No abstract

No abstract

No abstract

No abstract

A novel series of 2‐acetamide‐5‐phenylthio‐1,3,4‐thiadiazol derivatives containing a phenyl urea warhead were synthesized and evaluated as antiproliferative agents. The cytotoxic activities of the newly synthesized compounds were evaluated toward three human cancer cell lines, including HT‐29, A431, and PC3, as well as normal HDF cells, using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide assay. The biological results revealed the highest degree of cytotoxic effects for the 4‐chloro‐containing compound 9e against the A431 cell line. Further assessment by Western blot analysis assay confirmed the induction of apoptosis by compound 9e, with upregulation of Bax and downregulation of Bcl‐2 proteins in A431 cancer cells. In addition, compound 9e inhibited the phosphorylation of vascular endothelial growth factor and its receptor (VEGFR‐2) in A431 cancer cells while the total level of actin protein was unchanged. These results were confirmed by a three‐dimensional cell culture method using the hanging drop technique.

Background Increasing bacterial resistance to quinolones is concerning. Hence, the development of novel quinolones by chemical modifications to overcome quinolone resistance is an attractive perspective in this context. Objective In this study, it is aimed to design and synthesize a novel series of functionalized fluoroquinolones using ciprofloxacin and sarafloxacin cores by hybridization of quinazolinone derivatives. This objective was tested by a comprehensive set of in vitro antibacterial assays in addition to SAR (structure-activity relationship) characterisation studies. Methods A nucleophilic reaction of ciprofloxacin and sarafloxacin with 2-(chloromethyl)quinazolin-4(3H)-one in the presence of NaHCO 3 in dimethylformamide (DMF) was performed to obtain the desired compounds 5a-j. Novel compounds were characterised by 1 H, 13 C-NMR and IR spectroscopy, MS and elemental analysis. In silico pharmacokinetics prediction assays and molecular docking studies were performed to explore the binding characteristics and interactions. Antibacterial activities of the novel compounds were evaluated by Broth microdilution, well diffusion and disc diffusion assays against three gram-positive (Methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus aureus and Enterococcus faecalis) and three gramnegative bacteria (Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli). ResultsThe compounds exhibited moderate to good activities against gram-positive bacteria and weak to moderate activities against gram-negative bacteria. Amongst all ciprofloxacin-derivatives, compound 5d was the most potent agent with high antibacterial activity against gram-positive bacteria, including MRSA and S. aureus ((minimum inhibitory concentration (MIC) = 16 nM for both), that is 60 times more potent than ciprofloxacin as parent drug. Compound 5i from sarafloxacinderivatives was the most potent compound against MRSA and S. aureus (MIC = 0.125 μM). Well diffusion and disk diffusion assay results demonstrated confirmatory outcomes for the quantitative broth microdilution assay. Molecular docking study results were in accordance with the results of antibacterial activity assays. ConclusionThe results of the current study demonstrated that the novel ciprofloxacin and sarafloxacin derivatives synthesized here have promising antibacterial activities. Particularly, compounds 5d and 5i have potential for wider antibacterial applications following further analysis.

An efficient synthesis of the 3-(6-methoxy-2-naphtyl) 3-methyl-1,4-diaryl-2-azetanone through changes on the main functional group of 2-(6-methoxy-2-naphthyl) propanoic acid is described. Formally, this transformation can be regarded as a [2 + 2]cycloaddition of aromatic imines with methyl naphthylketene generated in situ. To confirm ketene formation, the stable free radical TEMPO (TO * , 2,2,6,6-Tetramethylpiperidinyloxy) was added to the reaction medium and the corresponding additive product was obtained, indicating the presence of this active intermediate in the reaction medium. This efficient method provides fast access to a variety of structurally diverse β-lactam derivatives. Also, some new β-lactam derivatives were evaluated for their anticonvulsant activity, as well as the impact of geometrical isomerism on their ability to interact with key residue of GABA A receptor binding pocket in molecular docking studies. Experimental results revealed that between all, cis-14 a seizure inhibition was done in a longer time in vivo especially in compare to diazepam. Also, in molecular docking studies, cis-14 a matched with the shape of the GABA A binding pocket which led to give the best position and lowest binding energy.

No abstract