Synthesis and Biological Evaluation of 2,3,4-Triaryl-1,2,4-oxadiazol-5-ones as p38 MAPK Inhibitors.

A series of azastilbene derivatives, characterized by the presence of the 1,2,4-oxadiazole-5-one system as a linker of the two aromatic rings of stilbenes, have been prepared as novel potential inhibitors of p38 MAPK. Biological assays indicated that some of the synthesized compounds are endowed with good inhibitory activity towards the kinase. Molecular modeling data support the biological results showing that the designed compounds possess a reasonable binding mode in the ATP binding pocket of p38α kinase with a good binding affinity.

1,2,4-Oxadiazole-5-ones as analogues of tamoxifen: synthesis and biological evaluation.

A series of 2,3,4-triaryl-substituted 1,2,4-oxadiazole-5-ones have been prepared as fixed-ring analogues of tamoxifen (TAM), a drug inhibitor of Estradiol Receptor (ER) used in breast cancer therapy, by an efficient synthetic protocol based on a 1,3-dipolar cycloaddition of nitrones to isocyanates. Some of the newly synthesized compounds (14d-f, 14h and 14k) show a significant cytotoxic effect in a human breast cancer cell line (MCF-7) possessing IC50 values between 15.63 and 31.82 µM. In addition, compounds 14d-f, 14h and 14k are able to increase the p53 expression levels, activating also the apoptotic pathway. Molecular modeling studies of novel compounds performed on the crystal structure of ER reveal the presence of strong hydrophobic interactions with the aromatic rings of the ligands similar to TAM. These data suggest that 1,2,4-oxadiazole-5-ones can be considered analogues of TAM, and that their anticancer activity might be partially due to ER inhibition.

Pyrimidine 2,4-Diones in the Design of New HIV RT Inhibitors.

The pyrimidine nucleus is a versatile core in the development of antiretroviral agents. On this basis, a series of pyrimidine-2,4-diones linked to an isoxazolidine nucleus have been synthesized and tested as nucleoside analogs, endowed with potential anti-HIV (human immunodeficiency virus) activity. Compounds 6a-c, characterized by the presence of an ethereal group at C-3, show HIV reverse transcriptase (RT) inhibitor activity in the nanomolar range as well as HIV-infection inhibitor activity in the low micromolar with no toxicity. In the same context, compound 7b shows only a negligible inhibition of RT HIV.

Graphene Quantum Dots Based Systems As HIV Inhibitors.

Graphene quantum dots (GQD) are the next generation of nanomaterials with great potential in drug delivery and target-specific HIV inhibition. In this study we investigated the antiviral activity of graphene based nanomaterials by using water-soluble GQD synthesized from multiwalled carbon nanotubes (MWCNT) through prolonged acidic oxidation and exfoliation and compared their anti-HIV activity with that exerted by reverse transcriptase inhibitors (RTI) conjugated with the same nanomaterial. The antiretroviral agents chosen in this study, CHI499 and CDF119, belong to the class of non-nucleoside reverse transcriptase inhibitors (NNRTI). From this study emerged the RTI-conjugated compound GQD-CHI499 as a good potential candidate for HIV treatment, showing an IC50 of 0.09 µg/mL and an EC50 value in cell of 0.066 µg/mL. The target of action in the replicative cycle of HIV of the drug conjugated samples GQD-CHI499 and GQD-CDF119 was also investigated by a time of addition (TOA) method, showing for both conjugated samples a mechanism of action similar to that exerted by NNRTI drugs.

A Palladium Iodide-Catalyzed Oxidative Aminocarbonylation-Heterocyclization Approach to Functionalized Benzimidazoimidazoles.

A novel carbonylative approach to the synthesis of functionalized 1H-benzo[d]imidazo[1,2-a]imidazoles is presented. The method consists of the oxidative aminocarbonylation of N-substituted-1-(prop-2-yn-1-yl)-1H-benzo[d]imidazol-2-amines, carried out in the presence of secondary nucleophilic amines, to give the corresponding alkynylamide intermediates, followed by in situ conjugated addition and double-bond isomerization, to give 2-(1-alkyl-1H-benzo[d]imidazo[1,2-a]imidazol-2-yl)acetamides. Products were obtained in good to excellent yields (64-96%) and high turnover numbers (192-288 mol of product per mol of catalyst) under relatively mild conditions (100 °C under 20 atm of a 4:1 mixture of CO-air), using a simple catalytic system, consisting of PdI2 (0.33 mol %) in conjunction with KI (0.33 equiv).

