المؤلفون: Ibba R., Corona P., Nonne F., Caria P., Serreli G., Palmas V., Riu F., Sestito S., Nieddu M., Loddo R., Sanna G., Sandra Piras S.

المساهمون: Ibba, R., Corona, P., Nonne, F., Caria, P., Serreli, G., Palmas, V., Riu, F., Sestito, S., Nieddu, M., Loddo, R., Sanna, G., Sandra Piras, S.

مصطلحات موضوعية: Antiviral compound, Benzotriazole, Coxsackievirus B5, Enteroviru, Picornaviridae, RNA-virus

الوصف: Several human diseases are caused by enteroviruses and are currently clinically untreatable, pushing the research to identify new antivirals. A notable number of benzo[d][1,2,3]triazol-1(2)-yl derivatives were designed, synthesized, and in vitro evaluated for cytotoxicity and antiviral activity against a wide spectrum of RNA positive- and negative-sense viruses. Five of them (11b, 18e, 41a, 43a, 99b) emerged for their selective antiviral activity against Coxsackievirus B5, a human enteroviruses member among the Picornaviridae family. The EC50 values ranged between 6 and 18.5 μM. Among all derivatives, compounds 18e and 43a were interestingly active against CVB5 and were selected to better define the safety profile on cell monolayers by transepithelial resistance test (TEER). Results indicated compound 18e as the hit compound to investigate the potential mechanism of action by apoptosis assay, virucidal activity test, and the time of addition assay. CVB5 is known to be cytotoxic by inducing apoptosis in infected cells; in this study, compound 18e was proved to protect cells from viral infection. Notably, cells were mostly protected when pre-treated with derivative 18e, which had, however, no virucidal activity. From the performed biological assays, compound 18e turned out to be non-cytotoxic as well as cell protective against CVB5 infection, with a mechanism of action ascribable to an interaction on the early phase of infection, by hijacking the viral attachment process.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/36986528; info:eu-repo/semantics/altIdentifier/wos/WOS:000958048200001; volume:16; issue:3; firstpage:1; lastpage:20; numberofpages:20; journal:PHARMACEUTICALS; https://hdl.handle.net/11584/364223Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85152399150

الإتاحة: https://doi.org/10.3390/ph16030429Test
https://hdl.handle.net/11584/364223Test

المؤلفون: Guay, KP, Ibba, R, Kiappes, JL, Vasiljević, S, Bonì, F, De Benedictis, M, Zeni, I, Le Cornu, JD, Hensen, M, Chandran, AV, Kantsadi, AL, Caputo, AT, Blanco Capurro, JI, Bayo, Y, Hill, JC, Hudson, K, Lia, A, Brun, J, Withers, SG, Martí, M, Biasini, E, Santino, A, De Rosa, M, Milani, M, Modenutti, CP, Hebert, DN, Zitzmann, N, Roversi, P

الوصف: Misfolded glycoprotein recognition and endoplasmic reticulum (ER) retention are mediated by the ER glycoprotein folding quality control (ERQC) checkpoint enzyme, UDP-glucose glycoprotein glucosyltransferase (UGGT). UGGT modulation is a promising strategy for broad-spectrum antivirals, rescue-of-secretion therapy in rare disease caused by responsive mutations in glycoprotein genes, and many cancers, but to date no selective UGGT inhibitors are known. The small molecule 5-[(morpholin-4-yl)methyl]quinolin-8-ol (5M-8OH-Q) binds a CtUGGTGT24 “WY” conserved surface motif conserved across UGGTs but not present in other GT24 family glycosyltransferases. 5M-8OH-Q has a 47 μM binding affinity for CtUGGTGT24 in vitro as measured by ligand-enhanced fluorescence. In cellula, 5M-8OH-Q inhibits both human UGGT isoforms at concentrations higher than 750 μM. 5M-8OH-Q binding to CtUGGTGT24 appears to be mutually exclusive to M5-9 glycan binding in an in vitro competition experiment. A medicinal program based on 5M-8OH-Q will yield the next generation of UGGT inhibitors.

