Carmen Limban

Antibacterial Activity of New Dibenzoxepinone Oximes with Fluorine and Trifluoromethyl Group Substituents

In this paper we present the antimicrobial activity of some newly synthesized dibenz[b,e]oxepin derivatives bearing the oximino moiety, and fluorine (F) and trifluoromethyl (CF3) group substituents. The chemical structure and purity of the new compounds were assessed by using elemental analysis, NMR and FTIR spectroscopy. The new compounds were screened for their antibacterial activity towards Gram-positive and Gram-negative strains, by qualitative and quantitative assays. Our results demonstrated that the CF3 and F disubstituted compounds could be considered for the further development of novel antimicrobial drugs.

Thioureides of 2-(phenoxymethyl)benzoic acid 4-R substituted: A novel class of anti-parasitic compounds

Fifty members of a novel class of antimicrobial compounds, 2-(4-R-phenoxymethyl)benzoic acid thioureides, were synthesized and characterized with respect to their activities against three parasites of human relevance, namely the protozoa Giardia lamblia and Toxoplasma gondii, and the larval (metacestode) stage of the tapeworm Echinococcus multilocularis. To determine the selective toxicity of these compounds, the human colon cancer cell line Caco2 and primary cultures of human foreskin fibroblasts (HFF) were also investigated. The new thioureides were obtained in a three-step-reaction process and subsequently characterized by their physical constants (melting point, solubility). The chemical structures were elucidated by (1)H NMR, (13)C NMR, IR spectral methods and elemental analysis. The analyses confirmed the final and intermediate compound structures and the synthesis. The compounds were then tested on the parasites in vitro. All thioureides, except two compounds with a nitro group, were totally ineffective against Giardia lamblia. 23 compounds inhibited the proliferation of T. gondii, three of them with an IC(50) of approximately 1 microM. The structural integrity of E. multilocularis metacestodes was affected by 22 compounds. In contrast, HFF were not susceptible to any of these thioureides, while Caco2 cells were affected by 17 compounds, two of them inhibiting proliferation with an IC(50) in the micromolar range. Thioureides may thus present a promising class of anti-infective agents.

Synthesis, Spectroscopic Properties and Antipathogenic Activity of New Thiourea Derivatives

A number of acylthioureas, 2-((4-methylphenoxy)methyl)-N-(aryl-carbamothioyl)benzamides (aryl = 3,5-dichlorophenyl, 2,3-dichlorophenyl, 3,4-dichloro-phenyl, 2,4,5-trichlorophenyl, 3,4,5-trichlorophenyl, 2-bromophenyl, 2,4-dibromophenyl, 2,5-dibromophenyl, 2-iodophenyl, 3-fluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluoro-phenyl, 2,4,6-trifluorophenyl) have been synthesized, characterized by elemental analysis, IR and NMR spectroscopy and tested for their interaction with bacterial cells in free and adherent state. The anti-pathogenic activity was correlated with the presence of one iodine, bromide or fluorine, and two or three chloride atoms on the N-phenyl substituent of the thiourea moiety, being significant especially on Pseudomonas aeruginosa and Staphylococcus aureus strains, known for their ability to grow in biofilms. Our results demonstrate the potential of these derivatives for further development of novel anti-microbial agents with antibiofilm properties.

In vitro evaluation of anti-pathogenic surface coating nanofluid, obtained by combining Fe3O4/C12 nanostructures and 2-((4-ethylphenoxy)methyl)-N-(substituted-phenylcarbamothioyl)-benzamides

In this paper, we report the design of a new nanofluid for anti-pathogenic surface coating. For this purpose, new 2-((4-ethylphenoxy)methyl)-N-(substituted-phenylcarbamothioyl)-benzamides were synthesized and used as an adsorption shell for Fe3O4/C12 core/shell nanosized material. The functionalized specimens were tested by in vitro assays for their anti-biofilm properties and biocompatibility. The optimized catheter sections showed an improved resistance to Staphylococcus aureus ATCC 25923 and Pseudomonas aeruginosa ATCC 27853 in vitro biofilm development, as demonstrated by the viable cell counts of biofilm-embedded bacterial cells and by scanning electron microscopy examination of the colonized surfaces. The nanofluid proved to be not cytotoxic and did not influence the eukaryotic cell cycle. These results could be of a great interest for the biomedical field, opening new directions for the design of film-coated surfaces with improved anti-biofilm properties.

