Discovery of a novel nitroimidazolyl-oxazolidinone hybrid with potent anti Gram-positive activity: Synthesis and antibacterial evaluation.

A number of linezolid analogues containing a nitroaryl-1,3,4-thiadiazole moiety, were prepared and evaluated as antibacterial agents against a panel of Gram-positive and Gram-negative bacteria. Among synthesized compounds, nitrofuran analogue 1b exhibited more potent inhibitory activity, with respect to other synthesized compounds and reference drug linezolid. The target compounds were also assessed for their cytotoxic activity against normal mouse fibroblast (NIH/3T3) cells using MTT assay. The results indicated that compound 1c exhibit potent antibacterial activity against Gram-positive bacteria at non-cytotoxic concentrations.

Establishment, characterization, and drug sensitivity of a new Ewing sarcoma cell line (SS-ES-1).

Ewing sarcoma (ES) is one of the most malignant tumors in children and young adults. We present here a new ES cell line, SS-ES-1, established from the left thoracic tumor of a 16-year-old female patient. The SS-ES-1 cells retained genotype, morphology, and growth rate for over 150 passages. Immunocytochemical staining showed the strong immunoreactivity for cytokeratin, epithelial membrane antigen, neurofilament, CD99, P53, Ki-67, platelet-derived growth factor receptor-ß, estrogen receptor-α (ER-α), and Bcl-2, but no reactivity for glial fibrillary acidic protein, epidermal growth factor receptor, and HER-2/neu. The presence of the type 1 EWS/FLI-1 fusion transcripts was confirmed by reverse transcriptase-polymerase chain reaction. On the basis of the MTT assay results, GW2974, a dual inhibitor of epidermal growth factor receptor and HER-2/neu, exhibited only a weak cytotoxic response in SS-ES-1 cells. In contrast, tyrphostin A9, a specific inhibitor of platelet-derived growth factor receptor, had a high cytotoxic effect against these cells. Surprisingly, it was found that SS-ES-1 cells displayed a high sensitivity to 4OH-tamoxifen. In conclusion, the SS-ES-1 cell line shows unique cellular properties, which makes it a useful model for studying various aspects of the biology of ES. In addition, the results suggest that ER can be a good therapeutic target for ER + ES.

Synthesis and in-vitro cytotoxicity of poly-functionalized 4-(2-arylthiazol-4-yl)-4H-chromenes.

A new series of 4-aryl-4H-chromenes bearing a 2-arylthiazol-4-yl moiety at the 4-position were prepared as potential cytotoxic agents. The in-vitro cytotoxic activity of the synthesized 4-aryl-4H-chromenes was investigated in comparison with etoposide, a well-known anticancer drug, using MTT colorimetric assay. Among them, the 2-(2-chlorophenyl)thiazol-4-yl analog 4b showed the most potent activity against nasopharyngeal epidermoid carcinoma KB, medulloblastoma DAOY, and astrocytoma 1321N1, and compound 4d bearing a 2-(4-chlorophenyl)thiazol-4-yl moiety at the 4-position of the chromene ring exhibited the best inhibitory activity against breast cancer cells MCF-7, lung cancer cells A549, and colon adenocarcinoma cells SW480 with IC(50 )values less than 5 microM. The ability of compound 4b to induce apoptosis was confirmed in a nuclear morphological assay by DAPI staining in the KB and MCF-7 cells.

Synthesis and antibacterial activity of isothiazolyl oxazolidinones and analogous 3(2H)-isothiazolones.