العلاقة: https://ora.ox.ac.uk/objects/uuid:40dc158b-da1e-4742-bca9-5ce1b6a189caTest; https://doi.org/10.1016/j.isci.2023.107919Test

الإتاحة: https://doi.org/10.1016/j.isci.2023.107919Test
https://ora.ox.ac.uk/objects/uuid:40dc158b-da1e-4742-bca9-5ce1b6a189caTest

المؤلفون: Caputo, AT, Ibba, R, Le Cornu, JD, Darlot, B, Hensen, M, Lipp, CB, Marcianò, G, Vasiljević, S, Zitzmann, N, Roversi, P

الوصف: None of the current data processing pipelines for X-ray crystallography fragment-based lead discovery (FBLD) consults all the information available when deciding on the lattice and symmetry (i.e., the polymorph) of each soaked crystal. Often, X-ray crystallography FBLD pipelines either choose the polymorph based on cell volume and point-group symmetry of the X-ray diffraction data or leave polymorph attribution to manual intervention on the part of the user. Thus, when the FBLD crystals belong to more than one crystal polymorph, the discovery pipeline can be plagued by space group ambiguity, especially if the polymorphs at hand are variations of the same lattice and, therefore, difficult to tell apart from their morphology and/or their apparent crystal lattices and point groups. In the course of a fragment-based lead discovery effort aimed at finding ligands of the catalytic domain of UDP–glucose glycoprotein glucosyltransferase (UGGT), we encountered a mixture of trigonal crystals and pseudotrigonal triclinic crystals—with the two lattices closely related. In order to resolve that polymorphism ambiguity, we have written and described here a series of Unix shell scripts called CoALLA (crystal polymorph and ligand likelihood-based assignment). The CoALLA scripts are written in Unix shell and use autoPROC for data processing, CCP4-Dimple/REFMAC5 and BUSTER for refinement, and RHOFIT for ligand docking. The choice of the polymorph is effected by carrying out (in each of the known polymorphs) the tasks of diffraction data indexing, integration, scaling, and structural refinement. The most likely polymorph is then chosen as the one with the best structure refinement Rfree statistic. The CoALLA scripts further implement a likelihood-based ligand assignment strategy, starting with macromolecular refinement and automated water addition, followed by removal of the water molecules that appear to be fitting ligand density, and a final round of refinement after random perturbation of the refined macromolecular model, in ...

العلاقة: https://ora.ox.ac.uk/objects/uuid:ad450f15-4c11-468a-81fe-2b6fa80be497Test; https://doi.org/10.3389/fmolb.2022.960248Test

الإتاحة: https://doi.org/10.3389/fmolb.2022.960248Test
https://ora.ox.ac.uk/objects/uuid:ad450f15-4c11-468a-81fe-2b6fa80be497Test

المؤلفون: Brogi S., Ibba R., Rossi S., Butini S., Calderone V., Gemma S., Campiani G.

المساهمون: Brogi, S., Ibba, R., Rossi, S., Butini, S., Calderone, V., Gemma, S., Campiani, G.

مصطلحات موضوعية: covalent inhibition, cysteine/serine/threonine protease, nitrile, protozoan parasite, viru, warhead, Cysteine, Cysteine Proteinase Inhibitor, Drug Discovery, Human, Cysteine Protease, Parasitic Diseases

