGMP, in turn, activates protein kinase G to phosphorylate a range of effector proteins in smooth muscle cells that reduce intracellular Ca²⁺ levels to inhibit both contractility and proliferation. The enzyme phosphodiesterase type 5 (PDE5) curtails the actions of cGMP by hydrolyzing it into inactive 5’-GMP. Small molecule PDE5 inhibitors (PDE5is), such as sildenafil, prolong the availability of cGMP and therefore, enhance NO-mediated signaling. PDE5is are the first-line treatment for erectile dysfunction but are also now approved for the treatment of pulmonary arterial hypertension (PAH) in adults. Persistent pulmonary hypertension in neonates (PPHN) is currently treated with inhaled NO, but this is an expensive option and around 1/3 of newborns are unresponsive, resulting in the need for alternative approaches. Here the development, chemistry and pharmacology of PDE5is, the use of sildenafil for erectile dysfunction and PAH, are summarized and then current evidence for the utility of further repurposing of sildenafil, as a treatment for PPHN, is critically reviewed.

The most typical feature of atherogenesis in humans at its early stage is the formation of foam cells in subendothelial arterial intima, which occurs as the consequence of intracellular cholesterol deposition. The main source of lipids accumulating in the arterial wall is circulating low-density lipoprotein (LDL). However, LDL particles should undergo proatherogenic modification to acquire atherogenic properties. One of the known types of atherogenic modification of LDL is enzymatic deglycosilation, namely, desialylation, which is the earliest change in the cascade of following multiple LDL modifications. The accumulating data make sialidases an intriguing and plausible therapeutic target, since pharmacological modulation of activity of these enzymes may have beneficial effects in several pathologies, including atherosclerosis. The hypothesis exists that decreasing LDL enzymatic desialylation may result in the prevention of lipid accumulation in arterial wall, thus breaking down one of the key players in atherogenesis at the cellular level. Several drugs acting as glycomimetics and inhibiting sialidase enzymatic activity already exist, but the concept of sialidase inhibition as an anti-atherosclerosis strategy remains unexplored to date. This review is focused on the potential possibilities of the repurposing of sialidase inhibitors for pathogenetic anti-atherosclerotic therapy.