Anti-Proliferative Potential of Cynaroside and Orientin-In Silico (DYRK2) and In Vitro (U87 and Caco-2) Studies.

Luteolin derivates are plant compounds with multiple benefits for human health. Stability to heat and acid hydrolysis and high resistance to (auto)oxidation are other arguments for the laden interest in luteolin derivates today. The present study was designed to compare the in silico and in vitro anti-proliferative potential of two luteolin derivates, luteolin-7-O-glucoside/cynaroside (7-Lut) and luteolin-8-C-glucoside/orientin (8-Lut). In silico investigations were carried out on the molecular target, namely, the human dual specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) in association with its natural ligand, curcumin (PDB ID: 5ZTN), by CLC Drug Discovery Workbench v. 1.5.1. software and Molegro Virtual Docker (MVD) v. MVD 2019.7.0. software. In vitro studies were performed on two human tumor cell lines, glioblastoma (U87) and colon carcinoma (Caco-2), respectively. Altogether, docking studies have revealed 7-Lut and 8-Lut as effective inhibitors of DYRK2, even stronger than the native ligand curcumin; in vitro studies indicated the ability of both luteolin glucosides to inhibit the viability of both human tumor cell lines, up to 85% at 50 and 100 µg/mL, respectively; the most augmented cytotoxic and anti-proliferative effects were obtained for U87 exposed to 7-Lut (IC50 = 26.34 µg/mL). The results support further studies on cynaroside and orientin to create drug formulas targeting glioblastoma and colon carcinoma in humans.

Potential Benefits of Dietary Plant Compounds on Normal and Tumor Brain Cells in Humans: In Silico and In Vitro Approaches.

Neuroblastoma can be accessed with compounds of larger sizes and wider polarities, which do not usually cross the blood-brain barrier. Clinical data indicate cases of spontaneous regression of neuroblastoma, suggesting a reversible point in the course of cell brain tumorigenesis. Dual specificity tyrosine-phosphorylation-regulated kinase2 (DYRK2) is a major molecular target in tumorigenesis, while curcumin was revealed to be a strong inhibitor of DYRK2 (PBD ID: 5ZTN). Methods: in silico studies by CLC Drug Discovery Workbench (CLC) and Molegro Virtual Docker (MVD) Software on 20 vegetal compounds from the human diet tested on 5ZTN against the native ligand curcumin, in comparison with anemonin. In vitro studies were conducted on two ethanolic extracts from Anemone nemorosa tested on normal and tumor human brain cell lines NHA and U87, compared with four phenolic acids (caffeic, ferulic, gentisic, and para-aminobenzoic/PABA). Conclusions: in silico studies revealed five dietary compounds (verbascoside, lariciresinol, pinoresinol, medioresinol, matairesinol) acting as stronger inhibitors of 5ZTN compared to the native ligand curcumin. In vitro studies indicated that caffeic acid has certain anti-proliferative effects on U87 and small benefits on NHA viability. A. nemorosa extracts indicated potential benefits on NHA viability, and likely dangerous effects on U87.

Lactones in the Synthesis of Prostaglandins and Prostaglandin Analogs.

In the total stereo-controlled synthesis of natural prostaglandins (PGs) and their structural analogs, a vast class of compounds and drugs, known as the lactones, are encountered in a few key steps to build the final molecule, as: δ-lactones, γ-lactones, and 1,9-, 1,11-, and 1,15-macrolactones. After the synthesis of 1,9-PGF2α and 1,15-PGF2α lactones, many 1,15-lactones of E2, E3, F2, F3, A2, and A3 were found in the marine mollusc Tethys fimbria and the quest for understanding their biological role stimulated the research on their synthesis. Then 1,9-, 1,11-, and 1,15-PG lactones of the drugs were synthesized as an alternative to the corresponding esters, and the first part of the paper describes the methods used for their synthesis. The efficient Corey procedure for the synthesis of prostaglandins uses the key δ-lactone and γ-lactone intermediates with three or four stereocenters on the cyclopentane fragment to link the PG side chains. The paper describes the most used procedures for the synthesis of the milestone δ-Corey-lactones and γ-Corey-lactones, their improvements, and some new promising methods, such as interesting, new stereo-controlled and catalyzed enantioselective reactions, and methods based on the chemical/enzymatic resolution of the compounds in different steps of the sequences. The many uses of δ-lactones not only for the synthesis of γ-lactones, but also for obtaining 9ß-halogen-PGs and halogen-substituted cyclopentane intermediates, as synthons for new 9ß-PG analogs and future applications, are also discussed.