The synthesis and antibacterial activity of several new 5-((3-oxoisothiazol-2(3H)-yl)methyl)-3-phenyloxazolidin-2-ones 8 and analogous 2-(4-substituted phenyl)-3(2H)-isothiazolones 3 and 4 substituted at 4 and/or 3-positions of the phenyl moiety with different groups of which some have shown to increase the antibacterial activity of both 3-aryl-2-oxazolidinones and 3(2H)-isothiazolones is described. The most active compounds were isothiazolyl oxazolidinones 8a,j with unsubstituted and 8b with 4-F substituted phenyl rings which showed activities higher than analogous 3(2H)-isothiazolones and comparable or superior to linezolid, vancomycin, and ciprofloxacin against some tested microorganisms. The change in position of F and/or the use of larger substituents gave compounds with reduced or no activity. Evaluation of cytotoxicity to mouse fibroblast (NIH/3T3) cells indicated that these compounds exhibit antibacterial activity at non-cytotoxic concentrations.

Cytotoxicity evaluation of Persica mouthwash on cultured human and mouse cell lines in the presence and absence of fetal calf serum.

BACKGROUND AND AIMS: The effectiveness of an ideal antimicrobial agent depends on its ability to kill microbes while causing minimal toxicity to host cells. Several studies have been reported on the antimicrobial effects of chewing sticks (Salvadora persica) on oral bacteria. The purpose of this study was to evaluate the cytotoxic effects of Persica and chlorhexidine (CHX) mouthwashes on cultured human and mouse cell lines. MATERIALS AND METHODS: This was an experimental study. The toxic effects of four dilutions of Persica and CHX mouthwashes on KB, Saos-2, J744 A1, and gingival fibroblast cells were evaluated by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay. The effect of fetal calf serum (FCS) components on the cytotoxicity of these mouthwashes was also investigated. STATISTICAL ANALYSIS: Analysis of variance and the Kruskal-Wallis test were used to evaluate the results. RESULTS: The results indicated that Persica , at concentrations higher than 0.1%, exerted a very significant cytotoxic effect on all the cell lines (P < or = 0.01). CHX, at a concentration of 0.001%, exerted toxic effects only on gingival fibroblasts; concentrations higher than 0.001% were required to produce significant cell death in the other cell lines. At all the concentrations under study, both Persica and CHX exerted significantly greater cytotoxic effects in the absence of FCS than in its presence (i.e., in control culture medium). The toxicities of both mouthwashes were attenuated in the presence of FCS (10%). CONCLUSION: Our results indicate that both Persica and CHX mouthwashes are toxic to macrophage, epithelial, fibroblast, and osteoblast cells in a concentration-dependent manner.

Diclofenac inhibits proliferation but not NGF-induced differentiation of PC12 cells.

Diclofenac is a non-steroidal anti-inflammatory drug that is prescribed for treatment of rheumatic diseases and as an analgesic. Although the information about these side effects has been widely reported, little is know about the effect of diclofenac on the neural cells. In this study, we investigated the effects of diclofenac on the proliferation and differentiation of PC12 cells. The cell proliferation was evaluated by using XTT assay in the both free-serum neurobasal medium supplemented with B27 supplement and DMEM/F12 medium containing 10% FBS. The nerve growth factor (NGF)-induced differentiation was assessed by measuring the neurite length. The drug toxicity was exhibited at the concentrations more than 310 microM in the supplemented neurobasal medium. The treatment of cells in the DMEM/F12 medium increased their sensitivity to diclofenac, with 40% and 75% growth inhibition at the 155 and 310 microM concentrations, respectively. The NGF-induced differentiation was not reduced by toxic and subtoxic concentrations of diclofenac. The results of this study indicated that diclofenac may be able to exhibit its neurotoxic effects through growth inhibition, but not differentiation inhibition. Supplement of B27 has several antioxidant compounds. Therefore, the difference of diclofenac cytotoxic effects in two culture media suggest that drug cytotoxicity may be related to the oxidative stress.

Conformationally constrained analogs of N-substituted piperazinylquinolones: synthesis and antibacterial activity of N-(2,3-dihydro-4-hydroxyimino-4H-1-benzopyran-3-yl)-piperazinylquinolones.

