18 research outputs found
New norfloxacin/nitric oxide donor hybrids: Synthesis and nitric oxide release measurement using a modified Griess colorimetric method
Get PDFOximes and nitrate esters are considered as important nitric oxide (NO) donors with diverse biological activities. Herein, we report the synthesis and characterization of new oxime and nitrate ester derivatives of norfloxacin as potential NO donor hybrids with expected synergistic antimicrobial activity. The release of NO from those hybrids was measured by a modified Griess method in which p-nitroaniline was employed instead of sulfanilamide. The increased electrophilicity of the intermediate 4-nitroaniline diazonium salt accelerated the coupling process and shortened the overall assessment time. The improved detection limits and enhanced sensitivity would pave the way for the future application of this method in nitrite determination in biological or non-biological systems
Discovery of antiproliferative and anti-FAK inhibitory activity of 1,2,4-triazole derivatives containing acetamido carboxylic acid skeleton
Get PDFSmall molecule inhibitors of the focal adhesion kinase are regarded as promising tools in our armamentarium for treating cancer. Here, we identified four 1,2,4-triazole derivatives that inhibit FAK kinase significantly and evaluated their therapeutic potential. Most tested compounds revealed potent antiproliferative activity in HepG2 and Hep3B liver cancer cells, in which 3c and 3d were the most potent (IC50 range; 2.88 ~ 4.83 µM). Compound 3d possessed significant FAK inhibitory activity with IC50 value of 18.10 nM better than the reference GSK-2256098 (IC50 = 22.14 nM). The preliminary mechanism investigation by Western blot analysis showed that both 3c and 3d repressed FAK phosphorylation comparable to GSK-2256098 in HepG2 cells. As a result of FAK inhibition, 3c and 3d inhibited the pro-survival pathways by decreasing the phosphorylation levels of PI3K, Akt, JNK, and STAT3 proteins. This effect led to apoptosis induction and cell cycle arrest. Taken together, these results indicate that 3d could serve as a potent preclinical candidate for the treatment of cancers
Design, synthesis and hypolipidemic activity of novel 2-(m-tolyloxy) isobutyric acid derivatives
No full textNovel 2-substituted isobutyric acid derivatives were synthesized and their hypolipidemic activity was evaluated in high cholesterol diet fed rat model. The amide 5a was found to decrease the levels of serum total cholesterol, LDL cholesterol and triglycerides in hyperlipidemic rats to a greater degree than the reference gemfibrozil
Design, synthesis and hypolipidemic activity of novel 2-(naphthalen-2-yloxy)propionic acid derivatives as desmethyl fibrate analogues
No full textA series of 2-(naphthalen-2-yloxy)propionic acid derivatives were prepared. The hypolipidemic activity of the new compounds as well as the intermediate acid 2 was evaluated in the high cholesterol diet (HCD) fed hyperlipidemic rat model. Interestingly, the S-alkylated mercaptotriazole 8b and the 1,3,4-oxadiazole 9 produced striking reduction of serum levels of total cholesterol (TC), triglycerides (TGs) and low-density lipoproteins (LDLs) and elevation of serum high-density lipoproteins (HDLs) being more active than the reference gemfibrozil. In addition, the 1,2,4-triazole 7a, the hydroxypyrazoline 10 and the pyrazolone derivative 11 exhibited good hypolipidemic activity on different lipid parameters
Facile one-pot three-component synthesis of 4,6-diaryl-3,4-dihydropyrimidine-2(1H)-thiones under ultrasonic irradiation
No full textWe developed a facile one-pot procedure for the synthesis of 4,6-diaryl-3,4-dihydropyrimidine-2(1H)-thione under ultrasonic irradiation. The method is based on a three components reaction of aldehydes, ketones, and thiourea under basic conditions affording isolated yields of up to 95% within a reaction time of 30–90 min
Synthesis and antimicrobial evaluation of new nitric oxide‐donating fluoroquinolone/oxime hybrids
No full textA new series of nitric oxide‐donating fluoroquinolone/oximes was prepared in this study. The nitric oxide release from the prepared compounds was measured using a modified Griess colorimetric method. The antitubercular evaluation of the synthesized compounds indicated that ketone derivatives 2b and 2e and oximes 3b and 3d exhibited somewhat higher activity than their respective parent fluoroquinolones. Mycobacterial DNA cleavage studies and molecular modeling of Mycobacterium tuberculosis DNA gyrase were pursued to explain the observed bioactivity. More important, antibacterial evaluation showed that oximes 3c–e are highly potent against Klebsiella pneumoniae, with minimum inhibitory concentration (MIC) values of 0.06, 0.08, and 0.034 µM, respectively, whereas ketone 2c and oxime 4c are more active against Staphylococcus aureus than ciprofloxacin (MIC values: 0.7, 0.38, and 1.6 µM, respectively). Notably, the antipseudomonal activities of compounds 2a and 4c were much higher than those of their respective parent fluoroquinolones
New fluoroquinolones/nitric oxide donor hybrids: design, synthesis and antitubercular activity
