Synthesis and studies of new purines/pyrimidine derivatives as multi-targeted agents involving various receptor sites in the immune system.

Pro-inflammation, which is developed due to the increased production of cytokines, mainly interleukin-6 (IL-6), during the working of immune system pathways, becomes a major concern these days for many researchers. So, it is desired to design, screen, and synthesize new molecules with multi-parametric features showing their efficacy for Toll-like receptors (TLRs) and inhibiting the disease-causing receptor sites like viral infections, cancers, etc. along with controlling inflammation, fever, and other side effects during such pathways. Further, looking at the literature, curcumin a multi-targeted agent is showing its efficiency toward various receptor sites involved in many diseases as mentioned above. This fascinated us to build up new molecules which behave like curcumin with minimum side effects. In silico studies, involving ADMET studies, toxicological data, and docking analyses, of newly synthesized compounds (3-5) along with tautomers of curcumin i.e., (1-2), and some reported compounds like 9 and 10 have been studied in detail. Great emphasis has been made on analyzing binding energies, protein-ligand structural interactions, stabilization of newly synthesized molecules against various selected receptor sites using such computational tools. Compound 3 is the most efficient multifunctional agent, which has shown its potential toward most of the receptor sites in docking analysis. It has also responded well in Molecular dynamics (MD) simulation toward 5ZLN, 4RJ3, 4YO9, 4YOJ, and 1I1R sites. Finally, studies were extended to understand in vitro anti-inflammatory activity for particularly compound 3 in comparison to diclofenac and curcumin, which signifies the efficiency of compound 3.

Hesperidin: A Potential Therapeutic agent against COVID-19.

COVID-19, aka Coronavirus Disease 2019, triggered by new severe acute respiratory syndrome coronavirus-2 or SARS-CoV-2, is now a public health emergency due to its rapid spread, high transmission efficiency, and severe viral pandemic that is significantly increasing the number of patients and associated deaths. At present, no specific treatment is available that can this highly contagious virus. The unavailability of effective and specific treatments and the severity of this epidemic situation potentiate medicinal chemists' in supporting new prophylactic or therapeutic interventions against COVID-19. This study discusses the therapeutic potential of hesperidin, a traditionally used herbal medicine with an exceptional safety profile. Recent studies on hesperidin advocate its promising potential in the prevention and management of COVID 19. This paper also discussess the recent clinical studies based on the previously documented antiviral activity of hesperidin. Herein, we propose the detailed preclinical and clinical manifestations of hesperidin based on its multifaceted bioactivities to develop a novel anti-COVID-19 lead.

Fermented natural product targeting gut microbiota regulate immunity and anti-inflammatory activity: A possible way to prevent COVID-19 in daily diet.

Low immune function makes the body vulnerable to being invaded by external bacteria or viruses, causing influenza and inflammation of various organs, and this trend is shifting to the young and middle-aged group. It has been pointed out that natural products fermented by probiotic have benign changes about their active ingredients in some studies, and it have shown strong nutritional value in anti-oxidation, anti-aging, regulating lipid metabolism, anti-inflammatory and improving immunity. In recent years, the gut microbiota plays a key role and has been extensively studied in improving immunity and anti-inflammation activity. By linking the relationship between natural products fermented by probiotic, gut microbiota, immunity, and inflammation, this review presents the modulating effects of probiotics and their fermented natural products on the body, including immunity-enhancing and anti-inflammatory activities by modulating gut microbiota, and it is discussed that the current understanding of its molecular mechanisms. It may become a possible way to prevent COVID-19 through consuming natural products fermented by probiotic in our daily diet.

A Comprehensive Review of Andrographis paniculata (Burm. f.) Nees and Its Constituents as Potential Lead Compounds for COVID-19 Drug Discovery.

The COVID-19 pandemic has intensively disrupted global health, economics, and well-being. Andrographis paniculata (Burm. f.) Nees has been used as a complementary treatment for COVID-19 in several Asian countries. This review aimed to summarize the information available regarding A. paniculata and its constituents, to provide critical points relating to its pharmacological properties, safety, and efficacy, revealing its potential to serve as a source of lead compounds for COVID-19 drug discovery. A. paniculata and its active compounds possess favorable antiviral, anti-inflammatory, immunomodulatory, and antipyretic activities that could be beneficial for COVID-19 treatment. Interestingly, recent in silico and in vitro studies have revealed that the active ingredients in A. paniculata showed promising activities against 3CLpro and its virus-specific target protein, human hACE2 protein; they also inhibit infectious virion production. Moreover, existing publications regarding randomized controlled trials demonstrated that the use of A. paniculata alone or in combination was superior to the placebo in reducing the severity of upper respiratory tract infection (URTI) manifestations, especially as part of early treatment, without serious side effects. Taken together, its chemical and biological properties, especially its antiviral activities against SARS-CoV-2, clinical trials on URTI, and the safety of A. paniculata, as discussed in this review, support the argument that A. paniculata is a promising natural source for drug discovery regarding COVID-19 post-infectious treatment, rather than prophylaxis.

