Antibacterial Evaluation and Virtual Screening of New Thiazolyl-Triazole Schiff Bases as Potential DNA-Gyrase Inhibitors.

The global spread of bacterial resistance to drugs used in therapy requires new potent and safe antimicrobial agents. DNA gyrases represent important targets in drug discovery. Schiff bases, thiazole, and triazole derivatives are considered key scaffolds in medicinal chemistry. Fifteen thiazolyl-triazole Schiff bases were evaluated for their antibacterial activity, measuring the growth inhibition zone diameter, the minimum inhibitory concentration (MIC), and the minimum bactericidal concentration (MBC), against Gram-positive (Staphylococcus aureus, Listeria monocytogenes) and Gram-negative (Escherichia coli, Salmonella typhimurium, Pseudomonas aeruginosa) bacteria. The inhibition of S. aureus and S. typhimurium was modest. Compounds B1, B2, and B9 showed a similar effect as ciprofloxacin, the antimicrobial reference, against L. monocytogenes. B10 displayed a better effect. Derivatives B1, B5-7, B9, and B11-15 expressed MIC values lower than the reference, against L. monocytogenes. B5, B6, and B11-15 strongly inhibited the growth of P. aeruginosa. All compounds were subjected to an in silico screening of the ADMET (absorption, distribution, metabolism, elimination, toxicity) properties. Molecular docking was performed on the gyrA and gyrB from L. monocytogenes. The virtual screening concluded that thiazolyl-triazole Schiff base B8 is the best drug-like candidate, satisfying requirements for both safety and efficacy, being more potent against the bacterial gyrA than ciprofloxacin.

Lipophilicity Evaluation of Some N1-Arylidene-Thiosemicarbazones and 1,3,4-Thiadiazolines with Antimicrobial Activity.

A: The lipophilic character of 20 previously reported compounds-derivatives of N 1 -arylidene-thiosemicarbazone (series ) and their corresponding 1,3,4-thiadiazolines (series )-has been determined by reversed-phase thin-layer chromatography, using i -propanol-water mixtures as eluents. Principal component analysis (PCA) allowed an objective estimation of the retention behavior of the tested compounds and also afforded to obtain a 2D scatterplot, described by the first two principal components, which had the effect of separating the compounds from each other most effectively. With the use of clustering methods ( K -means clustering) based on PCA data, the studied compounds were grouped into two congeneric classes. When comparing the obtained lipophilicity parameters' values with the antibacterial properties of the tested compounds, we noticed that the lipophilic character had no significant influence on their growth inhibitory activity.

Stapled Peptides by Late-Stage C(sp3 )-H Activation.

Despite the importance of stapled peptides for drug discovery, only few practical processes to prepare cross-linked peptides have been described; thus the structural diversity of available staple motifs is currently limited. At the same time, C-H activation has emerged as an efficient approach to functionalize complex molecules. Although there are many reports on the C-H functionalization of amino acids, examples of post-synthetic peptide C-H modification are rare and comprise almost only C(sp2 )-H activation. Herein, we report the development of a palladium-catalyzed late-stage C(sp3 )-H activation method for peptide stapling, affording an unprecedented hydrocarbon cross-link. This method was first employed to prepare a library of stapled peptides in solution. The compatibility with various amino acids as well as the influence of the size (i,i+3 and i,i+4) and length of the staple were investigated. Finally, a simple solid-phase procedure was also established.

Biological evaluation and molecular docking of some chromenyl-derivatives as potential antimicrobial agents.

Various thiosemicarbazones (TSCs) and their heterocyclic thiadiazolines (TDZ) possess important biological effects. In addition, chromenyl derivatives exhibit a wide range of pharmacological activities. Based on these findings and as a continuation of our research on nitrogen and sulfur containing compounds, we investigated a series of previously reported chromenyl-TSCs (1a-j) and chromenyl-TDZs (2a-j) for their in vitro antimicrobial activities against two bacterial and four fungal strains. MIC and MBC/MFC (µg/mL) values of these compounds were evaluated and compared to those of Spectinomycin, Moxifloxacin and Fluconazole, used as reference drugs. For a better understanding of the drug-receptor interactions, all the compounds were further subjected to molecular docking against four targets that were chosen based on the specific mechanism of action of the reference drugs used in the antimicrobial screening. All compounds tested showed equal or higher antibacterial/antifungal activities relative to the used reference drugs. In silico studies (molecular docking) revealed that all the investigated compounds showed good binding energies towards four receptor protein targets and supported their antimicrobial properties.

