5-(1H-Indol-3-ylmethylene)-4-oxo-2-thioxothiazolidin-3-yl)alkancarboxylic Acids as Antimicrobial Agents: Synthesis, Biological Evaluation, and Molecular Docking Studies

Background: Infectious diseases symbolize a global consequential strain on public health security and impact on the socio-economic stability all over the world. The increasing resistance to the current antimicrobial treatment has resulted in crucial need for the discovery and development of novel entity for the infectious treatment with different modes of action that could target both sensitive and resistant strains. Methods: Compounds were synthesized using classical methods of organic synthesis. Results: All 20 synthesized compounds showed antibacterial activity against eight Gram-positive and Gram-negative bacterial species. It should be mentioned that all compounds exhibited better antibacterial potency than ampicillin against all bacteria tested. Furthermore, 18 compounds appeared to be more potent than streptomycin against Staphylococcus aureus, Enterobacter cloacae, Pseudomonas aeruginosa, Listeria monocytogenes, and Escherichia coli. Three the most active compounds 4h, 5b, and 5g appeared to be more potent against MRSA than ampicillin, while streptomycin did not show any bactericidal activity. All three compounds displayed better activity also against resistant strains P. aeruginosa and E. coli than ampicillin. Furthermore, all compounds were able to inhibit biofilm formation 2- to 4-times more than both reference drugs. Compounds were evaluated also for their antifungal activity against eight species. The evaluation revealed that all compounds exhibited antifungal activity better than the reference drugs bifonazole and ketoconazole. Molecular docking studies on antibacterial and antifungal targets were performed in order to elucidate the mechanism of antibacterial activity of synthesized compounds. Conclusion: All tested compounds showed good antibacterial and antifungal activity better than that of reference drugs and three the most active compounds could consider as lead compounds for the development of new more potent agents

Cathepsin L inhibitors with activity against the liver fluke identified from a focus library of quinoxaline 1,4-di-N-Oxide derivatives

This article belongs to the Special Issue Recent Trends on Enzymes Inhibitors and Activators in Drug Research IIInfections caused by Fasciola species are widely distributed in cattle and sheep causing significant economic losses, and are emerging as human zoonosis with increasing reports of human cases, especially in children in endemic areas. The current treatment is chemotherapeutic, triclabendazole being the drug of preference since it is active against all parasite stages. Due to the emergence of resistance in several countries, the discovery of new chemical entities with fasciolicidal activity is urgently needed. In our continuous search for new fasciolicide compounds, we identified and characterized six quinoxaline 1,4-di-N-oxide derivatives from our in-house library. We selected them from a screening of novel inhibitors against FhCL1 and FhCL3 proteases, two essential enzymes secreted by juvenile and adult flukes. We report compounds C7, C17, C18, C19, C23, and C24 with an IC50 of less than 10 µM in at least one cathepsin. We studied their binding kinetics in vitro and their enzyme-ligand interactions in silico by molecular docking and molecular dynamic (MD) simulations. These compounds readily kill newly excysted juveniles in vitro and have low cytotoxicity in a Hep-G2 cell line and bovine spermatozoa. Our findings are valuable for the development of new chemotherapeutic approaches against fascioliasis, and other pathologies involving cysteine proteases

5,8-Dimethyl-9H-carbazole Derivatives Blocking hTopo I Activity and Actin Dynamics

Over the years, carbazoles have been largely studied for their numerous biological properties, including antibacterial, antimalarial, antioxidant, antidiabetic, neuroprotective, anticancer, and many more. Some of them have gained great interest for their anticancer activity in breast cancer due to their capability in inhibiting essential DNA-dependent enzymes, namely topoisomerases I and II. With this in mind, we studied the anticancer activity of a series of carbazole derivatives against two breast cancer cell lines, namely the triple negative MDA-MB-231 and MCF-7 cells. Compounds 3 and 4 were found to be the most active towards the MDA-MB-231 cell line without interfering with the normal counterpart. Using docking simulations, we assessed the ability of these carbazole derivatives to bind human topoisomerases I and II and actin. In vitro specific assays confirmed that the lead compounds selectively inhibited the human topoisomerase I and interfered with the normal organization of the actin system, triggering apoptosis as a final effect. Thus, compounds 3 and 4 are strong candidates for further drug development in multi-targeted therapy for the treatment of triple negative breast cancer, for which safe therapeutic regimens are not yet available

4-{[(E)-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl)methyl­idene]amino}-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one

The title Schiff base compound, C23H23N5O, was synthesized by the reaction of 4-amino­phenazone and 3,5-dimethyl-1-phenyl­pyrazole-4-carbaxaldehyde. The mol­ecule adopts an E configuration about the central C=N double bond. A weak intra­molecular C—H⋯O hydrogen bond generates an S(6) ring motif. The dihedral angle between the pyrazole rings is 24.72 (10)° and the dihedral angles between the pyrazole rings and the adjacent phenyl rings are 58.67 (10) and 46.58 (11)°. The crystal structure is stabilized by weak C—H⋯π inter­actions involving the pyrazolone and phenyl rings

(5E)-5-(2,4-Dichloro­benzyl­idene)-2-(piperidin-1-yl)-1,3-thia­zol-4(5H)-one

In the title compound, C15H14Cl2N2OS, the piperidine ring adopts a chair conformation. The dihedral angle between the thia­zolidine ring and the dichloro­benzene ring is 9.30 (4)°; this near coplanar conformation is stabilized by the formation of an intra­molecular C—H⋯S hydrogen bond, which generates an S(6) ring. In the crystal, mol­ecules are linked by C—H⋯O hydrogen bonds, forming [001] chains. Weak π–π inter­actions [centroid–centroid separation = 3.5460 (5) Å] consolidate the structure