الوصف: In the field of drug discovery, the nitrile group is well represented among drugs and biologically active compounds. It can form both non-covalent and covalent interactions with diverse biological targets, and it is amenable as an electrophilic warhead for covalent inhibition. The main advantage of the nitrile group as a warhead is mainly due to its milder electrophilic character relative to other more reactive groups (e.g., -CHO), reducing the possibility of unwanted reactions that would hinder the development of safe drugs, coupled to the ease of installation through different synthetic approaches. The covalent inhibition is a well-assessed design approach for serine, threonine, and cysteine protease inhibitors. The mechanism of hydrolysis of these enzymes involves the formation of a covalent acyl intermediate, and this mechanism can be exploited by introducing electrophilic warheads in order to mimic this covalent intermediate. Due to the relevant role played by the cysteine protease in the survival and replication of infective agents, spanning from viruses to protozoan parasites, we will review the most relevant and recent examples of protease inhibitors presenting a nitrile group that have been introduced to form or to facilitate the formation of a covalent bond with the catalytic cysteine active site residue.

وصف الملف: ELETTRONICO

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/35458759; info:eu-repo/semantics/altIdentifier/wos/WOS:000785463200001; volume:27; issue:8; firstpage:1; lastpage:14; numberofpages:14; journal:MOLECULES; https://hdl.handle.net/11365/1205957Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85128802527; https://www.mdpi.com/1420-3049/27/8/2561Test; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9029279Test/

الإتاحة: https://doi.org/10.3390/molecules27082561Test
https://hdl.handle.net/11365/1205957Test
https://www.mdpi.com/1420-3049/27/8/2561Test
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9029279Test/

المؤلفون: Pozzetti L., Ibba R., Rossi S., Taglialatela-Scafati O., Taramelli D., Basilico N., D'alessandro S., Parapini S., Butini S., Campiani G., Gemma S.

المساهمون: Pozzetti, L., Ibba, R., Rossi, S., Taglialatela-Scafati, O., Taramelli, D., Basilico, N., D'Alessandro, S., Parapini, S., Butini, S., Campiani, G., Gemma, S.

مصطلحات موضوعية: 2-arylbenzofuran, 2-arylindole, Chalcone, Leishmania spp, Antiparasitic Agent, Benzofuran, Biflavonoid, Chemical Phenomena, Chemistry Techniques, Synthetic, Human, Indole, Leishmania infantum, Molecular Structure, Structure-Activity Relationship

الوصف: The potential of natural and synthetic chalcones as therapeutic leads against different pathological conditions has been investigated for several years, and this class of compounds emerged as a privileged chemotype due to its interesting anti-inflammatory, antimicrobial, antiviral, and anticancer properties. The objective of our study was to contribute to the investigation of this class of natural products as anti-leishmanial agents. We aimed at investigating the structure–activity relationships of the natural chalcone lophirone E, characterized by the presence of benzofuran B-ring, and analogues on anti-leishmania activity. Here we describe an effective synthetic strategy for the preparation of the natural chalcone lophirone E and its application to the synthesis of a small set of chalcones bearing different substitution patterns at both the A and heterocyclic B rings. The resulting compounds were investigated for their activity against Leishmania infantum promastigotes disclosing derivatives 1 and 28a,b as those endowed with the most interesting activities (IC50 = 15.3, 27.2, 15.9 μM, respectively). The synthetic approaches here described and the early SAR investigations highlighted the potential of this class of compounds as antiparasitic hits, making this study worthy of further investigation.

وصف الملف: ELETTRONICO

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/35056779; info:eu-repo/semantics/altIdentifier/wos/WOS:000758450100001; volume:27; issue:2; firstpage:1; lastpage:20; numberofpages:20; journal:MOLECULES; http://hdl.handle.net/11365/1185724Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85122809895; https://www.mdpi.com/1420-3049/27/2/463Test; https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8778746Test/

الإتاحة: https://doi.org/10.3390/molecules27020463Test
http://hdl.handle.net/11365/1185724Test
https://www.mdpi.com/1420-3049/27/2/463Test
https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8778746Test/

المؤلفون: Riu, F, Ibba, R, Zoroddu, S, Sestito, S, Lai, M, Piras, S, Sanna, L, Bordoni, V, Bagella, L, Carta, A

