- Synthesis, biological evaluation and quantitative structure-active relationships of 1,3-thiazolidin-4-one derivatives. A promising chemical scaffold endowed with high antifungal potency and low cytotoxicity
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With reference to recent studies reporting on the various biological properties of the thiazolidinone scaffold, we synthesized more than a hundred compounds characterized by a 1,3-thiazolidin-4-one nucleus derivatised at the C2 with a hydrazine bridge linked to (cyclo)aliphatic or hetero(aryl) moieties, and their N-benzylated derivatives. These molecules were assayed as potential anti-Candida agents and they were shown to possess comparable, and in some cases higher biological activity than well-established topical and systemic antimycotic drugs (i.e. clotrimazole, fluconazole, ketoconazole, miconazole, tioconazole, amphotericin B). Compounds endowed with the lowest MICs underwent further testing in order to assess their cytotoxic effect (CC50) on Hep2 cells, which demonstrated their relative safety. Finally, QSAR and 3-D QSAR models were used to predict putative chemical modifications of the 1,3-thiazolidin-4-one scaffold in order to design new and potential more active compounds against Candida spp.
- Carradori, Simone,Bizzarri, Bruna,D'Ascenzio, Melissa,De Monte, Celeste,Grande, Rossella,Rivanera, Daniela,Zicari, Alessanda,Mari, Emanuela,Sabatino, Manuela,Patsilinakos, Alexandros,Ragno, Rino,Secci, Daniela
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p. 274 - 292
(2017/10/05)
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- Anti-Candida activity and cytotoxicity of a large library of new N-substituted-1,3-thiazolidin-4-one derivatives
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On the basis of the recent findings about the biological properties of thiazolidinones and taking into account the encouraging results about the antifungal activity of some (thiazol-2-yl)hydrazines, new N-substituted heterocyclic derivatives were designed combining the thiazolidinone nucleus with the hydrazonic portion. In details, 1,3-thiazolidin-4-ones bearing (cyclo)aliphatic or (hetero)aromatic moieties linked to the N1-hydrazine at C2 were synthesized and classified into three series according to the aromatic or bicyclic rings connected to the lactam nitrogen of the thiazolidinone. These molecules were assayed for their anti-Candida effects in reference to the biological activity of the conventional topic (clotrimazole, miconazole, tioconazole) and systemic drugs (fluconazole, ketoconazole, amphotericin B). Finally, we investigated the selectivity against fungal cells by testing the compounds endowed with the best MICs on Hep2 cells in order to assess their cell toxicity (CC50) and we noticed that two derivatives were less cytotoxic than the reference drug clotrimazole. Moreover, a preliminary molecular modelling approach has been performed against lanosterol 14-α demethylase (CYP51A1) to rationalize the activity of the tested compounds and to specify the target protein or enzyme.
- De Monte, Celeste,Carradori, Simone,Bizzarri, Bruna,Bolasco, Adriana,Caprara, Federica,Mollica, Adriano,Rivanera, Daniela,Mari, Emanuela,Zicari, Alessandra,Akdemir, Atilla,Secci, Daniela
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- Synthesis and pharmacological screening of a large library of 1,3,4-thiadiazolines as innovative therapeutic tools for the treatment of prostate cancer and melanoma
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Antimitotic agents are widely used in cancer chemotherapy but the numerous side effects and the onset of resistance limit their clinical efficacy. Therefore, with the purpose of discovering more selective and efficient anticancer agents to be administered alone or in combination with traditional drugs, we synthesized a large library of 1,3,4-thiadiazoline analogues, maintaining the pharmacophoric structure of an antiproliferative compound known as K858: this is a new inhibitor of kinesin Eg5, able to induce the mitotic arrest in colorectal cancer cells and in xenograft ovarian cancer cells. We screened 103 compounds to assess their antiproliferative activity on PC3 prostate cancer cell line. Two derivatives, compounds 32 (corresponding to K858) and 33, have shown to be the most effective against prostate tumor cells and also towards two melanoma cell lines (SK-MEL-5 and SK-MEL-28) at low micromolar concentrations, confirming the pharmacological activity of this scaffold and revealing the potential role of 1,3,4-thiadiazolines in the management of cancer.
