Natural and Semi-Synthetic Flavonoid Anti-SARS-CoV-2 Agents for the Treatment of Long COVID-19 Disease and Neurodegenerative Disorders of Cognitive Decline

Abstract

The aim of this review is to highlight the beneficial attributes of flavonoids, a diverse family of widely-distributed polyphenolic phytochemicals that have beneficial cell and tissue protective properties. Phytochemicals are widely distributed in plants, herbs and shrubs used in traditional complimentary medical formulations for centuries. The bioactive components that convey beneficial medicinal effects in these complex herbal preparations are now being identified using network pharmacology and molecular docking procedures that identify their molecular targets. Flavonoids have anti-oxidant, anti-inflammatory, antiviral, antibacterial and anti-cancer properties that have inspired the development of potent multifunctional derivatised flavonoids of improved efficacy. The antiviral properties of flavonoids and the emergence of the severe acute respiratory syndrome (SARS-CoV-2) pandemic has resulted in a resurgence of interest in phytochemicals in the search for efficacious compounds that can prevent viral infection or replication, with many promising plant compounds identified. Promising semi-synthetic flavonoid derivatives have also been developed that inhibit multiple pathological neurodegenerative processes; these offer considerable promise in the treatment of diseases of cognitive decline. Clinical trials are currently being undertaken to evaluate the efficacy of dietary supplements rich in flavonoids for the treatment of virally-mediated diseases. Such trials are expected to identify flavonoids with cell and tissue protective properties that can be harnessed in biomedical applications that may serve as supportive adjunctive procedures to conventional anti-viral drug therapies against diseases such as COVID-19.

The Potential of Flavonoids and Flavonoid Metabolites in the Treatment of Neurodegenerative Pathology in Disorders of Cognitive Decline

“…Current research has uncovered that dietary use of flavonoid-rich food sources essentially increases intellectual abilities and postpones or hinders the senescence cycle and related neurodegenerative problems, including AD [ 233 ]. During AD pathogenesis, multiple signalling pathways are involved, and to target a single pathway may relieve the symptoms but not provide a permanent cure [ 233 , 234 ]. Flavonoids scavenge free radical species (ROS), however, upon reaction with ROS, the antioxidant capacity of flavonoids can become compromised.…”

“…Recent evidence for at least some flavonoids shows that the oxidation of reactive phenolic residues can in fact enhance their antioxidant properties. This antioxidant activity arises from generation of metabolites that activate the Nrf2-Keap1 pathway [ 233 , 234 ], upregulating the cell’s endogenous antioxidant capacity, by the prevention of activation of prooxidant and proinflammatory NF-κB pathways [ 235 ]. Flavonoid metabolites, such as protocatechuic acid [ 236 , 237 ] and urolithin A [ 33 , 36 , 195 ] generated by the gut microbiome, also have potent direct antioxidant activities or provide mitochondrial protection by promoting mitochondrial biogenesis and metabolic activity, enhancing neural cell activity in the CNS in neurodegenerative conditions [ 203 , 238 ].…”

“…Hesperidin’s antioxidant, anti-inflammatory, and neuroprotective properties are useful in the treatment of neurodegenerative conditions [ 239 ] and have inspired the development of therapeutic multifunctional flavone and chalcone analogs of improved efficacy. Hesperitin also has considerable potential in the treatment of neurological disorders and has inspired the development of multifunctional agents of improved efficacy [ 26 , 233 , 234 ]. The central position of chalcones in medicinal chemistry, and its amenability to chemical modification, facilitates its use as a template for the development of multifunctional analog chalcone/flavone forms of improved efficacy in a number of depressive neurodegenerative disorders, including PD and AD.…”

Aging and long COVID-19 syndrome: what’s new in 2023?

“…28,29 However, clearly extensive individualized assessments and an ensuing array of treatment options based on the patient's personal profile appears imperative to avert what has been termed a pervasive and possible future case of widespread 'medical devastation'. 30,31 Specific attention to the possible important role of blood clotting pathologies, oxidative stress, endothelial damage, 27 persistent autoimmune symptoms and indications, 32 and possible nutrient deficiencies [33][34][35][36] and weighting their importance is key to mitigating one or more of these possible determinants that may be fostering some degree of post acute COVID-19 fatigue, shortness of breath, and muscle weakness, as well as persistent inflammation. 37,38 The role of organ damage, post-critical care practices and methods, post COVID viral infections and other explanations may also direct clinicians more ably as to what must remedies are indicated in the individual case to assure optimal outcomes.…”

An update on animal models of intervertebral disc degeneration and low back pain: Exploring the potential of artificial intelligence to improve research analysis and development of prospective therapeutics

“…Flavonoids are a widely distributed family of polyphenolic dietary plant compounds that possess anti‐oxidant and anti‐inflammatory properties through their abilities to inhibit LOX, COX, NFκB, and iNOS activity [reviewed in 320 ]. They also induce nuclear factor‐erythroid factor 2‐related factor 2 (Nrf2) gene expression in cells.…”