Synthesis and antimicrobial properties of new 2-((4-ethylphenoxy)methyl)benzoylthioureas

New acylthiourea derivatives, 2-((4-ethylphenoxy)methyl)-N-(phenylcarbamothioyl)benzamides, were tested by qualitative and quantitative methods on various bacterial and fungal strains and proved to be active at low concentrations against Gram-positive and Gram-negative bacteria as well as fungi. These compounds were prepared by the reaction of 2-((4-ethylphenoxy)methyl)benzoyl isothiocyanate with various primary aromatic amines, and were characterised by melting point and solubility. The structures were identified by elemental analysis, 1H and 13C NMR, and IR spectral data. The level of antimicrobial activity of the new 2-((4-ethylphenoxy)methyl)benzoylthiourea derivatives was dependent on the type, number and position of the substituent on the phenyl group attached to thiourea nitrogen. The iodine and nitro substituents favoured the antimicrobial activity against the Gram-negative bacterial strains, while the highest inhibitory effect against Gram-positive and fungal strains was exhibited by compounds with electron-donating substituents such as the methyl and ethyl groups.

Synthesis and Antimicrobial Evaluation of Dibenzo(b,e)oxepin-11(6H)-one O-Benzoyloxime Derivatives

A series of dibenzo[b,e]ox(thi)epin-11(6H)-one O-benzoyloximes has been synthesized and structurally elucidated by means of IR, 1H-NMR, 13C-NMR, MS, and elemental analysis. The newly developed compounds were screened at concentrations of 200–25 μg/mL for their antibacterial activity against Gram+ve organisms such as Methicillin-Resistant Staphylococcus Aureus (MRSA), Gram−ve organisms such as Escherichia coli (E. coli), and at the same concentration range for their antifungal activity against fungal strain Aspergillus niger (A. niger) by the cup plate method. Ofloxacin and ketoconazole (10 μg/mL) were used as reference standards for antibacterial and antifungal activity, respectively. The dibenzo[b,e]oxepines 6a–c and 6e–h showed low antimicrobial activity (MIC 125–200 μg/mL) compared to the reference substances, whereas a major improvement (MIC 50–75 μg/mL) was achieved with the synthesis of the corresponding bromomethyl derivative 6d. Moreover, replacement of oxygen by its bioisosteric sulfur led to isomeric dibenzo[b,e]thi-epine derivatives 6g,h which significantly exhibited higher antimicrobial activity (MIC 25–50 μg/mL) against all tested culture strains used in the present study, demonstrating that a change of chemical class from dibenzo[b,e]oxepine to dibenzo[b,e]thiepine significantly improves the antimicrobial activity. Further variation, such as the oxidation of the thiepine sulfur to the corresponding isomeric dibenzo[b,e]thiepine 5,5-dioxide derivative 9, comparatively failed to exhibit high activity (MIC 200 μg/mL) against S. aureus, E. coli or A. niger.

Optimized Anti-pathogenic Agents Based on Core/Shell Nanostructures and 2-((4-Ethylphenoxy)ethyl)-N-(substituted- phenylcarbamothioyl)-benzamides

The purpose of this study was to design a new nanosystem for catheter surface functionalization with an improved resistance to Staphylococcus aureus ATCC 25923 and Pseudomonas aeruginosa ATCC 27853 colonization and subsequent biofilm development. New 2-((4-ethylphenoxy)methyl)-N-(substituted-phenylcarbamothioyl)-benzamides were synthesized and used for coating a core/shell nanostructure. Their chemical structures were elucidated by NMR, IR and elemental analysis, being in agreement with the proposed ones. Fe3O4/C12 of up to 5 nm size had been synthesized with lauric acid as a coating agent and characterized by XRD, FT-IR, TGA, TEM and biological assays. The catheter pieces were coated with the fabricated nanofluid in magnetic field. The microbial adherence ability was investigated in 6 multiwell plates by using culture based methods and Scanning Electron Microscopy (SEM). The nanoparticles coated with the obtained compounds 1a–c inhibited the adherence and biofilm development ability of the S. aureus and P. aeruginosa tested strains on the catheter functionalized surface, as shown by the reduction of viable cell counts and SEM examination of the biofilm architecture. Using the novel core/shell/adsorption-shell to inhibit the microbial adherence could be of a great interest for the biomedical field, opening new directions for the design of film-coated surfaces with improved anti-biofilm properties.