ß-Ketophosphonates with Pentalenofuran Scaffolds Linked to the Ketone Group for the Synthesis of Prostaglandin Analogs.

ß-Ketophosphonates with pentalenofurane fragments linked to the keto group were synthesized. The bulky pentalenofurane skeleton is expected to introduce more hindrance in the prostaglandin analogues of type III, greater than that obtained with the bicyclo[3.3.0]oct(a)ene fragments of prostaglandin analogues I and II, to slow down (retard) the inactivation of the prostaglandin analogues by oxidation of 15α-OH to the 15-keto group via the 15-PGDH pathway. Their synthesis was performed by a sequence of three high yield reactions, starting from the pentalenofurane alcohols 2, oxidation of alcohols to acids 3, esterification of acids 3 to methyl esters 4 and reaction of the esters 4 with lithium salt of dimethyl methanephosphonate at low temperature. The secondary compounds 6b and 6c were formed in small amounts in the oxidation reactions of 2b and 2c, and the NMR spectroscopy showed that their structure is that of an ester of the acid with the starting alcohol. Their molecular structures were confirmed by single crystal X-ray determination method for 6c and XRPD powder method for 6b.

Molecular Docking Study on Several Benzoic Acid Derivatives against SARS-CoV-2.

Several derivatives of benzoic acid and semisynthetic alkyl gallates were investigated by an in silico approach to evaluate their potential antiviral activity against SARS-CoV-2 main protease. Molecular docking studies were used to predict their binding affinity and interactions with amino acids residues from the active binding site of SARS-CoV-2 main protease, compared to boceprevir. Deep structural insights and quantum chemical reactivity analysis according to Koopmans' theorem, as a result of density functional theory (DFT) computations, are reported. Additionally, drug-likeness assessment in terms of Lipinski's and Weber's rules for pharmaceutical candidates, is provided. The outcomes of docking and key molecular descriptors and properties were forward analyzed by the statistical approach of principal component analysis (PCA) to identify the degree of their correlation. The obtained results suggest two promising candidates for future drug development to fight against the coronavirus infection.

New Substituted Benzoylthiourea Derivatives: From Design to Antimicrobial Applications.

The increasing threat of antimicrobial resistance to all currently available therapeutic agents has urged the development of novel antimicrobials. In this context, a series of new benzoylthiourea derivatives substituted with one or more fluorine atoms and with the trifluoromethyl group have been tested, synthesized, and characterized by IR, NMR, CHNS and crystal X-ray diffraction. The molecular docking has provided information regarding the binding affinity and the orientation of the new compounds to Escherichia coli DNA gyrase B. The docking score predicted the antimicrobial activity of the studied compounds, especially against E. coli, which was further demonstrated experimentally against planktonic and biofilm embedded bacterial and fungal cells. The compounds bearing one fluorine atom on the phenyl ring have shown the best antibacterial effect, while those with three fluorine atoms exhibited the most intensive antifungal activity. All tested compounds exhibited antibiofilm activity, correlated with the trifluoromethyl substituent, most favorable in para position.

New HSV-1 Anti-Viral 1'-Homocarbocyclic Nucleoside Analogs with an Optically Active Substituted Bicyclo[2.2.1]Heptane Fragment as a Glycoside Moiety.

New 1'-homocarbanucleoside analogs with an optically active substituted bicyclo[2.2.1]heptane skeleton as sugar moiety were synthesized. The pyrimidine analogs with uracil, 5-fluorouracil, thymine and cytosine and key intermediate with 6-chloropurine (5) as nucleobases were synthesized by a selective Mitsunobu reaction on the primary hydroxymethyl group in the presence of 5-endo-hydroxyl group. Adenine and 6-substituted adenine homonucleosides were obtained by the substitution of the 6-chlorine atom of the key intermediate 5 with ammonia and selected amines, and 6-methoxy- and 6-ethoxy substituted purine homonucleosides by reaction with the corresponding alkoxides. No derivatives appeared active against entero, yellow fever, chikungunya, and adeno type 1viruses. Two compounds (6j and 6d) had lower IC50 (15 ± 2 and 21 ± 4 µM) and compound 6f had an identical value of IC50 (28 ± 4 µM) to that of acyclovir, suggesting that the bicyclo[2.2.1]heptane skeleton could be further studied to find a candidate for sugar moiety of the nucleosides.

Current Perspectives on Biological Screening of Newly Synthetised Sulfanilamide Schiff Bases as Promising Antibacterial and Antibiofilm Agents.