Synthesis and Biological Evaluation of Pyrimidine-oxazolidin-2-arylimino Hybrid Molecules as Antibacterial Agents.

Pyrimidine-1,3-oxazolidin-2-arylimino hybrids have been synthesized as a new class of antibacterial agents. The synthetic approach exploits a Cu(II)-catalyzed intramolecular halkoxyhalogenation of alkynyl ureas, followed by a Suzuki coupling reaction with 2,4-dimethoxypyrimidin-5-boronic acid. Biological screenings revealed that most of the compounds showed moderate to good activity against two Gram-positive (B. subtilis, S. aureus) and three Gram-negative (P. aeruginosa, S. typhi, K. pneumonia) pathogenic strains. A molecular docking study, performed in the crystal structure of 50S ribosomal unit of Haloarcula marismortui, indicated that pyrimidine-oxazolidin-2-arylimino hybrids 8c and 8h exhibited a high binding affinity (-9.65 and -10.74 kcal/mol), which was in agreement with their good antibacterial activity. The obtained results suggest that the combination of pyrimidine and oxazolidone moieties can be considered as a valid basis to develop new further modifications towards more efficacious antibacterial compounds.

Synthesis of spiro[isoindole-1,5'-isoxazolidin]-3(2H)-ones as potential inhibitors of the MDM2-p53 interaction.

A series of spiro[isoindole-1,5-isoxazolidin]-3(2H)-ones has been synthesized by 1,3-dipolar cycloaddition of N-benzylnitrone with isoindolin-3-methylene-1-ones. The regio- and stereoselectivity of the process have been rationalized by computational methods. The obtained compounds show cytotoxic properties and antiproliferative activity in the range of 9-22 µM. Biological tests suggest that the antitumor activity could be linked to the inhibition of the protein-protein p53-MDM2 interaction. Docking measurements support the biological data.

Synthesis and biological properties of 5-(1H-1,2,3-triazol-4-yl)isoxazolidines: a new class of C-nucleosides.

A novel series of C-nucleosides, featuring the presence of a 1,2,3-triazole ring linked to an isoxazolidine system, has been designed as mimetics of the pyrimidine nucleobases. An antiproliferative effect was observed for compounds 17a and 17b: the growth inhibitory effect reaches the 50% in HepG2 and HT-29 cells and increases up to 56% in the SH-SY5Y cell line after 72 h of incubation at a 100 µM concentration.

C-5'-Triazolyl-2'-oxa-3'-aza-4'a-carbanucleosides: Synthesis and biological evaluation.

A novel series of 2'-oxa-3'-aza-4'a-carbanucleosides, featured with a triazole linker at the 5'-position, has been developed by exploiting a click chemistry reaction of 5'-azido-2'-oxa-3'-aza-4'a-carbanucleosides with substituted alkynes. Biological tests indicate an antitumor activity for the synthesized compounds: most of them inhibit cell proliferation of Vero, BS-C-1, HEp-2, MDCK, and HFF cells with a CC50 in the range of 5.0-40 µM. The synthesized compounds do not show any antiviral activity.

Synthesis and biological activity of new arenediyne-linked isoxazolidines.

Arenediyne-isoxazolidine conjugates have been synthesized as a new scaffold for the development of bioactive mimics. Some of the synthesized compounds are endowed with antiproliferative activity against three human cancer cell lines. Their thermal reactivity suggests that the biological activity probably could not be linked to the Bergman cyclization.

3,4-DHPEA-EA from Olea Europaea L. is effective against standard and clinical isolates of Staphylococcus sp.

BACKGROUND: The aim of the present work was to evaluate the antibacterial effect of 3,4-DHPEA-EA (methyl-4-(2-(3,4-dihydroxyphenethoxy)-2-oxoethyl)-3-formyl-2-methyl-3,4-dihydro-2H-pyran-5-carboxylate), a derivate of oleuropein, against a range of Gram-positive bacteria, including ATCC strains, food and clinical isolates. METHODS: The minimum inhibitory concentrations (MICs) of 3,4-DHPEA-EA were determined by the broth microdilution method and the Bioscreen C. RESULTS: 3,4-DHPEA-EA was effective against ATCC and clinical isolates of Staphylococcus aureus (MIC values between 125 and 250 µg/ml) and ATCC and clinical isolates of Staphylococcus epidermidis (MIC values between 7.81 and 62.5 µg/ml). No significant differences were observed between the two solvents (methanol and DMSO) used to dissolve 3,4-DHPEA-EA. CONCLUSIONS: The results obtained could be used to develop novel therapies for the treatment of skin infections. Further studies need to be performed to elucidate the formation of 3,4-DHPEA-EA by acid hydrolysis of oleuropein in the human stomach.