- De Monte, Celeste,Carradori, Simone,Secci, Daniela,D'Ascenzio, Melissa,Guglielmi, Paolo,Mollica, Adriano,Morrone, Stefania,Scarpa, Susanna,Aglianò, Anna Maria,Giantulli, Sabrina,Silvestri, Ida
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p. 245 - 262
(2015/11/03)
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- Synthesis of a novel series of thiazole-based histone acetyltransferase inhibitors
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Acetylation, which targets a broad range of histone and non-histone proteins, is a reversible mechanism and plays a critical role in eukaryotic genes activation/deactivation. Acetyltransferases are very well conserved through evolution. This allows the use of a simple model organism, such as budding yeast, for the study of their related processes and to discover specific inhibitors. Following a simple yeast-based chemogenetic approach, we have identified a novel HAT (histone acetyltransferase) inhibitor active both in vitro and in vivo. This new synthetic compound, 1-(4-(4-chlorophenyl)thiazol-2- yl)-2-(propan-2-ylidene)hydrazine, named BF1, showed substrate selectivity for histone H3 acetylation and inhibitory activity in vitro on recombinant HAT Gcn5 and p300. Finally, we tested BF1 on human cells, HeLa as control and two aggressive cancer cell lines: a neuroblastoma from neuronal tissue and glioblastoma from brain tumour. Both global acetylation of histone H3 and specific acetylation at lysine 18 (H3AcK18) were lowered by BF1 treatment. Collectively, our results show the efficacy of this novel HAT inhibitor and propose the utilization of BF1 as a new, promising tool for future pharmacological studies.
- Secci, Daniela,Carradori, Simone,Bizzarri, Bruna,Bolasco, Adriana,Ballario, Paola,Patramani, Zoi,Fragapane, Paola,Vernarecci, Stefano,Canzonetta, Claudia,Filetici, Patrizia
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p. 1680 - 1689
(2014/03/21)
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- Evaluation of a large library of (thiazol-2-yl)hydrazones and analogues as histone acetyltransferase inhibitors: Enzyme and cellular studies
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Recently we described some (thiazol-2-yl)hydrazones as antiprotozoal, antifungal and anti-MAO agents as well as Gcn5 HAT inhibitors. Among these last compounds, CPTH2 and CPTH6 showed HAT inhibition in cells and broad anticancer properties. With the aim to identify HAT inhibitors more potent than the two prototypes, we synthesized several new (thiazol-2-yl)hydrazones including some related thiazolidines and pyrimidin-4(3H)-ones, and we tested the whole library existing in our lab against human p300 and PCAF HAT enzymes. Some compounds (1x, 1c', 1d', 1i' and 2m) were more efficient than CPTH2 and CPTH6 in inhibiting the p300 HAT enzyme. When tested in human leukemia U937 and colon carcinoma HCT116 cells (100 μM, 30 h), 1x, 1i' and 2m gave higher (U937 cells) or similar (HCT116 cells) apoptosis than CPTH6, and were more potent than CPTH6 in inducing cytodifferentiation (U937 cells).
- Carradori, Simone,Rotili, Dante,De Monte, Celeste,Lenoci, Alessia,D'Ascenzio, Melissa,Rodriguez, Veronica,Filetici, Patrizia,Miceli, Marco,Nebbioso, Angela,Altucci, Lucia,Secci, Daniela,Mai, Antonello
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p. 569 - 578
(2014/06/09)
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- Design, synthesis and biological characterization of thiazolidin-4-one derivatives as promising inhibitors of Toxoplasma gondii
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We designed and synthesized a large number of novel thiazolidin-4-one derivatives for the evaluation of their anti-Toxoplasma gondii activity. This scaffold was functionalized at the N1-hydrazine portion with aliphatic, cycloaliphatic and (hetero)aromatic moieties. Then, a benzyl pendant was introduced at the lactamic NH of the core nucleus to evaluate the influence of this chemical modification on biological activity. The compounds were subjected to several in vitro assays to assess their anti-parasitic efficacy, cytotoxicity on fibroblasts, inhibition of tachyzoite invasion/attachment and replication after treatment. Results showed that fourteen of these thiazole-based compounds compare favorably to control compound trimethoprim in terms of parasite growth inhibition.