Enzyme-assisted extraction of anthocyanins and other phenolic compounds from blackcurrant (Ribes nigrum L.) press cake: From processing to bioactivities.

The effects of commercial enzymes (pectinases, cellulases, beta-1-3-glucanases, and pectin lyases) on the recovery of anthocyanins and polyphenols from blackcurrant press cake were studied considering two solid:solvent ratios (1:10 and 1:4 w/v). ß-glucanase enabled the recovery of the highest total phenolic content - 1142 mg/100 g, and the extraction of anthocyanins was similar using all enzymes (∼400 mg/100 g). The use of cellulases and pectinases enhanced the extraction of antioxidants (DPPH - 1080 mg/100 g; CUPRAC - 3697 mg/100 g). The freeze-dried extracts presented antioxidant potential (CUPRAC, DPPH), which was associated with their biological effects in different systems: antiviral activity against both non-enveloped viruses (enterovirus coxsackievirus A-9) and enveloped coronaviruses (HCoV-OC43), and cytotoxicity towards cancer cells (A549 and HCT8). No cytotoxic effects on normal human lung fibroblast (IMR90) were observed, and no anti-inflammatory activity was detected in lipopolysaccharides-treated murine immortalised microglial cells.

Can Extracts from the Leaves and Fruits of the Cotoneaster Species Be Considered Promising Anti-Acne Agents?

This study aimed to evaluate the phenolic profile and biological activity of the extracts from the leaves and fruits of Cotoneaster nebrodensis and Cotoneaster roseus. Considering that miscellaneous species of Cotoneaster are thought to be healing in traditional Asian medicine, we assumed that this uninvestigated species may reveal significant therapeutic properties. Here, we report the simultaneous assessment of chemical composition as well as biological activities (antioxidant, anti-inflammatory, antibacterial, and cytotoxic properties) of tested species. Complementary LC-MS analysis revealed that polyphenols (especially flavonoids and proanthocyanidins) are the overriding phytochemicals with the greatest significance in tested biological activities. In vitro chemical tests considering biological activities revealed that obtained results showed different values depending on concentration, extraction solvent as well as phenolic content. Biological assays demonstrated that the investigated extracts possessed antibacterial properties and were not cytotoxic toward normal skin fibroblasts. Given the obtained results, we concluded that knowledge of the chemical composition and biological activities of investigated species are important to achieve a better understanding of the utilization of these plants in traditional medicine and be useful for further research in their application to treat various diseases, such as skin disorders.

Resolvins, Protectins, and Maresins: DHA-Derived Specialized Pro-Resolving Mediators, Biosynthetic Pathways, Synthetic Approaches, and Their Role in Inflammation.

Marine organisms are an important source of natural products with unique and diverse chemical structures that may hold the key for the development of novel drugs. Docosahexaenoic acid (DHA) is an omega-3 fatty acid marine natural product playing a crucial regulatory role in the resolution of inflammation and acting as a precursor for the biosynthesis of the anti-inflammatory specialized pro-resolving mediators (SPMs) resolvins, protectins, and maresins. These metabolites exert many beneficial actions including neuroprotection, anti-hypertension, or anti-tumorigenesis. As dysregulation of SPMs is associated with diseases of prolonged inflammation, the disclosure of their bioactivities may be correlated with anti-inflammatory and pro-resolving capabilities, offering new targets for drug design. The availability of these SPMs from natural resources is very low, but the evaluation of their pharmacological properties requires their access in larger amounts, as achieved by synthetic routes. In this report, the first review of the total organic syntheses carried out for resolvins, protectins, and maresins is presented. Recently, it was proposed that DHA-derived pro-resolving mediators play a key role in the treatment of COVID-19. In this work we also review the current evidence on the structures, biosynthesis, and functional and new-found roles of these novel lipid mediators of disease resolution.

Synthesis and Investigation of Flavanone Derivatives as Potential New Anti-Inflammatory Agents.