Enantiomerically pure phosphonated carbocyclic 2'-oxa-3'-azanucleosides: synthesis and biological evaluation.

Starting from enantiomeric pure 1-[(3S,5R)- and 1-[(3R,5S)-3-(hydroxymethyl)-2-methylisoxazolidin-5-yl]-5-methylpyrimidine-2,4(1H,3H)-diones (-)7a and (+)7b, obtained by lipase-catalyzed resolution, pure diethyl{[(3S,5R)-2-methyl-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)isoxazolidin-3-yl]methyl}phosphonate (-)12a and diethyl{[(3R,5S)-2-methyl-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)isoxazolidin-3-yl]methyl}phosphonate (+)12b have been synthesized. The obtained compounds showed no cytotoxic activity versus the U937 cell line in comparison with AZT, and were poorly able to inhibit HIV infection in vitro.

Footprint of sustained poleward warm water flow within East Antarctic submarine canyons.

The intrusion of relatively warm water onto the continental shelf is widely recognized as a threat to Antarctic ice shelves and glaciers grounded below sea level, as enhanced ocean heat increases their basal melt. While the circulation of warm water has been documented on the East Antarctic continental shelf, the modes of warm water transport from the deep ocean onto the shelf are still uncertain. This makes predicting the future responses of major East Antarctic marine-grounded glaciers, such as Totten and Ninnis glaciers, particularly challenging. Here, we outline the key role of submarine canyons to convey southward flowing currents that transport warm Circumpolar Deep Water toward the East Antarctic shelf break, thus facilitating warm water intrusion on the continental shelf. Sediment drifts on the eastern flank of the canyons provide evidence for sustained southward-directed flows. These morpho-sedimentary features thus highlight areas potentially prone to enhanced ocean heat transport toward the continental shelf, with repercussions for past, present, and future glacial melting and consequent sea level rise.

Synthesis and biological evaluation of furopyrimidine N,O-nucleosides.

A series of modified N,O-nucleosides, characterized by the presence of a furopyrimidine moiety, has been synthesized by exploiting a Sonogashira cross coupling reaction of 1-isoxazolidinyl-5-iodouracil with alkynes, followed by treatment with CuI in refluxing TEA/MeOH mixture. The obtained compounds were screened against both RNA and DNA viruses. None of the compounds were endowed with antiviral activity at subtoxic concentrations. However, some of them were able to inhibit proliferation of MRC-5, Vero, BS-C-1 cells by 50% (CC50) at concentrations ranging from 0.7 to 62.5 mM.

Synthesis and biological evaluation of 3-hydroxymethyl-5-(1H-1,2,3-triazol) isoxazolidines.

A synthetic approach towards a series of 3-hydroxymethyl-5-(1H-1,2,3-triazol)isoxazolidines has been reported, according to a procedure based on the cycloaddition reaction, under microwave irradiation, of a nitrone with 1-vinyl triazoles, prepared by a click reaction of azides with alkynes. Biological tests show that the synthesized compounds are able to inhibit proliferation of follicular and anaplastic human thyroid cancer cell lines, with IC50 values ranging from 3.87 to 8.76 lM. The obtained compounds induce caspase-3 activation and DNA fragmentation prevalently in follicular human thyroid cancer cell lines.

Antiviral Compounds to Address Influenza Pandemics: An Update from 2016-2022.

In recent decades, the world has gained experience of the dangerous effects of pandemic events caused by emerging respiratory viruses. In particular, annual epidemics of influenza are responsible for severe illness and deaths. Even if conventional influenza vaccines represent the most effective tool for preventing virus infections, they are not completely effective in patients with severe chronic disease and immunocompromised and new small molecules have emerged to prevent and control the influenza viruses. Thus, the attention of chemists is continuously focused on the synthesis of new antiviral drugs able to interact with the different molecular targets involved in the virus replication cycle. To date, different classes of influenza viruses inhibitors able to target neuraminidase enzyme, hemagglutinin protein, Matrix-2 (M2) protein ion channel, nucleoprotein or RNA-dependent RNA polymerase have been synthesized using several synthetic strategies comprising the chemical modification of currently used drugs. The best results, in terms of inhibitory activity, are in the nanomolar range and have been obtained from the chemical modification of clinically used drugs such as Peramivir, Zanamivir, Oseltamir, Rimantadine, as well as sialylated molecules, and hydroxypyridinone derivatives. The aim of this review is to report, covering the period 2016-2022, the most recent routes related to the synthesis of effective influenza virus inhibitors.