المساهمون: Riu, F, Ibba, R, Zoroddu, S, Sestito, S, Lai, M, Piras, S, Sanna, L, Bordoni, V, Bagella, L, Carta, A

مصطلحات موضوعية: Benzotriazole-acrylonitrile, antiproliferative compound, colchicine-binding site inhibitor, cell growth inhibition, molecular docking

الوصف: Introduction: Colchicine-binding site inhibitors are some of the most interesting ligands belonging to the wider family of microtubule-destabilising agents. Results: A novel series of 4 '-fluoro-substituted ligands (5-13) was synthesised. The antiproliferative activity assays resulted in nM values for the new benzotriazole-acrylonitrile derivatives. Compound 5, the hit compound, showed an evident blockade of HeLa cell cycle in the G2-M phase, but also a pro-apoptotic potential, and an increase of early and late apoptotic cells in HeLa and MCF-7 cell cycle analysis. Confocal microscopy analysis showed a segmented shape and a collapse of the cytoskeleton, as well as a consistent cell shrinkage after administration of 5 at 100 nM. Derivative 5 was also proved to compete with colchicine at colchicine-binding site, lowering its activity against tubulin polymerisation. In addition, co-administration of 5 and doxorubicin in drug-resistant A375 melanoma cell line highlighted a synergic potential in terms of inhibition of cell viability. Discussion: The 4 '-fluoro substitution of benzotriazole-acrylonitrile scaffold brought us a step forward in the optimisation process to obtain compound 5 as promising MDA antiproliferative agent at nanomolar concentration.

العلاقة: info:eu-repo/semantics/altIdentifier/wos/WOS:000841677000001; volume:37; issue:1; firstpage:2223; lastpage:2240; numberofpages:18; journal:JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY; https://hdl.handle.net/11388/301891Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85136012376

الإتاحة: https://doi.org/10.1080/14756366.2022.2111680Test
https://hdl.handle.net/11388/301891Test

المؤلفون: Piras S., Murineddu G., Loriga G., Carta A., Battistello E., Merighi S., Gessi S., Corona P., Asproni B., Ibba R., Temml V., Schuster D., Pinna G. A.

المساهمون: Piras, S., Murineddu, G., Loriga, G., Carta, A., Battistello, E., Merighi, S., Gessi, S., Corona, P., Asproni, B., Ibba, R., Temml, V., Schuster, D., Pinna, G. A.

مصطلحات موضوعية: μ-receptors affinity, analgesic activity, 9,10-diazatricyclo[4.2.1.12,5]decane (DTD), 2,7- diazatricyclo[4.4.0.03,8]decane, DTD derivatives, rigid benzo-condensed structure

الوصف: Opioid analgesics are clinically used to relieve severe pain in acute postoperative and cancer pain, and also in the long term in chronic pain. The analgesic action is mediated by μ-, δ-, and κ-receptors, but currently, with few exceptions for k-agonists, μ-agonists are the only ones used in therapy. Previously synthesized compounds with diazotricyclodecane cores (DTDs) have shown their effectiveness in binding opioid receptors. Fourteen novel diazatricyclodecanes belonging to the 9-propionyl-10-substituted-9,10-diazatricyclo[4.2.1.12,5]decane (compounds 20–23, 53, 57 and 59) and 2-propionyl-7-substituted-2,7-diazatricyclo[4.4.0.03,8]decane (compounds 24–27, 54, 58 and 60) series, respectively, have been synthesized and their ability to bind to the opioid μ-, δ-and κ-receptors was evaluated. Five of these derivatives, compounds 20, 21, 24, 26 and 53, showed μ-affinity in the nanomolar range with a negligible affinity towards δ-and κ-receptors and high μ-receptor selectivity. The synthesized compounds showed μ-receptor selectivity higher than those of previously reported methylarylcinnamyl analogs.

