Ghaneya S. Hassan

Celecoxib analogs bearing benzofuran moiety as cyclooxygenase-2 inhibitors: Design, synthesis and evaluation as potential anti-inflammatory agents

Novel series of celecoxib analogs endowed with benzofuran moiety 3a-e and 9a-d were synthesized and evaluated for COX-1/COX-2 inhibitory activity in vitro. The most potent and selective COX-2 inhibitors - compounds 3c, 3d, 3e, 9c and 9d - were assessed for their anti-inflammatory activity and ulcerogenic liability in vivo. The 3-(pyridin-3-yl)pyrazole derivatives 3c and 3e exhibited the highest anti-inflammatory activity, that is equipotent to celecoxib. Furthermore, the tested compounds proved to have better gastric safety profile compared to celecoxib. In particular, compound 3e demonstrated about 40% reduction in ulcerogenic potential relative to the reference drug. Finally, molecular docking simulation of the new compounds in COX-2 active site and drug likeness studies showed good agreement with the obtained pharmaco-biological results.

Synthesis and in vitro cytotoxic activity of novel pyrazolo[3,4-d]pyrimidines and related pyrazole hydrazones toward breast adenocarcinoma MCF-7 cell line

New series of pyrazolo[3,4-d]pyrimidines (7a-e and 13a-d) and pyrazole hydrazones 17a-d were synthesized and evaluated for their antiproliferative activity against human breast adenocarcinoma MCF-7 cell line. Most of the tested compounds exploited potent to moderate growth inhibitory activity, in particular compound 7e exhibited superior potency to the reference drug cisplatin (IC(50)=7.60 and 13.29 μM, respectively). The antitumor activity of the new compounds was accompanied by significant increase in the activity of superoxide dismutase with concomitant decrease in the activities of catalase and glutathione peroxidase and reduced glutathione level. Accordingly, the overproduction of hydrogen peroxide, nitric oxide and other free radicals allowed reactive oxygen species (ROS)-mediated tumor cells death, as monitored by reduction in the synthesis of protein and nucleic acids.

Synthesis and biological evaluation of novel coumarin-pyrazoline hybrids endowed with phenylsulfonyl moiety as antitumor agents.

Two groups of coumarin-pyrazoline hybrids were synthesized. The target compounds were obtained by cyclization of the coumarin chalcones with various substituted hydrazines to produce the corresponding pyrazolines through 1,4-addition on α,β-unsaturated carbonyl system. Selected compounds were investigated for their anticancer activity toward 60 cancer cell lines according to US NCI protocol where breast cancer MCF7 and colon cancer HCT-116 were the most susceptible to the influence of compounds 7d, 8c and 9c. Encouraged by this, all final compounds were screened against colorectal cell line HCT-116. The tested compounds exhibited high potency with IC(50) ranging from 0.01 μM to 2.8 μM. Moreover, compound 9c which possessed the highest cytotoxicity proved to have weak enzyme inhibitory activity against PI3K (p110α/p85α).

Design, synthesis and vasorelaxant evaluation of novel coumarin-pyrimidine hybrids.

The main objective of the present work depends on the hybridization of coumarin moiety as a vasorelaxant scaffold and pyrimidine ring with known potential cardiovascular activity in order to prepare some new potent antihypertensive candidates. Hence, two groups of pyrimidinyl coumarin derivatives were synthesized and evaluated for their vasorelaxing activity. These compounds were prepared via two routes; either preparation of the guanidinocoumarin 4 followed by a cocktail of cyclization reactions to yield a different array of 6-(substituted pyrimidin-2-yl)aminocoumarins 5-17, or through cyclization of the precursor chalcones 22a-g with guanidine hydrochloride to generate the corresponding final compounds, 8-(6-aryl-2-aminopyrimidin-4-yl)-7-methoxycoumarins 23a-g. The effect of these compounds and the coumarin intermediates 3, 4, 21 and 22a-g on nor-epinephrine induced contracture in thoracic rat aortic rings was investigated using prazocin as reference drug. Several derivatives showed promising activities either equal or even better than that of prazocin (IC(50) 0.487 mM). The most prospective compounds; the pyrimidinylamino coumarin derivatives 8, 17 (IC(50) 0.411, IC(50) 0.421 mM) and the chalcones 22b, 22e (IC(50) 0.371, 0.374 mM) that displayed the highest activity can be a base for lead optimization and simple but efficient design of new compounds. 2D-QSAR analysis was applied to find a correlation between the experimental vasorelaxant activities of the newly synthesized coumarin derivatives and their different physicochemical parameters. The result of this study showed that the increase in aqueous solubility while retaining good hydrophobic character of the overall molecule is the key for maintaining high relaxation activity.

Synthesis and anticancer activity of some 8-substituted-7-methoxy-2H-chromen-2-one derivatives toward hepatocellular carcinoma HepG2 cells.