A series of novel quinolone agents bearing a particular bulky and conformationally constrained bicyclic substituent (2,3-dihydro-4-hydroxyimino-4H-1-benzopyran-3-yl- moiety) on the piperazine ring of 7-piperazinyl quinolones (norfloxacin, enoxacin, ciprofloxacin, and levofloxacin) were synthesized and evaluated against a panel of Gram-positive and Gram-negative bacteria. Among these derivatives, ciprofloxacin counterpart 9c, highly inhibited the tested Gram-positive bacteria, superior to that of the reference drugs, and displayed antibacterial activity at non-cytotoxic concentrations.

Synthesis and antibacterial activity of nitroaryl thiadiazole-gatifloxacin hybrids.

A number of gatifloxacin analogues containing a nitroaryl-1,3,4-thiadiazole moiety attached to the piperazine ring at C-7 position were prepared and evaluated as antibacterial agents against a panel of gram-positive and gram-negative bacteria. Among synthesized compounds, nitrofuran analog 6a exhibited more potent inhibitory activity against gram-positive bacteria including Staphylococcus epidermidis (MIC=0.0078 microg/mL), Bacillus subtilis (MIC=0.0039 microg/mL), Enterococcus faecalis (MIC=0.125 microg/mL) and Micrococcus luteus (MIC=0.125 microg/mL), with respect to other synthesized compounds and reference drug gatifloxacin. The target compounds were also assessed for their cytotoxic activity against normal mouse fibroblast (NIH/3T3) cells using MTT assay. The results indicated that these compounds exhibit antibacterial activity at non-cytotoxic concentrations.

N-Substituted piperazinyl quinolones as potential cytotoxic agents: structure-activity relationships study.

As part of a continuing search for new potential anticancer candidates in the piperazinyl quinolone series, the cytotoxicity evaluation of new N-substituted piperazinyl quinolones was of our interest. The growth inhibitory activities of 12 new compounds, namely N-[2-(5-chlorothiophen-2-yl)-2-oxoethyl] and N-[2-(5-chlorothiophen-2-yl)-2-oxyiminoethyl] piperazinyl quinolones 1-12 were determined against six cancer cell lines using MTT colorimetric assay. Preliminary screening showed that most of the new N-[2-(5-chlorothiophen-2-yl)ethyl]piperazinyl quinolones 4-12 containing (un)substituted oxime moiety showed significant cytotoxic activity and the modification of functionality on ethyl spacer produced a relatively minor change of activity. Thus, in the piperazinyl quinolone series, cytotoxic activity can be positively modulated through the introduction of 2-(5-chlorothiophen-2-yl)ethyl residue on the piperazine ring. The results revealed that the introduction of 2-(5-chlorothiophen-2-yl)ethyl moiety on the piperazine ring of quinolone antibacterials (ciprofloxacin, norfloxacin and enoxacin) changes the biological profile of piperazinyl quinolones from antibacterials to cytotoxic agents.

Synthesis and anti-Helicobacter pylori activity of 5-(nitroaryl)-1,3,4-thiadiazoles with certain sulfur containing alkyl side chain.

A series of 5-(nitroaryl)-1,3,4-thiadiazoles bearing certain sulfur containing alkyl side chain similar to pendent residue in tinidazole molecule were synthesized and evaluated against Helicobacter pylori using disk diffusion method. The synthesized compounds were also evaluated for their antibacterial, antifungal and cytotoxic effects. Study of the structure-activity relationships of this series of compounds indicated that both the structure of the nitroaryl unit and the pendent group on 2-position of 1,3,4-thiadiazole ring dramatically impact the anti-H. pylori activity. While compound 7a containing 2-[2-(ethylsulfonyl)ethylthio]-side chain from nitrothiophene series was the most potent compound tested against clinical isolates of H. pylori, however, nitroimidazoles 6c and 7c were found to be more promising compounds because of their respectable anti-H. pylori activity besides less cytotoxic effects.

2-Hydroxyphenacyl azoles and related azolium derivatives as antifungal agents.