وصف الملف: STAMPA

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/34576918; info:eu-repo/semantics/altIdentifier/wos/WOS:000701272600001; volume:26; issue:18; firstpage:5448-1; lastpage:5448-19; numberofpages:19; journal:MOLECULES; https://hdl.handle.net/11392/2474890Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85114612247; https://www.mdpi.com/1420-3049/26/18/5448Test

الإتاحة: https://doi.org/10.3390/molecules26185448Test
https://hdl.handle.net/11392/2474890Test
https://www.mdpi.com/1420-3049/26/18/5448Test

المؤلفون: Ibba R., Piras S., Corona P., Riu F., Loddo R., Delogu I., Collu G., Sanna G., Caria P., Dettori T., Carta A.

المساهمون: Ibba, R., Piras, S., Corona, P., Riu, F., Loddo, R., Delogu, I., Collu, G., Sanna, G., Caria, P., Dettori, T., Carta, A.

مصطلحات موضوعية: antimetabolite, antiproliferative activity, antiviral, benzotriazole derivative, coxsackieviru, dicarboxamides

الوصف: Cancer and viral infections continue to threaten humankind causing death worldwide. Hence, the discovery of new anticancer and antiviral agents still represents a major scientific goal. Heterocycles designed to mimic the chemical structure of natural pyrimidines and purines have been designed over the years, exerting their activity acting as false substrates on several different targets. We reported a series of bis-benzotriazole-dicarboxamide derivatives which inhibit viral helicase of poliovirus, and hence we planned structure modifications to obtain different series of new dicarboxamides. Here, the synthesis and characterization of 56 new compounds: 31 bis-benzotriazole dicarboxamides and 25 mono-substituted acidic derivatives are reported. The synthesized compounds were tested for their antiviral and antitumor activity. Mostly, compounds 4a, 4c and 4d showed antiviral activity against tested Picornaviruses, Coxsackievirus B5 and Poliovirus-1. Likewise, four derivatives (3b, 3d, 4d, 9b) showed notable antiproliferative activity inhibiting cell growth in two distinct antitumor screenings. Compound 3b was selected as the antitumor lead compound for the wide range of activity and the potency proved. The lead compound was proved to induce apoptosis in SK-MES1 tumor cells, in a dose-dependent manner.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/34017818; info:eu-repo/semantics/altIdentifier/wos/WOS:000651404800001; volume:9; firstpage:1; lastpage:19; numberofpages:19; journal:FRONTIERS IN CHEMISTRY; https://hdl.handle.net/11584/320502Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85106054553

الإتاحة: https://doi.org/10.3389/fchem.2021.660424Test
https://hdl.handle.net/11584/320502Test

المؤلفون: Ibba R., Carta A., Madeddu S., Caria P., Serreli G., Piras S., Sestito S., Loddo R., Sanna G.

المساهمون: Ibba, R., Carta, A., Madeddu, S., Caria, P., Serreli, G., Piras, S., Sestito, S., Loddo, R., Sanna, G.

مصطلحات موضوعية: EV-A71, TEER, Antiviral, Apoptosis assay, Benzimidazole derivative, Neurological complication, Penetration assay, Timecourse, Animal, Antiviral agent, Apoptosi, Benzimidazole, Caco-2 Cell, Chlorocebus aethiop, Enterovirus A, human, Hand, foot and mouth disease, HeLa cell, Vero cell, Viral load, Viral plaque assay

