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Concerning the growing interest in the role played by the CCL20/CCR6 axis in IBD pathogenesis and in the search for novel anti-IBD small molecules, we have recently discovered the first small-molecule (MR120) endowed with protective action against TNBS-induced colitis and zymosan-induced peritonitis. This protective action occurs through interference with the CCL20/CCR6 signaling. The aim of the present work is to expand the preclinical investigation of MR120, evaluating its beneficial anti-inflammatory effect on a model of chronic colitis obtained by cyclically exposing C57BL/6 mice to 3% DSS. Subcutaneous administration of MR120 at 1 mg/kg, the same dose effective against acute inflammation, helped attenuate several systemic and local inflammatory responses induced by DSS. Besides significantly improving murine health conditions, MR120 counteracted mucosal macroscopic injury, the increase of colonic edema and neutrophils oxidative activity, and mitigated spleen enlargement, while not significantly lowering intestinal IL-6 concentration. Overall, repeated daily treatment with MR120 for approximately 30 days was well tolerated and showed moderate protection in a relevant model of chronic colitis, in line with the beneficial effect previously observed in acute models of intestinal inflammation. Although more potent analogues of MR120 will be needed to more fully evaluate their clinical translatability, the present work provides a valuable example of in vivo efficacy of CCL20/CCR6 modulators in a chronic model of IBD., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Eph/ephrin system is an emerging target for cancer therapy but the lack of potent, stable and orally bioavailable compounds is impairing the development of the field. Since 2009 our research group has been devoted to the discovery and development of small molecules targeting Eph/ephrin system and our research culminated with the synthesis of UniPR129, a potent but problematic Eph/ephrin antagonist. Herein, we describe the in vitro pharmacological properties of two derivatives (UniPR139 and UniPR502) stemmed from structure of UniPR129. These two compounds acted as competitive and reversible antagonists of all Eph receptors reducing both ephrin-A1 and -B1 binding to EphAs and EphBs receptors in the low micromolar range. The compounds acted as antagonists inhibiting ephrin-A1-dependent EphA2 activation and UniPR139 exerted an anti-angiogenic effect, inhibiting HUVEC tube formation in vitro and VEGF-induced vessel formation in the chick chorioallantoic membrane assay. Finally, the oral bioavailability of UniPR139 represents a step forward in the search of molecules targeting the Eph/ephrin system and offers a new pharmacological tool useful for future in vivo studies., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Amino acid conjugates of lithocholic acid (LCA) have been recently described as effective disruptors of the EphA2-ephrin-A1 interaction able to inhibit EphA2 phosphorylation in intact cells and thus able to block prometastatic responses such as cellular retraction and angiogenesis. However, these LCA-based compounds were significantly more potent at disrupting the EphA2-ephrin-A1 interaction than at blocking phenotype responses in cells, which might reflect an unclear mechanism of action or a metabolic issue responsible for a reduction of the compound concentration at the cell's surface. Through the synthesis of new compounds and their examination by a combination of cell-based assays and real-time interaction analysis by surface plasmon resonance, we showed at molecular level that l-tryptophan conjugates of lithocholic acid disrupt EphA2-ephrin-A1 interaction by targeting the EphA 2 receptor and that the presence of a polar group in position 3 of steroid scaffold is a key factor to increase the effective concentration of the compounds in cancer cell lines., (Copyright © 2015 Elsevier Inc. All rights reserved.)

We report the synthesis, the antioxidant and the inhibitory activity (IC50) on metalloproteinases (MMPs) 3 and 13 of 2-benzo[d]isothiazolylimino-5-benzylidene-4-thiazolidinones. Their potential as protective agents in osteoarthritis (OA) was evaluated by biological assays on chondrocytes cultures, stimulated by IL-1β. The chondroprotective capability, related both to antioxidant activity and to inhibition of MMPs, was studied in vitro, by determining nitric oxide production and glycosaminoglycans release. Moreover, selected derivatives 1h and 1g was studied for nuclear factor kappaB (NF-κB) inhibition by Western Blot analysis and for MMP-3 protein release using ELISA test. The structure-activity relationship of tested compounds demonstrates a favorable effect of the para substitution on the 5-benzilydene ring. Compound 1g shows a potent and selective activity on MMP-3 versus MMP-13. Accordingly, 1g possesses high antioxidant effect, NO lowering and GAGs restoring capability and also reduces the production of MMPs and NF-κB expression. Thus 1g can be considered as new potential chondroprotective agents., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