Flavonoids are polyphenols with broad known pharmacological properties. A series of 2,3-dihydroflavanone derivatives were thus synthesized and investigated for their anti-inflammatory activities. The target flavanones were prepared through cyclization of 2'-hydroxychalcone derivatives, the later obtained by Claisen-Schmidt condensation. Since nitric oxide (NO) represents an important inflammatory mediator, the effects of various flavanones on the NO production in the LPS-induced RAW 264.7 macrophage were assessed in vitro using the Griess test. The most active compounds were flavanone (4G), 2'-carboxy-5,7-dimethoxy-flavanone (4F), 4'-bromo-5,7-dimethoxy-flavanone (4D), and 2'-carboxyflavanone (4J), with IC50 values of 0.603, 0.906, 1.030, and 1.830 µg/mL, respectively. In comparison, pinocembrin achieved an IC50 value of 203.60 µg/mL. Thus, the derivatives synthesized in this work had a higher NO inhibition capacity compared to pinocembrin, demonstrating the importance of pharmacomodulation to improve the biological potential of natural molecules. SARs suggested that the use of a carboxyl-group in the meta-position of the B-ring increases biological activity, whereas compounds carrying halogen substituents in the para-position were less active. The addition of methoxy-groups in the meta-position of the A-ring somewhat decreased the activity. This study successfully identified new bioactive flavanones as promising candidates for the development of new anti-inflammatory agents.

Biophysical and Biological Tools to Better Characterize the Stability, Safety and Efficacy of a Cosmeceutical for Acne-Prone Skin.

(1) Background: Acne is a widespread skin disease, especially among adolescents. Following the COVID-19 pandemic and the use of masks, the problem has been affecting a greater number of people, and the attention of the skin care beauty routine cosmetics has been focused on the "Maskne", caused by the sebum excretion rate (SER) that stimulates microbial proliferation. (2) Methods: the present study was focused on the rheological characterization and quality assurance of the preservative system of an anti-acne serum. The biological effectiveness (cytotoxicity-skin and eye irritation-antimicrobial, biofilm eradication and anti-inflammatory activity) was evaluated in a monolayer cell line of keratinocytes (HaCaT) and on 3D models (reconstructed human epidermis, RHE and human reconstructed corneal epithelium, HCE). The Cutibacterium acnes, as the most relevant acne-inducing bacterium, is chosen as a pro-inflammatory stimulus and to evaluate the antimicrobial activity of the serum. (3) Results and Conclusions: Rheology allows to simulate serum behavior at rest, extrusion and application, so the serum could be defined as having a solid-like behavior and being pseudoplastic. The preservative system is in compliance with the criteria of the reference standard. Biological effectiveness evaluation shows non-cytotoxic and irritant behavior with a good antimicrobial and anti-inflammatory activity of the formulation, supporting the effectiveness of the serum for acne-prone skin treatment.

The Potential Impact of Statins in the Treatment of Patients with COVID-19 Infection.

INTRODUCTION: Statins are cholesterol-lowering drugs that also have anti-inflammatory/ immunomodulatory properties, and have been suggested as an adjunct therapy for COVID-19. METHODS: To investigate the clinical impact of statins as a potential therapeutic approach in the treatment of cases infected with COVID-19, a systematic search was performed using PubMed and Google Scholar databases. To extend the search results, a set of keywords were used as follows: ("corona virus" OR "Covid-19" OR "SARS-Cov-2" OR "Severe Acute Respiratory Syndrome Coronavirus 2" OR coronavirus) AND (Statins), alongside a manual search in Google Scholar search engine. RESULTS: It has also been suggested that statins could influence the entry of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) into cells by altering the expression of the angiotensin-converting enzyme 2 (ACE2) and CD143 receptors. Statins may be beneficial for COVID-19 patients according to its pleiotropic effects, although, from the clinical aspect, these pleiotropic effects of statins may not be as strong as in preclinical phase on COVID-19. A retrospective study showed favorable effects for statins in SARS-CoV-2 infection. CONCLUSION: Patients with SARS-CoV-2 infection have a high risk of cardiovascular and thrombotic complications and pleiotropic effects of statins may help manage the COVID-19. There is growing evidence that supports the need for trials of statin treatment in COVID-19 infection.

New C9 -Monoterpenoid Alkaloids Featuring a Rare Skeleton with Anti-Inflammatory and Antiviral Activities from Forsythia suspensa.

Forsyqinlingines C (1) and D (2), two C9 -monoterpenoid alkaloids bearing a rare skeleton, were isolated from the ripe fruits of Forsythia suspensa. Their structures, including absolute configurations, were fully elucidated by extensive spectroscopic data and ECD experiments. The plausible biogenetic pathway for compounds 1 and 2 was also proposed. In vitro, two C9 -monoterpenoid alkaloids showed anti-inflammatory activity performed by the inhibitory effect on the release of ß-glucuronidase in rat polymorphonuclear leukocytes (PMNs), as well as antiviral activity against influenza A (H1N1) virus and respiratory syncytial virus (RSV).

Green synthesis of zinc oxide nanoparticles using Anoectochilus elatus, and their biomedical applications.

