Phoebe F. Lamie

Cyclooxygenase-2 and 15-lipoxygenase inhibition, synthesis, anti-inflammatory activity and ulcer liability of new celecoxib analogues: Determination of region-specific pyrazole ring formation by NOESY

Two new series of 1,5-diaryl pyrazoline (3a-f) and 1,5-diaryl pyrazole (5a and 5b) were designed as both COX-2 and 15-LOX inhibitors. All the prepared compounds were fully characterized by all spectral and element analysis. Their anti-inflammatory activity and ulcer index were included. Pyrazoline 3f is the most effective with IC50=1.14 and 4.7μM against COX-2 and 15-LOX respectively, and more potent than celecoxib and meclofenamate references. In addition 3a, 3b, 5a, and 5b were safer with low ulcer index than celecoxib. Docking study was performed for the most active compounds such as 2b, 3a, and 3f on COX-2 and 15-LOX enzymes.

3-Methyl-2-phenyl-1-substituted-indole derivatives as indomethacin analogs: design, synthesis and biological evaluation as potential anti-inflammatory and analgesic agents

Abstract In a new group of 3-methyl-2-phenyl-1-substituted-indole derivatives (10a–f), the indomethacin analogs were prepared via the Fisher indole synthesis reaction of propiophenone with appropriately substituted phenylhydrazine hydrochloride. This is followed by the insertion of the appropriate benzyl or benzoyl fragment. All the synthesized compounds were evaluated for their anti-inflammatory (in vitro and in vivo) and analgesic activities. The methanesulphonyl derivatives 10d, e and f showed the highest anti-inflammatory (in vitro and in vivo) and analgesic activities. In addition, molecular docking studies were performed on compounds 10a–f and the results were in agreement with that obtained from the in vitro COX inhibition assays. The significant anti-inflammatory and analgesic activities exhibited by 10d and 10e warrant continued preclinical development as potential anti-inflammatory and analgesic agents.

Azole-hydrazone derivatives: Design, synthesis, in vitro biological evaluation, dual EGFR/HER2 inhibitory activity, cell cycle analysis and molecular docking study as anticancer agents

In this research, three series of azole-hydrazone derivatives namely, benzimidazole, benzoxazole and benzothiazole were designed and synthesized. Their structures were confirmed by elemental analysis and spectroscopic techniques. Stereochemical configuration of the synthesized compounds (Z/E) was determined. The new derivatives were tested in vitro against both human breast adenocarcinoma (MCF-7) and human hepatic adenocarcinoma (HepG2) cell lines. The most active compounds 3h (IC50 = 0.067 μM against MCF-7) and 3l (IC50 = 0.027 μM against HepG2) were further tested for Epidermal Growth Factor Receptor (EGFR) inhibitory activity. The most active 3h on EGFR was then screened for HER2 and VEGFR enzymes. Caspase-3/9 protein level expression were measured for the two compounds 3h and 3l. Cell cycle analysis showed pre G1 apoptosis and cell cycle arrest at G2/M phase. Up-regulation of Bax and down-regulation of Bcl-2 protein expression level confirmed apoptosis. Molecular docking analysis was performed for all the synthesized compounds inside the active site of EGFR.

Design, synthesis and biological evaluation of novel thiophene and theinopyrimidine derivatives as anticancer agents

Some novel thiophene and theinopyrimidine derivatives have been synthesized. Their structures were confirmed by elemental analyses, infrared, 1H NMR, 13C NMR and mass spectral data. All the target compounds were screened against liver adenocarcinoma (HepG2) cell line. Compounds 9c, 9b, 10b, and 7c in a sequent were the most potent compounds between all the test compounds with IC50 values [0.01063, 0.01158, 0.01729, 0.01957 µM], respectively. Compounds 13b, 7b, 5d, 9a, 8a, and 11b showed higher activity with IC50 values ranged from 0.02231 to 0.03673 µM when compared with 5-flurouracil (A) as a reference drug (IC50 = 0.0384 µM).

Design and synthesis of three series of novel antitumor–azo derivatives

Three new series of thiazoles, quinolones, and thiazolidinones merged with benzimidazole, benzoxazole, and benzothiazole nuclei were synthesized. The compounds were subjected to Infrared, 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, mass spectrometry, and elemental analyses. Cytotoxic activity of compounds were evaluated against breast (MCF-7) and colon (HCT-116) cell lines. Seven of the compounds had IC50 values between 0.0112 and 0.0198 µM and are hence more potent than the reference drug doxorubicin (IC50 = 0.0084 and 0.0088 µM against MCF-7 and HCT-116, respectively).