A facile synthesis of model 4-oxopyrido[3',2':4,5]thieno[3,2-b]indole-3-carboxylic acids 9a-e was achieved via Stille arylation of 2-chloro-3-nitro-4-oxothieno[2,3-b]pyridine-5-carboxylate and a subsequent microwave-assisted phosphite-mediated Cadogan reaction. The new compounds were tested for their in vitro antimicrobial and antiproliferative activity. Compounds 9a-c and 9e exhibited very high potency against Gram positive Bacillus subtilis and Bacillus megaterium at concentrations 0.000015-0.007 μg/mL. They also displayed excellent activity towards other Gram positive bacilli and staphylococci and Gram negative Haemophilus influenzae, being in most cases superior or equal to commercial fluoroquinolones. Both 9a and 9c were inhibitors of the DNA gyrase activity. As concerns antitumor properties, compounds 9b-e showed growth inhibition of MCF-7 breast tumor and A549 non-small cell lung cancer cells with IC(50) 1.6-2.8 μM and 2.6-6.9 μM, respectively, coupled with absence of cytotoxicity towards normal cells. These compounds are promising as dual acting chemotherapeutics., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

A simple and efficient synthesis of 6-fluoro-4-oxopyrido[2,3-a]carbazole-3-carboxylic acids (13a-e) and a structurally related 6-fluoro-4-oxothieno[2',3':4,5]pyrrolo[3,2-h]quinoline (13f) was achieved via Stille arylation of 7-chloro-6-fluoro-8-nitro-4-oxoquinoline-3-carboxylate and a subsequent microwave-assisted phosphite-mediated Cadogan reaction. The new compounds were tested for their in vitro antimicrobial and antiproliferative activity. The ability of 13a-f to inhibit the activity of DNA gyrase and topoisomerase IV was also investigated. The thieno isostere (13f) emerged as the most active antibacterial, while the 9-fluoro derivative (13e) was the most potent against multidrug-resistant staphylococci. Compounds 13a, 13c-f displayed growth inhibition against MCF-7 breast tumor and A549 non-small cell lung cancer cells coupled with an absence of cytotoxicity toward normal human-derm fibroblasts (HuDe). Compound 13e was the most active anticancer against MCF-7 cells, with greater potency than ellipticine (IC(50) 0.8 and 1.6muM, respectively). The most active compounds in this series show promise as dual acting anticancer and antibacterial chemotherapeutics., (Copyright 2010 Elsevier Ltd. All rights reserved.)

2-Heteroarylimino-5-benzylidene-4-thiazolidinones, unsubstituted or carrying hydroxy, methoxy, nitro and chloro groups on the benzene ring, were synthesised and assayed in vitro for their antimicrobial activity against gram positive and gram negative bacteria, yeasts and mould. The antimicrobial activity of the 2-benzo[d]thiazolyl- and of the 2-benzo[d]isothiazolyl-imino-5-benzylidene-4-thiazolidinones is, on the whole, lower in comparison with the high activity detected for the derivatives of the 2-thiazolylimino-5-benzylidene-4-thiazolidinone class. Nevertheless most of the benzo[d]thiazole analogues display good inhibition of the growth of gram positive bacilli and staphylococci, including methicillin-resistant Staphylococcus strains. Among the 2-benzo[d]isothiazole analogues a few derivatives show a strong and selective activity against bacilli. Moreover, it is worth noting that the replacement of the thiazole nucleus for the benzo[d]thiazole bicyclic system in the parent 2-(benzo[d]thiazol-2-ylimino)thiazolidin-4-one leads to significant antifungal properties against both yeasts and moulds, properties not shown by the analogous 2-thiazolyl- and 2-benzo[d]isothiazolyl-imino)thiazolidin-4-ones. The structure-activity relationship of 33 analogues possessing the 2-heteroarylimino-4-thiazolidinone structure is analysed through QSAR models.