No full textNew nitric oxide (NO) donating fluoroquinolones/nitrate ester hybrids were prepared and their structures were characterizedby various spectroscopic and analytical tools. The release of NO from the prepared nitrate esters was measured using the modified Griess colorimetric method. Evaluation of antitubercular activity showed that most of tested compounds exhibited comparable or higher activity than the parent fluoroquinolones. Compounds 2b, 3a, 4a, 5a, and 2d showed better activity than ciprofloxacin. Nevertheless, none of the new compounds were superior to the parent fluoroquinolones in terms of DNA cleavage stimulation in mycobacteria. The additional growth inhibition effect that is distinct from gyrase poisoning may be due to release of NO or enhancement of lipophilicity. These data are augmented by docking results where the docked compounds did not exert additional significant bindings over the parent fluoroquinolones
Design, synthesis and mechanistic study of N-4-Piperazinyl Butyryl Thiazolidinedione derivatives of ciprofloxacin with Anticancer Activity via Topoisomerase I/II inhibition
No full textAbstract A new group of thiazolidine-2,4-dione derivatives of ciprofloxacin having butyryl linker 3a-l was synthesized via an alkylation of thiazolidine-2,4-diones with butyryl ciprofloxacin with yield range 48–77% andfully characterized by various spectroscopic and analytical tools. Anti-cancer screening outcomes indicated that 3a and 3i possess antiproliferative activities against human melanoma LOX IMVI cancer cell line with IC50 values of 26.7 ± 1.50 and 25.4 ± 1.43 µM, respectively, using doxorubicin and cisplatin as positive controls with an IC50 of 7.03 ± 0.40 and 5.07 ± 0.29 µM, respectively. Additionally, compound 3j showed promising anticancer activity against human renal cancer A498 cell line with IC50 value of 33.9 ± 1.91 µM while doxorubicin and cisplatin showed IC50 values of 3.59 ± 0.20 and 7.92 ± 0.45, respectively. On the other hand, compound 3i did not show considerable anti-bacterial activity against S. aureus, E. coli and P. aeruginosa, and only moderate activity against K. pneumoniae with only a tenth of the activity of ciprofloxacin, confirming the cytotoxicity observed. Mechanistically, compound 3i inhibited both topoisomerase I and II with IC50 of 4.77 ± 0.26 and 15 ± 0.81 µM. Furthermore, it induced cell cycle arrest at S phase in melanoma LOX IMVI cells. Moreover, 3i provoked substantial levels of early, late apoptosis and necrosis in melanoma LOX IMVI cell line comparable to that induced by doxorubicin. Furthermore, compound 3i increased the expression level of active caspase-3 by 49 folds higher in LOX IMVI cell, increased protein expression level of Bax more than the control by 3 folds and inhibited PARP-1by 33% in LOX IMVI. All results were supported by theoretical docking studies on both tested enzymes confirming potential cytotoxicity for the synthesized hybrids
FAK inhibitors as promising anticancer targets: present and future directions.
No full textFAK, a nonreceptor tyrosine kinase, has been recognized as a novel target class for the development of targeted anticancer agents. Overexpression of FAK is a common occurrence in several solid tumors, in which the kinase has been implicated in promoting metastases. Consequently, designing and developing potent FAK inhibitors is becoming an attractive goal, and FAK inhibitors are being recognized as a promising tool in our armamentarium for treating diverse cancers. This review comprehensively summarizes the different classes of synthetically derived compounds that have been reported as potent FAK inhibitors in the last three decades. Finally, the future of FAK-targeting smart drugs that are designed to slow down the emergence of drug resistance is discussed
In Vitro Anticancer Activity of Novel Ciprofloxacin Mannich Base in Lung Adenocarcinoma and High-Grade Serous Ovarian Cancer Cell Lines via Attenuating MAPK Signaling Pathway
No full textNovel drugs are desperately needed in order to combat a significant challenge due to chemo-therapeutic resistance and bad prognosis. This research aimed to assess the anticancer activity of a newly synthesized ciprofloxacin Mannich base (CMB) on ovarian cancer (OVCAR-3) and lung cancer (A-549) cell lines and to investigate probable involved molecular mechanisms. The cytotoxic and pro-apoptotic impact of CMB on both cell lines was investigated using MTT assay, Annexin V assay, and cell cycle analysis, as well as caspase-3 activation. Western blotting was carried out to evaluate downstream targets of the MAPK pathway, while qRT PCR was used to evaluate the gene expression pattern of the p53/Bax/Bcl2 pathway. CMB treatment showed significantly reduced cell proliferation in both OVCAR-3 and A-549 cells with half maximum inhibitory concentration (IC50) = 11.60 and 16.22 µg/mL, respectively. CMB also induced apoptosis, S phase cell cycle arrest, and up-regulated expression of p53, p21, and Bax while down-regulated Bcl2 expression. CMB also halted cell proliferation by deactivating the MAPK pathway. In conclusion, CMB may be regarded as a potential antiproliferative agent for lung and ovarian cancers due to anti-proliferative and pro-apoptotic actions via inhibition of the MAPK pathway and p53/Bax/Bcl2