Bacterial aerobic methane cycling by the marine sponge-associated microbiome.

BACKGROUND: Methanotrophy by the sponge-hosted microbiome has been mainly reported in the ecological context of deep-sea hydrocarbon seep niches where methane is either produced geothermically or via anaerobic methanogenic archaea inhabiting the sulfate-depleted sediments. However, methane-oxidizing bacteria from the candidate phylum Binatota have recently been described and shown to be present in oxic shallow-water marine sponges, where sources of methane remain undescribed. RESULTS: Here, using an integrative -omics approach, we provide evidence for sponge-hosted bacterial methane synthesis occurring in fully oxygenated shallow-water habitats. Specifically, we suggest methane generation occurs via at least two independent pathways involving methylamine and methylphosphonate transformations that, concomitantly to aerobic methane production, generate bioavailable nitrogen and phosphate, respectively. Methylphosphonate may be sourced from seawater continuously filtered by the sponge host. Methylamines may also be externally sourced or, alternatively, generated by a multi-step metabolic process where carnitine, derived from sponge cell debris, is transformed to methylamine by different sponge-hosted microbial lineages. Finally, methanotrophs specialized in pigment production, affiliated to the phylum Binatota, may provide a photoprotective function, closing a previously undescribed C1-metabolic loop that involves both the sponge host and specific members of the associated microbial community. CONCLUSION: Given the global distribution of this ancient animal lineage and their remarkable water filtration activity, sponge-hosted methane cycling may affect methane supersaturation in oxic coastal environments. Depending on the net balance between methane production and consumption, sponges may serve as marine sources or sinks of this potent greenhouse gas. Video Abstract.

Truncated phosphonated C-1'-branched N,O-nucleosides: a new class of antiviral agents.

Truncated phosphonated C-1'-branched N,O-nucleosides have been synthesized in good yields by 1,3-dipolar cycloaddition methodology, starting from N-methyl-C-(diethoxyphosphoryl)nitrone 7. Preliminary biological assays show that ß-anomers are able to inhibit HIV in vitro infection at concentrations in the micromolar range. Higher SI values with respect to AZT indicated that the compounds were endowed with low cytotoxicity.

Antiviral activity of seed extract from Citrus bergamia towards human retroviruses.

The effects of an extract from Citrus bergamia (BSext) and those of two products purified from the same extract, that is, nomilin and limonin, and reference compounds, towards HTLV-1 have been reported. Moreover, they were also compared with those obtained towards HIV-1. Results showed that the efficacy of both BSext and limonin in inhibiting HTLV-1 as well as HIV-1 expression in infected cells, as evaluated by comparable quantitative assays, was close to that of the effective, reference compounds, respectively. The protective effect of BSext and of the purified products was associated with the inhibition of both HTLV-1 and HIV-1 RT activities in conceptually similar, cell-free assays. The cytotoxicity of the assayed compounds of natural origin was substantially less pronounced than that of the reference compounds, thus showing a favourable selectivity index for the novel BSext product.

Synthesis of C-4'truncated phosphonated carbocyclic 2'-oxa-3'-azanucleosides as antiviral agents.

A new template of C-4'-truncated phosphonated nucleosides (TPCOANs) has been obtained in good yields according to two different routes which exploit the reactivity of a phosphonated nitrone. The one-step procedure based on the 1,3-dipolar cycloaddition of a phosphonated nitrone with vinyl nucleobases leads to the unnatural alpha-nucleosides as the main adducts. On the other hand, the target beta-anomers have been obtained in high yield by a two-step procedure based on the 1,3-dipolar cycloaddition of a phosphonated nitrone with vinyl acetate followed by nucleosidation reaction. The reactivity of the phosphonated nitrone has been investigated trough quantum mechanical DFT calculations at the B3LYP/D95+(d,p) theory level. Preliminary biological assays show that beta-anomers of TPCOANs are able to inhibit the reverse transcriptase of different retroviruses at concentrations in the nanomolar range, with a potency comparable with that of tenofovir.