- D'Ascenzio, Melissa,Bizzarri, Bruna,De Monte, Celeste,Carradori, Simone,Bolasco, Adriana,Secci, Daniela,Rivanera, Daniela,Faulhaber, Nathan,Bordón, Claudia,Jones-Brando, Lorraine
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- Synthesis and cytotoxicity of novel (thiazol-2-yl)hydrazine derivatives as promising anti-Candida agents
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Thirty-eight new (4-(4-substituted-phenyl/2,4-disubstituted-phenyl)- thiazol-2-yl)hydrazine derivatives were synthesized in good yield and assayed for their in vitro anti-Candida activity, compared to topical and systemic antifungal drugs, against twenty-two clinical isolates of Candida spp. The concurrent presence of aliphatic chains or cycloaliphatic rings at N1-hydrazine and a 4-methyl/4-methoxyphenyl at C4 position of the thiazole nucleus exhibited an interesting anti-Candida inhibitory activity. Moreover, some of the most active compounds showed synergistic antifungal effects and lower cell toxicity when combined with clotrimazole.
- Carradori, Simone,Secci, Daniela,Bolasco, Adriana,Rivanera, Daniela,Mari, Emanuela,Zicari, Alessandra,Lotti, Lavinia Vittoria,Bizzarri, Bruna
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p. 102 - 111
(2013/10/01)
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- Synthesis, anti-Candida activity, and cytotoxicity of new (4-(4-iodophenyl)thiazol-2-yl)hydrazine derivatives
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Novel (4-(4-iodophenyl)-thiazol-2-yl)hydrazine derivatives were assayed for their in vitro anti-Candida activity, compared to topical and systemic antifungal drugs, against twenty-seven clinical isolates. The presence of aliphatic chains or specific heteroaromatic rings on hydrazone moiety at position C2 and a 4-iodophenyl at C4 of the thiazole ring gave a promising inhibitory activity especially against Candida albicans and Candida krusei. The most active compounds have been also evaluated for their cytotoxicity and in association with clotrimazole for anti-Candida activity.
- Secci, Daniela,Bizzarri, Bruna,Bolasco, Adriana,Carradori, Simone,D'Ascenzio, Melissa,Rivanera, Daniela,Mari, Emanuela,Polletta, Lucia,Zicari, Alessandra
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experimental part
p. 246 - 253
(2012/08/28)
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- Investigations on the 2-thiazolylhydrazyne scaffold: Synthesis and molecular modeling of selective human monoamine oxidase inhibitors
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A new series of [4-(3-methoxyphenyl)-thiazol-2-yl]hydrazyne derivatives were synthesized in good yield (71-99%) and characterized by elemental analysis and 1H NMR studies. The compounds were assayed for their in vitro human monoamine oxidase (hMAO) inhibitory activity and selectivity and most of them showed IC50 values in the nanomolar range, thus demonstrating our interest in this privileged scaffold. The most active and selective derivative (20), bearing a pyridine moiety on the CN, displayed IC50 = 3.81 ± 0.12 nM and selectivity ratio = 119 toward hMAO-B. Molecular modeling studies were carried out on recent and high resolution hMAO-A and hMAO-B crystallographic structures to better justify the enzyme-inhibitor interaction toward hMAO isoforms and to explain the structure-activity relationship of this kind of inhibitors.
- Chimenti, Franco,Bolasco, Adriana,Secci, Daniela,Chimenti, Paola,Granese, Arianna,Carradori, Simone,Yanez, Matilde,Orallo, Francisco,Ortuso, Francesco,Alcaro, Stefano
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experimental part
p. 5715 - 5723
(2010/09/09)
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- Synthesis and anti-Helicobacter pylori activity of 4-(coumarin-3-yl) thiazol-2-ylhydrazone derivatives
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A novel class of coumarin-thiazole conjugated systems (1-31) were synthesized by Hantzsch condensation between α-bromo-3-acetyl coumarin and several thiosemicarbazone intermediates. This scaffold was also evaluated for selective antibacterial activity against 20 isolates of H. pylori clinical strains, including four metronidazole resistant ones.
- Chimenti, Franco,Bizzarri, Bruna,Bolasco, Adriana,Secci, Daniela,Chimenti, Paola,Granese, Arianna,Carradori, Simone,D'Ascenzio, Melissa,Scaltrito, M. Maddalena,Sisto, Francesca
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experimental part
p. 1269 - 1274
(2011/01/05)
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