Study of the Relationships between the Structure, Lipophilicity and Biological Activity of Some Thiazolyl-carbonyl-thiosemicarbazides and Thiazolyl-azoles.

Lipophilicity, as one of the most important physicochemical parameters of bioactive molecules, was investigated for twenty-two thiazolyl-carbonyl-thiosemicarbazides and thiazolyl-azoles. The determination was carried out by reversed-phase thin-layer chromatography, using a binary isopropanol-water mobile phase. Chromatographically obtained lipophilicity parameters were correlated with calculated log P and log D and with some biological parameters, determined in order to evaluate the anti-inflammatory and antioxidant potential of the investigated compounds, by using principal component analysis (PCA). The PCA grouped the compounds based on the nature of their substituents (X, R and Y), indicating that their nature, electronic effects and molar volumes influence the lipophilicity parameters and their anti-inflammatory and antioxidant effects. Also, the results of the PCA analysis applied on all the experimental and computed parameters show that the best anti-inflammatory and antioxidant compounds were correlated with medium values of the lipophilicity parameters. On the other hand, the knowledge of the grouping patterns of the tested variables allows the reduction of the number of parameters, determined in order to establish the biological activity.

Synthesis of new N-substituted 5-arylidene-2,4-thiazolidinediones as anti-inflammatory and antimicrobial agents.

A novel series of 5-arylidene-2,4-thiazolidinediones (TZDs) 2a-p was synthesized from the condensation of 3-((2-phenylthiazol-4-yl)methyl)thiazolidine-2,4-dione with different benzaldehyde derivatives. All the structures were confirmed by their spectral (IR, ¹H NMR, ¹³C NMR and mass) and elemental analytical data. The new molecules were evaluated in vivo as anti-inflammatory agents in an acute experimental inflammation, evaluating the acute phase bone marrow response and phagocyte activity. All compounds, excepting one, reduced the absolute leukocytes count due to the lower neutrophil percentage. Phagocytary index was decreased by the same molecules, while only half of them reduced the phagocytary activity. The effect was superior to meloxicam, the reference anti-inflammatory drug, for the majority of the TZD derivatives. The new molecules were also investigated for their antimicrobial properties on Gram-positive and Gram-negative bacteria and one fungal strain. Two compounds (2e and 2n) manifested growth inhibition capacity on all the tested strains.

New anti-inflammatory thiazolyl-carbonyl-thiosemicarbazides and thiazolyl-azoles with antioxidant properties as potential iNOS inhibitors.

The objective of this study was to investigate the anti-inflammatory and antioxidant activity of new thiazolyl-carbonyl-thiosemicarbazides and thiazolyl-azole derivatives as potential iNOS inhibitors. The in vivo anti-inflammatory effects of the new thiazole compounds were studied in a turpentine oil induced inflammation model. Their anti-inflammatory activity was assessed by evaluating the acute phase bone marrow response, phagocytes' activity, NO synthesis and antioxidant capacity. The new thiazole compounds have anti-inflammatory effects by lowering bone marrow acute phase response and oxidative stress. The best anti-inflammatory and antioxidant effect was found for thiazolyl-carbonyl-thiosemicarbazides Th-1-8, thiazolyl-1,3,4-oxadiazole Th-20 and thiazolyl-1,3,4-thiadiazole Th-21. Virtual screening of thiazole derivatives against the oxygenase domain of chain A from 2Y37 revealed that all twenty-two compounds bind the active site of inducible nitric oxide synthase (iNOS). Based on the virtual screening and on the results obtained above, the activity may be due to their capacity to reduce the NO synthesis by blocking the bind of L-Arg in the active site of iNOS, the compounds binding the synthase by hydrogen bonds between the NH (2 and/or 4) of thiosemicarbazide fragment (Th-2-8) or N2/N3 from azole cycles and by the thiol function (Th-9-22).