Novel Hybrid Formulations Based on Thiourea Derivatives and Core@Shell Fe3O4@C18 Nanostructures for the Development of Antifungal Strategies

The continuously increasing global impact of fungal infections is requiring the rapid development of novel antifungal agents. Due to their multiple pharmacological activities, thiourea derivatives represent privileged candidates for shaping new drugs. We report here the preparation, physico-chemical characterization and bioevaluation of hybrid nanosystems based on new 2-((4-chlorophenoxy)methyl)-N-(substituted phenylcarbamo-thioyl)benzamides and Fe3O4@C18 core@shell nanoparticles. The new benzamides were prepared by an efficient method, then their structure was confirmed by spectral studies and elemental analysis and they were further loaded on Fe3O4@C18 nanostructures. Both the obtained benzamides and the resulting hybrid nanosystems were tested for their efficiency against planktonic and adherent fungal cells, as well as for their in vitro biocompatibility, using mesenchymal cells. The antibiofilm activity of the obtained benzamides was dependent on the position and nature of substituents, demonstrating that structure modulation could be a very useful approach to enhance their antimicrobial properties. The hybrid nanosystems have shown an increased efficiency in preventing the development of Candida albicans (C. albicans) biofilms and moreover, they exhibited a good biocompatibility, suggesting that Fe3O4@C18core@shell nanoparticles could represent promising nanocarriers for antifungal substances, paving the way to the development of novel effective strategies with prophylactic and therapeutic value for fighting biofilm associated C. albicans infections.

Novel N-phenylcarbamothioylbenzamides with anti-inflammatory activity and prostaglandin E2 inhibitory properties

A number of 2-((4-ethylphenoxy)methyl)-N-(substituted-phenylcarbamothioyl) benzamides (1a–h) were synthesized via reaction of 2-((4-ethylphenoxy)methyl)benzoyl isothiocyanate (2) as a key intermediate with several substituted primary aromatic amines. The new compounds were characterized by proton nuclear magnetic resonance (1H-NMR), carbon-13 nuclear magnetic resonance (13C-NMR), infrared spectrometry (IR), mass spectrometry (MS), and elemental analysis. The anti-inflammatory activity of 1a–h was investigated by acute carrageenan-induced paw edema in mice using the reference drug indomethacin. The results obtained indicated that, of the derivatives developed, 1a and 1d–h exhibited significantly higher anti-inflammatory activity (26.81%–61.45%) when compared with the reference drug indomethacin (22.43%) (P = 0.0490 for 1a, 0.0015 for 1d, 0.0330 for 1f, and P < 0.001 for 1e and 1h). Moreover, the ulcer incidence of 20% for 1e and 1h was clearly lower when compared with the indomethacin group (in which the ulcer incidence was 80%). Of particular note, the ulcer index of 0.2 for 1e was significantly less than that in the indomethacin group (0.6, P = 0.014). Additionally, prostaglandin E2 (PGE2) inhibitory properties were found to be high with 1e (68.32 pg/mL), significantly different from those of the placebo group (530.13 pg/mL, P < 0.001), and equipotent to the effect observed in the indomethacin-pretreated group (96.13 pg/mL, P > 0.05). Moreover, the PGE2 level of 54.15 pg/mL with 1h was also significantly different from that of the placebo group (P < 0.001) and of the indomethacin group (P < 0.05). The significant inhibition of PGE2 observed with 1e (68.32 pg/mL) and 1h (54.15 pg/mL) agree with their observed ulcer incidences. Our overall findings for N-phenylcarbamothioylbenzamides 1a–h clearly suggest that the compounds exhibit an anti-inflammatory effect, potently inhibit PGE2 synthesis, and markedly demonstrate low ulcer incidence.

The use of structural alerts to avoid the toxicity of pharmaceuticals

In order to identify compounds with potential toxicity problems, particular attention is paid to structural alerts, which are high chemical reactivity molecular fragments or fragments that can be transformed via bioactivation by human enzymes into fragments with high chemical reactivity. The concept has been introduced in order to reduce the likelihood that future candidate substances as pharmaceuticals will have undesirable toxic effects. A significant proportion (∼78–86%) of drugs characterized by residual toxicity contain structural alerts; there is also evidence indicating the formation of active metabolites as a causal factor for the toxicity of 62–69% of these molecules. On the other hand, the pharmacological action of certain drugs depends on the formation of reactive metabolites. Detailed assessment of the potential for the formation of active metabolites is recommended to characterize a biologically active compound. Although many prescribed drugs frequently contain structural alerts and form reactive metabolites, the vast majority of these drugs are administered in low daily doses. Avoiding structural alerts has become almost a norm in new drug design. An in-depth review of the biochemical reactivity of these structural alerts for new drug candidates is critical from a safety point of view and is currently being monitored in the discovery of drugs. The chemical strategies applied to structural alerts in molecules to limit the toxicity are: • partial replacement or full replacement of the structural alert;• reduction of electronic density;• introduction of a structural element of metabolic interest (metabolic switching);• multiple approaches. Therefore, chemical intervention strategies to eliminate bioactivation are often interactive processes; their success depends largely on a close working relationship between drug chemists, pharmacologists and researchers in metabolic science.