The aim of the work was to investigate the mechanism of binding between human metalloproteinase-3 (MMP-3) and new compounds belonging to the benzisothiazolylamidines class. In vitro tests suggest that these molecules, endowed with antinflammatory and cartilage antidegenerative activity, could act as ligands toward MMP-3. In lack of experimental structural informations, we performed molecular docking simulations to probe the interactions of benzisothiazolylamidines with matrix metalloproteinase-3, using the docking package GOLD and the software HINT as a post-process scoring function. Both GOLD and HINT predicted a binding mode for the compounds under analysis within the hydrophobic S1' pocket of MMP-3, without interaction with the catalytic Zn(2+) ion. The scores assigned by the programs to the interaction between the tested benzisothiazolylamidines and human MMP-3 were consistent with a potential direct enzyme inhibitory activity. The highest affinity was predicted for the N-(benzo[d]isothiazol-3-yl)-4-chlorobenzamidine (2), emerged as the most active derivative also in the in vitro tests.

New 2-thiazolylimino-5-arylidene-4-thiazolidinones (compounds 4a-j), unsubstituted or carrying hydroxy, methoxy, nitro and chloro groups on the benzene ring, were synthesized and assayed in vitro for their antimicrobial activity against Gram positive and Gram negative bacteria, yeasts and mould. The compounds were very potent towards all tested Gram positive microorganisms (MIC ranging from 0.03 to 6 microg/mL in most of the cases) and Gram negative Haemophilus influenzae (MIC 0.15-1.5 microg/mL), whereas no effectiveness was exhibited against Gram negative Escherichia coli and fungi up to the concentration of 100 microg/mL. The 5-arylidene derivatives showed an antibacterial efficacy considerably greater than that of the parent 2-(thiazol-2-ylimino)thiazolidin-4-one 3, suggesting that the substituted and unsubstituted 5-arylidene moiety plays an important role in enhancing the antimicrobial properties of this class of compounds. The remarkable inhibition of the growth of penicillin-resistant staphylococci makes these substances promising agents also for the treatment of infections caused by microorganisms resistant to currently available drugs.

Three new series of benzo[d]isothiazole, benzothiazole and thiazole Schiff bases were synthesized and tested in vitro with the aim of identifying novel lead compounds active against emergent and re-emergent human and cattle infectious diseases (AIDS, hepatitis B and C, tuberculosis, bovine viral diarrhoea) or against drug-resistant cancers (leukaemia, carcinoma, melanoma, MDR tumors) for which no definitive cure or efficacious vaccine is available at present. In particular, these compounds were evaluated in vitro against representatives of different virus classes, such as a HIV-1 (Retrovirus), a HBV (Hepadnavirus) and the single-stranded RNA(+) viruses Yellow fever virus (YFV) and Bovine viral diarrhoea virus (BVDV), both belonging to Flaviviridae. Title compounds were also tested against representatives of Gram-positive and Gram-negative bacteria (Staphylococcus aureus, Salmonella spp.), various atypic mycobacterial strains (Mycobacterium fortuitum and Mycobacterium smegmatis), yeast (Candida albicans) and mould (Aspergillus fumigatus). None of the compounds showed antiviral or antimicrobial activity. The benzo[d]isothiazole compounds showed a marked cytotoxicity (CC(50)=4-9 microM) against the human CD4(+) lymphocytes (MT-4) that were used to support HIV-1 growth. For this reason, the most cytotoxic compounds of this series were evaluated for their antiproliferative activity against a panel of human cell lines derived from haematological and solid tumors. The results highlighted that all the benzo[d]isothiazole derivatives inhibited the growth of leukaemia cell lines, whereas only one of the above mentioned compounds (1e) showed antiproliferative activity against two solid tumor-derived cell lines.