Growing resistance to antimicrobials, combined with pathogens that form biofilms, presents significant challenges in healthcare. Modifying current antimicrobial agents is an economical approach to developing novel molecules that could exhibit biological activity. Thus, five sulfanilamide Schiff bases were synthesized under microwave irradiation and characterized spectroscopically and in silico. They were evaluated for their antimicrobial and antibiofilm activities against both Gram-positive and Gram-negative bacterial strains. Their cytotoxic potential against two cancer cell lines was also determined. Gram-positive bacteria were susceptible to the action of these compounds. Derivatives 1b and 1d inhibited S. aureus's growth (MIC from 0.014 mg/mL) and biofilm (IC from 0.029 mg/mL), while compound 1e was active against E. faecalis's planktonic and sessile forms. Two compounds significantly reduced cell viability at 5 µg/mL after 24 h of exposure (1d-HT-29 colorectal adenocarcinoma cells, 1c-LN229 glioblastoma cells). A docking study revealed the increased binding affinities of these derivatives compared to sulfanilamide. Hence, these Schiff bases exhibited higher activity compared to their parent drug, with halogen groups playing a crucial role in both their antimicrobial and cytotoxic effects.

Contribution to the Synthesis, Characterization, Separation and Quantification of New N-Acyl Thiourea Derivatives with Antimicrobial and Antioxidant Potential.

The present study aimed to synthesize, characterize, and validate a separation and quantification method of new N-acyl thiourea derivatives (1a-1o), incorporating thiazole or pyridine nucleus in the same molecule and showing antimicrobial potential previously predicted in silico. The compounds have been physiochemically characterized by their melting points, IR, NMR and MS spectra. Among the tested compounds, 1a, 1g, 1h, and 1o were the most active against planktonic Staphylococcus aureus and Pseudomonas aeruginosa, as revealed by the minimal inhibitory concentration values, while 1e exhibited the best anti-biofilm activity against Escherichia coli (showing the lowest value of minimal inhibitory concentration of biofilm development). The total antioxidant activity (TAC) assessed by the DPPH method, evidenced the highest values for the compound 1i, followed by 1a. A routine quality control method for the separation of highly related compounds bearing a chlorine atom on the molecular backbone (1g, 1h, 1i, 1j, 1m, 1n) has been developed and validated by reversed-phase high-performance liquid chromatography (RP-HPLC), the results being satisfactory for all validation parameters recommended by the ICH guidelines (i.e., system suitability, specificity, the limits of detection and quantification, linearity, precision, accuracy and robustness) and recommending it for routine separation of these highly similar compounds.

New N-acyl Thiourea Derivatives: Synthesis, Standardized Quantification Method and In Vitro Evaluation of Potential Biological Activities.

New N-acyl thiourea derivatives with heterocyclic rings have been synthesized by first obtaining isothiocyanate, which further reacted with a heterocyclic amine, characterized by (FT-IR, NMR spectroscopy and FT-ICR) and tested for their in vitro antimicrobial, anti-biofilm and antioxidant activities to obtain a drug candidate in a lead-optimization process. From the tested compounds, those bearing benzothiazole (1b) and 6-methylpyridine (1d) moieties revealed anti-biofilm activity against E. coli ATCC 25922 at MBIC values of 625 µg/mL. Compound 1d exhibited the highest antioxidant capacity (~43%) in the in vitro assay using 1,1-diphenyl-2-picrylhydrazyl (DPPH). Considering the in vitro results, the highest anti-biofilm and antioxidant activities were obtained for compound 1d. Therefore, a reversed-phase high-performance liquid chromatography (RP-HPLC) method has been optimized and validated for the quantitative determination of compound 1d. The detection and quantitation limits were 0.0174 µg/mL and 0.0521 µg/mL, respectively. The R2 correlation coefficient of the LOQ and linearity curves were greater than 0.99, over the concentration range of 0.05 µg/mL-40 µg/mL. The precision and accuracy of the analytical method were within 98-102%, confirming that the method is suitable for the quantitative determination of compound 1d in routine quality control analyses. Evaluating the results, the promising potential of the new N-acyl thiourea derivatives bearing 6-methylpyridine moiety will be further investigated for developing agents with anti-biofilm and antioxidant activities.

Studies Regarding the Antimicrobial Behavior of Clotrimazole and Limonene.

