Anti-quorum sensing potential of ketoprofen and its derivatives against Pseudomonas aeruginosa: insights to in silico and in vitro studies.

Antibiotics are usually used for the treatment of bacterial infections, but multidrug-resistant strains are a phenomenon that has been growing at an increasing rate worldwide. Thus, there is an increasing need for novel strategies for combatting infectious diseases. Many pathogenic bacteria apply quorum sensing (QS) to regulate their pathogenicity and virulence factors production. This circuit makes the QS system an attractive target for antibacterial therapy. In the present study, an important member of non-steroidal anti-inflammatory drugs (NSAIDs), by reducing the biofilm and producing QS-regulated virulence factors, ketoprofen and its synthetic derivatives were screened against the Pseudomonas aeruginosa PAO1. All compounds showed anti-biofilm activity (16-79%) and most of them presented anti-virulence activity. In the co-treatment of ketoprofen, G20, G21, or G77 with tobramycin, biofilm is significantly reduced (potentiated to > 50%) in the number of cells protected inside the impermeable matrix. The in silico studies in addition to the similarities between the chemical structures of PqsR natural ligands and ketoprofen derivatives reinforce the possibility that the mechanism of action is through PqsR inhibition. Based on the results, the anti-pathogenic effect was more appreciable in ketoprofen, G77, and G20.

Synthesis and biological evaluation of novel benzo[c]acridine-diones as potential anticancer agents and tubulin polymerization inhibitors.

A new series of novel benzo[c]acridine-diones possessing pharmacophoric elements of antitubulins with central dihydropyridine bridge were designed and synthesized as potential anticancer agents and tubulin polymerization inhibitors. The cytotoxic activity of the synthesized compounds was evaluated against eight cancer cell lines including MCF-7, A2780, HeLa, HepG2, DU145, A549, PC3, and LNCAP cancer cells and normal cells human umbilical vein endothelial cell (HUVEC) through 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay, wherein ß-lapachone and combretastatin A-4 were used as positive controls. Some of our compounds (4c and 4g) showed significant cytotoxic activity on cancer cells with IC50 values in the range of 5.23-24.32 µM. None of the synthesized compounds showed significant cytotoxicity on normal HUVEC cells. Among all investigated derivatives, compound 4g showed promising greater antiproliferative activity against all tested cancer cells with the highest sensitivity observed for the PC3 cell line. Results from the flow cytometry analysis of PC3 and MCF-7 cancer cells treated with 4g showed an induced cell-cycle arrest at G2/M, and therefore induced apoptosis which occurred at low concentration of test compound, whereas annexin V-FITC/propidium iodide staining assay in the aforementioned cancer cell lines treated with 4g showed that 4g can cause necrosis in PC3 and MCF-7 cancer cells at higher concentration. Compound 4g proved to be an inhibitor of tubulin polymerization in a mode similar to that of colchicine and in a dose-dependent manner. Molecular docking studies of 4g into the colchicine-binding site of tubulin exhibited a possible mode of interaction between this compound and tubulin.

Synthesis, Characterization and In-vitro Evaluation of Novel Naphthoquinone Derivatives and Related Imines: Identification of New Anticancer Leads.

Quinones such as 1,4-naphthoquinones are abundant in nature and naphthoquinone based natural products are known to possess anticancer activity. This pharmacophore is known to convey anticancer activity to some drugs such as streptonigrin, mitomycin A, etc. We synthesized and characterized different classes of naphthoquinone derivatives including bis naphthoquinone, 2-arylaminonaphthoquinone, benzoxantene-6,11-dione and benzoacridine-5,6-dione derivatives instead of the expected 2-hydroxy-3-(substituted phenyl(aryl amino)methyl)naphthalene-1,4-dione derivatives from the reaction of 2-hydroxy1,4-naphthoquinone (lawson) with different benzaldehydes and aryl amines. Benzoacridine-5,6-dione derivatives and related imines showed potent anti-breast cancer activity in MCF-7 cancer cells. The in-vitro results revealed that five compounds benzoacridinedione derivatives (6b and 7b) and imines (13, 14 and 15) by the IC50 range of 5.4-47.99 µM are the most potent anti-breast cancer structures.