Federica Giuzio*, Maria Grazia Bonomo, Alessia Catalano*, Vittoria Infantino, Giovanni Salzano, Magnus Monné, Athina Geronikaki, Anthi Petrou, Stefano Aquaro, Maria Stefania Sinicropi#, Carmela Saturnino#

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is an RNA virus belonging to the coronavirus family responsible for coronavirus disease 2019 (COVID-19). It primarily affects the pulmonary system, which is the target of chronic obstructive pulmonary disease (COPD), for which many new compounds have been developed. In this study, phosphodiesterase 4 (PDE4) inhibitors are being investigated. The inhibition of PDE4 enzyme produces antiinflammatory and bronchodilator effects in the lung by inducing an increase in cAMP concentrations. Piclamilast and rolipram are known selective inhibitors of PDE4, which are unfortunately endowed with common side effects, such as nausea and emesis. The selective inhibition of the phosphodiesterase 4B (PDE4B) subtype may represent an intriguing technique for combating this highly contagious disease with fewer side effects. In this article, molecular docking studies for the selective inhibition of the PDE4B enzyme have been carried out on 21 in-house compounds. The compounds were docked into the pocket of the PDE4B catalytic site, and in most cases, they were almost completely superimposed onto piclamilast. Then, in order to enlarge our study, drug-likeness prediction studies were performed on the compounds under study

Antioxidant and anti-lipoxygenase activities of extracts from different parts of Lavatera cretica L. grown in Algarve (Portugal)

Background: Lavatera cretica L. was used in folk medicine as anti-inflammatory among other applications. As inflammation is many times associated with oxidative processes, the aim of the present work was to evaluate the ability of aqueous extracts obtained from different parts of L. cretica to prevent oxidation or inflammation using several methods in vitro. Materials and Methods: The capacity of samples for preventing lipid peroxidation, scavenging free radicals, chelating metal ions, reducing power, and inhibiting lipoxygenase activity was investigated. This last assay also permits to evaluate the anti-inflammatory activity. The quantification of total phenols was performed using Folin-Chiocalteu reagent. Results: The highest concentrations of total polyphenols and flavonoids were found in the leaf extract (254.62 6.50 mg gallic acid equivalent/gram; dry weight). Leaf and flower extracts were the most active for scavenging 2,2-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt free radicals [Inhibition concentration (IC 50 = 2.88 0.54 and IC50 = 4.37 0.54 g/mL, respectively)], and leaf extract was also the best for scavenging hydroxyl radicals (IC 50 = 0.81 0.05 g/mL). Bract plus sepal extract possessed the best capacity for preventing lipid peroxidation when lecithin liposome was the lipid substrate (IC 50 = 0.19 0.03 g/mL) and scavenging superoxide anion radicals (IC 50 = 1.13 0.48 g/mL). Leaf and flower extracts were the best lipoxygenase inhibitors (IC 50 = 0.013 0.0034 g/mL in both extracts). Conclusions: L. cretica extracts were able to scavenge free radicals, inhibit lipid peroxidation and lipoxygenase activity. With these attributes, this plant can have an important role in the treatment of neurodegenerative disorders

Are Nutraceuticals Effective in COVID‐19 and Post‐COVID Prevention and Treatment?

The beginning of the end or the end of the beginning? After two years mastered by coronavirus disease 19 (COVID‐19) pandemic, we are now witnessing a turnaround. The reduction of severe cases and deaths from COVID‐19 led to increasing importance of a new disease called post‐COVID syndrome. The term post‐COVID is used to indicate permanency of symptoms in patients who have recovered from severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. Immune, antiviral, antimicrobial therapies, as well as ozone therapy have been used to treat COVID‐19 disease. Vaccines have then become available and administered worldwide to prevent the insurgence of the disease. However, the pandemic is not over yet at all given the emergence of new omicron variants. New therapeutic strategies are urgently needed. In this view, great interest was found in nutraceutical products, including vitamins (C, D, and E), minerals (zinc), melatonin, probiotics, flavonoids (quercetin), and curcumin. This review summarizes the role of nutraceuticals in the prevention and/or treatment of COVID‐19 disease and post‐COVID syndrome

SuperPred: drug classification and target prediction

The drug classification scheme of the World Health Organization (WHO) [Anatomical Therapeutic Chemical (ATC)-code] connects chemical classification and therapeutic approach. It is generally accepted that compounds with similar physicochemical properties exhibit similar biological activity. If this hypothesis holds true for drugs, then the ATC-code, the putative medical indication area and potentially the medical target should be predictable on the basis of structural similarity. We have validated that the prediction of the drug class is reliable for WHO-classified drugs. The reliability of the predicted medical effects of the compounds increases with a rising number of (physico-) chemical properties similar to a drug with known function. The web-server translates a user-defined molecule into a structural fingerprint that is compared to about 6300 drugs, which are enriched by 7300 links to molecular targets of the drugs, derived through text mining followed by manual curation. Links to the affected pathways are provided. The similarity to the medical compounds is expressed by the Tanimoto coefficient that gives the structural similarity of two compounds. A similarity score higher than 0.85 results in correct ATC prediction for 81% of all cases. As the biological effect is well predictable, if the structural similarity is sufficient, the web-server allows prognoses about the medical indication area of novel compounds and to find new leads for known targets