الوصف: Enterovirus A71 (EV-A71) infection has emerged as a significant public health concern at the global level. Epidemic events of EV-A71 have been reported worldwide, and this succession of outbreaks has heightened concern that EV-A71 may become a public health threat. In recent years, widespread A71 enterovirus also occurred in European countries. EV-A71 infection causes hand-foot-mouth disease (HFMD), herpangina, and fever. However, it can sometimes induce a variety of neurological complications, including encephalitis, aseptic meningitis, pulmonary edema, and acute flaccid paralysis. We identified new benzimidazole derivatives and described theirin vitrocytotoxicity and broad-spectrum anti-enterovirus activity. Among them, derivative 2b resulted in interesting activity against EV-A71, and therefore it was selected for further investigations. Compound 2b proved to be able to protect cell monolayers from EV-A71-induced cytopathogenicity, with an EC50 of 3 μM. Moreover, Vero-76 cells resulted in being significantly protected from necrosis and apoptosis when treated with 2b at 20 and 80 μM. Compound 2b reduced viral adsorption to Vero-76 cells, and when evaluated in a time-of-addition assay, the derivative had the highest effect when added during the infection period. Moreover, derivative 2b reduced viral penetration into host cells. Besides, 2b did not affect intestinal monolayers permeability, showing no toxic effects. A detailed insight into the efficacy of compound 2b against EV-A71 showed a dose-dependent reduction in the viral titer, also at low concentrations. Mechanism of action investigations suggested that our derivative can inhibit viral endocytosis by reducing viral attachment to and penetration into host cells. Pharmacokinetic and toxicity predictions validated compound 2b as a good candidate for furtherin vivoassays.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/33406781; info:eu-repo/semantics/altIdentifier/wos/WOS:000610806500001; volume:13; issue:1; numberofpages:19; journal:VIRUSES; http://hdl.handle.net/11584/320500Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85100327501

الإتاحة: https://doi.org/10.3390/v13010058Test
http://hdl.handle.net/11584/320500Test

المؤلفون: Obinu A., Porcu E. P., Piras S., Ibba R., Carta A., Molicotti P., Migheli R., Dalpiaz A., Ferraro L., Rassu G., Gavini E., Giunchedi P.

المساهمون: Obinu, A., Porcu, E. P., Piras, S., Ibba, R., Carta, A., Molicotti, P., Migheli, R., Dalpiaz, A., Ferraro, L., Rassu, G., Gavini, E., Giunchedi, P.

مصطلحات موضوعية: Antitubercular activity, Drug-resistant tuberculosi, Gelucire, @Oral permeation, Solid lipid nanoparticle, Witepsol@

الوصف: The role of mycobacterial effiux pumps in drug-resistant tuberculosis has been widely reported. Recently, a new compound, named SS13, has been synthesized, and its activity as a potential effiux inhibitor has been demonstrated. In this work, the chemical–physical properties of the SS13 were investigated; furthermore, a formulative study aimed to develop a formulation suitable for oral administration was performed. SS13 shows nonintrinsic antitubercular activity, but it increases the antitubercular activity of all the tested drugs on several strains. SS13 is insoluble in different simulated gastrointestinal media; thus, its oral absorption could be limited. Solid lipid nanoparticles (SLNs) were, therefore, developed by using two different lipids, Witepsol and/or Gelucire. Nanoparticles, having a particle size (range of 200–450 nm with regards to the formulation composition) suitable for intestinal absorption, are able to load SS13 and to improve its permeation through the intestinal mucosa compared to the pure compound. The cytotoxicity is influenced by the concentration of nanoparticles administered. These promising results support the potential application of these nanocarriers for increasing the oral permeation of SS13 in multidrug-resistant tuberculosis management.

وصف الملف: ELETTRONICO

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/33255304; info:eu-repo/semantics/altIdentifier/wos/WOS:000602453100001; volume:12; issue:12; firstpage:1132-1; lastpage:1132-24; numberofpages:24; journal:PHARMACEUTICS; http://hdl.handle.net/11392/2435247Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85097389900; https://www.mdpi.com/1999-4923/12/12/1132/pdf?version=1608704403Test; https://www.mdpi.com/1999-4923/12/12/1132Test

الإتاحة: https://doi.org/10.3390/pharmaceutics12121132Test
http://hdl.handle.net/11392/2435247Test
https://www.mdpi.com/1999-4923/12/12/1132/pdf?version=1608704403Test
https://www.mdpi.com/1999-4923/12/12/1132Test