Novel tetrazole and cyanamide derivatives as inhibitors of cyclooxygenase-2 enzyme: design, synthesis, anti-inflammatory evaluation, ulcerogenic liability and docking study

Abstract Nineteen new compounds containing tetrazole and/or cyanamide moiety have been designed and synthesised. Their structures were confirmed using spectroscopic methods and elemental analyses. Anti-inflammatory activity for all the synthesised compounds was evaluated in vivo. The most active compounds 4c, 5a, 5d–f, 8a and b and 9a and b were further investigated for their ulcerogenic liability and analgesic activity. Pyrazoline derivatives 9b and 8b bearing trimethoxyphenyl part and SO2NH2 or SO2Me pharmacophore showed equal or nearly the same ulcerogenic liability (UI: 0.5, 0.75, respectively), to celecoxib (UI: 0.50). Most of tested compounds showed potent central and/or peripheral analgesic activities. Histopathological investigations were done to evaluate test compounds effect on rats gastric tissue. The obtained results were in consistent with the in vitro data on COX evaluation. Docking study was also done for all the target compounds inside COX-2-active site.

Synthesis of New Quinolone Derivatives Linked to Benzothiazole orBenzoxazole Moieties as Anticancer and Anti-Oxidant Agents

A new series of substituted quinolones linked to benzothiazole and/or benzoxazole moieties 5a-l was synthesized. 6-Benzoxazol-2-yl/benzothiazol-2-yl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl esters 3a&b were reacted with hydrazine to give the hydrazide derivatives 4a&b and finally, 4a&b were reacted with different aromatic aldehydes giving the target compounds 5a-l. The benzylidene derivatives 5a-l were screened for their cytotoxic activities against breast carcinoma cell lines (MCF-7) and anti-oxidant properties. All the tested compounds 5a-l showed from high to moderate activity as anticancer and anti-oxidant agents. Compounds 5h and 5l showed the highest cytotoxicr activity against MCF-7 (IC50: 0.058 and 0.052 uM, respectively) than 4-(benzothiazol-2-yl) aniline the reference drug (IC50: 0.065 uM). Moreover, compounds 5e, 5g and 5h showed the highest anti-oxidant activity. The structure of the compounds 5a-l was confirmed using IR, 1H NMR, mass spectroscopy and elemental analysis.

Design, synthesis, and biological evaluation of novel 1,2-diaryl-4-substituted-benzylidene-5(4H)-imidazolone derivatives as cytotoxic agents and COX-2/LOX inhibitors

A new series of 1,2‐diaryl‐4‐substituted‐benzylidene‐5(4H)‐imidazolone derivatives 4a–l was synthesized. Their structures were confirmed by different spectroscopic techniques (IR, 1H NMR, DEPT‐Q NMR, and mass spectroscopy) and elemental analyses. Their cytotoxic activities in vitro were evaluated against breast, ovarian, and liver cancer cell lines and also normal human skin fibroblasts. Cyclooxygenase (COX)‐1, COX‐2 and lipoxygenase (LOX) inhibitory activities were measured. The synthesized compounds showed selectivity toward COX‐2 rather than COX‐1, and the IC50 values (0.25–1.7 µM) were lower than that of indomethacin (IC50 = 9.47 µM) and somewhat higher than that of celecoxib (IC50 = 0.071 µM). The selectivity index for COX‐2 of the oxazole derivative 4e (SI = 3.67) was nearly equal to that of celecoxib (SI = 3.66). For the LOX inhibitory activity, the new compounds showed IC50 values of 0.02–74.03 µM, while the IC50 of the reference zileuton was 0.83 µM. The most active compound 4c (4‐chlorobenzoxazole derivative) was found to have dual COX‐2/LOX activity. All the synthesized compounds were docked inside the active site of the COX‐2 and LOX enzymes. They linked to COX‐2 through the N atom of the azole scaffold, while CO of the oxazolone moiety was responsible for the binding to amino acids inside the LOX active site.

Design and synthesis of novel benzimidazole, benzoxazole and benzothiazole derivatives bearing biologically active thiazole, dihydroquinolone and thiazolidinone moieties as a new class of antitumor agents

A new (ZB-Ag2O, Al 2O3-MoO3 – Ag2O) catalyst for dNO,dNOx and dCH has been prepared from silver oxide carried on a matrix of mixture from Syrian natural zeolite, Syrian bentonite and Al2O3-MoO3–Ag2O. Mineralogical studies were made to identical the components of the catalyst, montmorillonite and phylippsite and others were observed. The DTA diagrams indicated characteristic indothermal and exothermal reaction. The adsorption – desorption of N2 measurements were carried out at -196°C. A slight decrease of surface area after having the catalyst been covered with Ag2O. Catalytic experiments were conducted by means of a flow micro pulse-like reactor using the gas emitted from car exhaust. A maximal dNOx rate on the (ZB-Ag2O, Al2O3-MoO3 – Ag2O) catalyst was observed at 185°C. The catalytic data make it possible to suggest a mechanism for the ongoing reactions.

RETRACTED: Design, synthesis, structure–activity relationship and kinase inhibitory activity of substituted 3-methyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ones

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the author who confirmed that the purity of some of the described compounds is below acceptable standards and thus the biochemical results reported in the paper have no validity.