2-Hydroxyphenacyl azole and 2-hydroxyphenacyl azolium compounds have been described as a new class of azole antifungals. Most target compounds showed significant in vitro antifungal activities against tested fungi (Candida albicans, Saccharomyces cerevisiae, Aspergillus niger, and Microsporum gypseum) with low MICs values included in the range of 0.25-32 microg/mL comparable to reference drug fluconazole. The most active compounds were also assessed for their cytotoxicity using MTT colorimetric assay on normal mouse fibroblast (NIH/3T3) cells. The results of antifungal activity and toxicity tests indicated that these compounds display antifungal activity at non-cytotoxic concentrations.

Functionalized N(2-oxyiminoethyl) piperazinyl quinolones as new cytotoxic agents.

PURPOSE: The prokaryotic type II topoisomerases (DNA gyrase and topoisomerase IV) and the eukaryotic type II topoisomerases represent the cellular targets for quinolone antibacterial agents and a wide variety of anticancer drugs, respectively. In view of the mechanistic similarities and sequence homologies exhibited by the two enzymes, tentative efforts to selectively shift from an antibacterial to an antitumoral activity was made by synthesizing a series of functionalized N-(2-oxyiminoethyl)piperazinyl quinolones, in which the C-7 piperazine ring of antibacterial quinolones, ciprofloxacin and norfloxacin, is attached by a certain N-[2-(furan-2-yl)-2-oxyiminoethyl] and N-[2-(thiophen-2-yl)-2-oxyiminoethyl] moieties. Thus, as part of a continuing search for potential anticancer drug candidates in the N-substituted piperazinyl quinolones series, the cytotoxicity evaluation of functionalized N-(2-oxyiminoethyl) piperazinyl quinolones was our interest. METHODS: The growth inhibitory activities of synthesized N-[2-(furan-2-yl)-2-oxyiminoethyl] and N-[2-(thiophen-2-yl)-2-oxyiminoethyl] piperazinyl quinolones were determined against seven cancer cell lines using an in vitro cell culture system (MTT assay). RESULTS: Preliminary screening showed that some of N-(2-oxyiminoethyl) piperazinyl quinolone analogs containing O-benzyl group displayed in vitro cytotoxic activity comparable or higher than reference drug etoposide. CONCLUSIONS: These studies demonstrate that introduction of O-benzylmoiety on oxime group of N-(2-oxyimino) piperazinyl quinolone series changes the biological profile of piperazinyl quinolones from antibacterial to cytotoxic activity. As can be deduced from these data, O-benzyl functionalized N-(2-oxyiminoethyl) piperazinyl quinolones have excellent potential as a new class of cytotoxic agents.

In vitro cytotoxicity and phototoxicity of N-piperazinyl quinolone derivatives with a 2-thienyl group.

We examined the cytotoxic potential of nine N-[2-substituted-2-(2-thienyl)ethyl] piperazinyl quinolone derivatives on human oral epithelial mouth carcinoma (KB) and human squamous carcinoma (A431) cell lines. Phototoxic properties of these compounds were also evaluated by mouse 3T3 fibroblast under ultraviolet-A (UVA) irradiation. The percent of cell viability was evaluated by MTT assay. Compound 6 having a 4-[2-(phenylmethoxyimino)-2-(2-thienyl)ethyl] group attached to N4 position of piperazine ring of enoxacin showed the highest cytotoxicity potential on both A431 and KB cell lines (IC50 of 3.11+/-0.52 and 4.91+/-1.94 microg/ml, respectively). While some of the other tested compounds exhibited clear phototoxic potential in 3T3 cell line, compound 6 showed only a minor potential of phototoxicity. These findings suggest the high potential of 4-[2-(phenylmethoxyimino)-2-(2-thienyl)ethyl] derivative of enoxacin as a cytotoxic compound with low potency of phototoxic reactions. The mentioned chemical was identified to be of special interest for further characterization.