Zinc and its derivatives requirement increased to enhance human immunity against the different pandemics, including covid-19. Green synthesis is an emerging field of research. Zinc oxide (ZnO) nanoparticles have been prepared from Anoectochilus elatus and characterized using absorption, vibrational and electron microscope analysis. They were carried for antibacterial, inflammatory control tendency, and potential antioxidant activities. The brine shrimp lethal assay tested the biologically derived nanomaterial toxicity and the lethal concentration (LC50) is 599.79 µg/ml. The inhibition against the important disease-causing pathogens was measured against four-gram negative, gram-positive bacteria and two fungus pathogens. The nanomaterial exposed inhibition zone for gram-positive bacteria between 17 mm and 25 mm. The inhibition zone against gram-negative bacteria exists between 19 mm and 24 mm. The anti-inflammatory activity was assessed by inhibition of protein denaturation and protease inhibitory activity using nanomaterial. The antioxidant activity was examined using four assays for the therapeutic activities. The average size range of 60-80 nm nanoparticles has prepared and exposed the good biological activity between 50 µg/ml and 100 µg/ml. The comparative results of anti-inflammatory and antioxidant assay results with standards such as Aspirin and vitamin C exposed that two to three times higher concentrations are required for the fifty percent of inhibitions. The prepared low-cost nanoparticle has exhibited excellent biological activity without any side effects and may enhance immunity.

Research Progress in Anti-Inflammatory Bioactive Substances Derived from Marine Microorganisms, Sponges, Algae, and Corals.

Inflammation is the body's defense reaction in response to stimulations and is the basis of various physiological and pathological processes. However, chronic inflammation is undesirable and closely related to the occurrence and development of diseases. The ocean gives birth to unique and diverse bioactive substances, which have gained special attention and been a focus for anti-inflammatory drug development. So far, numerous promising bioactive substances have been obtained from various marine organisms such as marine bacteria and fungi, sponges, algae, and coral. This review covers 71 bioactive substances described during 2015-2020, including the structures (65 of which), species sources, evaluation models and anti-inflammatory activities of these substances. This review aims to provide some reference for the research progress of marine-organism-derived anti-inflammatory metabolites and give more research impetus for their conversion to novel anti-inflammatory drugs.

Dual targeting of cytokine storm and viral replication in COVID-19 by plant-derived steroidal pregnanes: An in silico perspective.

The high morbidity and mortality rate of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) infection arises majorly from the Acute Respiratory Distress Syndrome and "cytokine storm" syndrome, which is sustained by an aberrant systemic inflammatory response and elevated pro-inflammatory cytokines. Thus, phytocompounds with broad-spectrum anti-inflammatory activity that target multiple SARS-CoV-2 proteins will enhance the development of effective drugs against the disease. In this study, an in-house library of 117 steroidal plant-derived pregnanes (PDPs) was docked in the active regions of human glucocorticoid receptors (hGRs) in a comparative molecular docking analysis. Based on the minimal binding energy and a comparative dexamethasone binding mode analysis, a list of top twenty ranked PDPs docked in the agonist conformation of hGR, with binding energies ranging between -9.8 and -11.2 kcal/mol, was obtained and analyzed for possible interactions with the human Janus kinases 1 and Interleukins-6 and SARS-CoV-2 3-chymotrypsin-like protease, Papain-like protease and RNA-dependent RNA polymerase. For each target protein, the top three ranked PDPs were selected. Eight PDPs (bregenin, hirundigenin, anhydroholantogenin, atratogenin A, atratogenin B, glaucogenin A, glaucogenin C and glaucogenin D) with high binding tendencies to the catalytic residues of multiple targets were identified. A high degree of structural stability was observed from the 100 ns molecular dynamics simulation analyses of glaucogenin C and hirundigenin complexes of hGR. The selected top-eight ranked PDPs demonstrated high druggable potentials and favourable in silico ADMET properties. Thus, the therapeutic potentials of glaucogenin C and hirundigenin can be explored for further in vitro and in vivo studies.

Mechanistic Aspects and Therapeutic Potential of Quercetin against COVID-19-Associated Acute Kidney Injury.

The inflammatory mediator and oxidant agent storm caused by the SARS-CoV-2 infection has been strongly associated with the failure of vital organs observed in critically ill patients with coronavirus disease 2019 (COVID-19) and the death of thousands of infected people around the world. Acute kidney injury (AKI) is a common renal disorder characterized by a sudden and sustained decrease in renal function with a critical influence on poor prognosis and lethal clinical outcomes of various etiologies, including some viral infection diseases. It is known that oxidative stress and inflammation play key roles in the pathogenesis and development of AKI. Quercetin is a natural substance that has multiple pharmacological properties, such as anti-inflammatory action, and is used as a dietary supplement. There is evidence of the anti-coronavirus activities of this compound, including against the target SARS-CoV-2 3CLpro. The ability to inhibit coronavirus and its inflammatory processes is strongly desired in a new drug for the treatment of COVID-19. Therefore, in this review, the dual effect of quercetin is discussed from a mechanistic perspective in relation to AKI kidney injury and its nephroprotective potential to SARS-CoV-2 patients.