The paper presents the results of the studies performed to establish the effect of the mixtures between limonene and clotrimazole against microbial pathogens involved in dermatological diseases, such as Candida albicans, Staphyloccocus aureus, and Escherichia coli. Preliminary data obtained from the studies performed in microplates revealed a possible synergism between the mixture of clotrimazole and limonene for Staphylococcus aureus. Studies performed "in silico" with programs such as CLC Drug Discovery Workbench and MOLEGRO Virtual Docker, gave favorable scores for docking each compound on a specific binding site for each microorganism. The tests performed for validation, with the clotrimazole (0.1%) and different sources of limonene (1.9% citrus essential oils), showed a synergistic effect on Staphylococcus aureus in the case of the mixtures between clotrimazole and the essential oils of Citrus reticulata or Citrus paradisi. The studies performed on Staphylococcus aureus MRSA showed a synergistic effect between clotrimazole and the essential oils obtained from Citrus bergamia, Citrus aurantium, or Citrus paradisi. In the case of Pseudomonas aeruginosa, essential oils and clotrimazole used alone did not exhibit antimicrobial activities, but the mixtures between clotrimazole and the essential oils of Citrus bergamia or Citrus sinensis exhibited a synergistic antimicrobial effect.

The microbiota-related coinfections in COVID-19 patients: a real challenge.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of ongoing global pandemic of coronavirus disease 2019 (COVID-19), has infected millions of people around the world, especially the elderly and immunocompromised individuals. The infection transmission rate is considered more rapid than other deadly pandemics and severe epidemics encountered earlier, such as Ebola, Zika, Influenza, Marburg, SARS, and MERS. The public health situation therefore is really at a challenging crossroads. MAIN BODY: The internal and external and resident microbiota community is crucial in human health and is essential for immune responses. This community tends to be altered due to pathogenic infections which would lead to severity of the disease as it progresses. Few of these resident microflora become negatively active during infectious diseases leading to coinfection, especially the opportunistic pathogens. Once such a condition sets in, it is difficult to diagnose, treat, and manage COVID-19 in a patient. CONCLUSION: This review highlights the various reported possible coinfections that arise in COVID-19 patients vis-à-vis other serious pathological conditions. The local immunity in lungs, nasal passages, oral cavity, and salivary glands are involved with different aspects of COVID-19 transmission and pathology. Also, the role of adaptive immune system is discussed at the site of infection to control the infection along with the proinflammatory cytokine therapy.

Computational investigations of three main drugs and their comparison with synthesized compounds as potent inhibitors of SARS-CoV-2 main protease (Mpro): DFT, QSAR, molecular docking, and in silico toxicity analysis.

In this study, we examined five previously synthesized compounds and checked their binding affinity towards the SARS-CoV-2 main protease (Mpro) by molecular docking study, and compared the data with three FDA approved drugs, i.e., Remdesivir, Ivermectine and Hydroxychlorochine. In addition, we have investigated the docking study against the main protease of SARS-CoV-2 (Mpro) by using Autodock 4.2 software package. The results suggested that the investigated compounds have property to bind the active position of the protein as reported in approved drugs. Hence, further experimental studies are required. The formation of intermolecular interactions, negative values of scoring functions, free binding energy and the calculated binding constants confirmed that the studied compounds have significant affinity for the specified biotarget. These studied compounds were passed the drug-likeness criteria as suggested by calculating ADME data by SwissADME server. Moreover, the ADMET properties suggested that the investigated compounds to be orally active compounds in human. Furthermore, density functional computations (DFT) were executed by applying GAUSSIAN 09 suit program. In addition, Quantitative Structure-Activity Relationship (QSAR) was studied by applying HyperChem Professional 8.0.3 program.

The recent challenges of highly contagious COVID-19, causing respiratory infections: Symptoms, diagnosis, transmission, possible vaccines, animal models, and immunotherapy.

COVID-19 is highly contagious pathogenic viral infection initiated from Wuhan seafood wholesale market of China on December 2019 and spread rapidly around the whole world due to onward transmission. This recent outbreak of novel coronavirus (CoV) was believed to be originated from bats and causing respiratory infections such as common cold, dry cough, fever, headache, dyspnea, pneumonia, and finally Severe Acute Respiratory Syndrome (SARS) in humans. For this widespread zoonotic virus, human-to-human transmission has resulted in nearly 83 lakh cases in 213 countries and territories with 4,50,686 deaths as on 19 June 2020. This review presents a report on the origin, transmission, symptoms, diagnosis, possible vaccines, animal models, and immunotherapy for this novel virus and will provide ample references for the researchers toward the ongoing development of therapeutic agents and vaccines and also preventing the spread of this disease.