Based on the reported anticancer activity of coumarin and pyrazoline derivatives, the present investigation dealt with the design and synthesis of coumarin derivatives bearing diversely substituted pyrazoline moieties 7-10. The non-cyclic isosteres 11a-e of compounds 10a-e were synthesized for comparative reasons. The target compounds were synthesized from 8-acetyl-7-methoxycoumarin that underwent Claisen-Schmidt condensation with various aldehydes to give the chalcones 6a-e, followed by reaction with hydrazine hydrate, phenyl hydrazine or semicarbazide under the appropriate conditions. Cytotoxicity of the synthesized compounds was evaluated in vitro against liver HepG2 cell line. Compounds were active in the nanomolar range. The most active compounds were investigated for their telomerase inhibition and proapoptotic activities.

Design, synthesis and anti-ulcerogenic effect of some of furo-salicylic acid derivatives on acetic acid-induced ulcerative colitis

Ulcerative colitis is a chronically recurrent inflammatory bowel disease of unknown origin. The present work describes design and synthesis of 3-aminofurosalicylic acid 4, azo-conjugates with aniline 2a, 4-ASA 2b or sulphapyridine 2c as well as N-arylsulphonamido 5, chlorosulphonyl 6, aminosulphonyl 7 and N-arylaminosulphonyl derivatives 8 (positional isosters of 5). All the synthesized compounds were evaluated for their anti-ulcerogenic effect on acetic acid-induced ulcerative colitis in rats. It was noticed that oral treatment with sulphasalazine (a reference drug) and the tested compounds 2a, 2c, 4 and 5c in equimolar doses significantly reduced the intensity of lesion score, ulcer area, ulcer index and wet weight/length ratio compared to the control group. On the other hand, compounds 2b, 5a, 5b and 7 had a lower anti-ulcerogenic efficacy. Also, the antimicrobial activity of the synthesized compounds was screened in vitro using the agar diffusion assay technique. In addition, docking of the tested compounds into cycloxygenase II using molecular operating environment (MOE) was performed in order to rationalize the obtained biological results and their mechanism of action.

Design and synthesis of some pyrazole derivatives of expected anti-inflammatory and analgesic activities

Design and synthesis of some pyrazole derivatives 4–11 of expected anti-inflammatory and analgesic activities. In addition, docking of the tested compounds into cyclooxygenase II using (MOE) was performed to rationalize the obtained biological results and their mechanism of action. The structures of the new compounds were elucidated by spectral and elemental analyses. All the newly synthesized compounds were evaluated for their anti-inflammatory activity using the carrageenan-induced rat paw edema method. Analgesic activity of the target compounds was measured using the p-benzoquinone writhing-induced method, and their ability to induce gastric toxicity was also evaluated. Results showed that the newly synthesized compounds exhibited weak to good activities compared to ibuprofen and celecoxib as reference drugs. Some compounds, such 4a and 11b exhibited significant anti-inflammatory activity with gastric ulcerogenic potential less than that of ibuprofen. Results of the analgesic activity showed that compounds possessing good anti-inflammatory activity showed also good analgesic. Substitution of pyrazole ring with at least one aryl moiety was found to be essential for anti-inflammatory and analgesic activities. Free NH (of pyrazole ring) and/or acidic group (COOH) will improve the anti-inflammatory activity.Graphical abstract

Design and Synthesis of Novel Benzopyran-2-one Derivatives of Expected Antimicrobial Activity through DNA Gyrase-B Inhibition

In an attempt to find a new class of antibacterial agents, we have synthesized thirty new coumarin (2H‐benzopyran‐2‐one) analogues. These derivatives include substituted azetidin‐2‐ones (β‐lactam) 3a–f, pyrrolidin‐2‐ones 4a–f, 2H‐1,3,4‐oxadiazoles 5a–f, and thiazolidin‐4‐ones 6a–f attached to 4‐phenyl‐2H‐benzopyran‐2‐one through an oxyacetamido or an oxymethyl bridge. The target compounds were synthesized starting from 2‐oxo‐4‐phenyl‐2H‐benzo[b]pyran‐7‐yl‐oxyacetic acid hydrazides 2a–f. The new compounds were evaluated as DNA gyrase‐B inhibitors through molecular modeling and docking techniques using the Molsoft ICM 3.4‐8C program. The synthesized compounds were also screened for antibacterial activity against four different species of Gram‐positive and Gram‐negative bacteria; as well as screening against C. albicans for antifungal activity. The molecular modeling data were in accordance with the antimicrobial screening results.

Benzoxepin derivatives: design, synthesis, and pharmacological evaluation with sedative–hypnotic effect

A series of novel benzoxepin-derived compounds were synthesized and evaluated for their sedative–hypnotic effect using Phenobarbital-induced sleep test in mice. Compound 6 in which the Phenobarbital moiety was incorporated into the benzoxepin nucleus was the most active one. Molecular modeling, including fitting to a 3D-pharmacophore model using Discovery Studio 2.1 programs into optimized benzodiazepine receptor (hypothesis) showed high fit values. The experimental studies for the in vivo sedative–hypnotic effect of compounds 2–6 and 11a–c were consistent with the molecular modeling.Graphical abstractA series of novel benzoxepin-derived compounds were synthesized and evaluated for their sedative–hypnotic effect using Phenobarbital-induced sleep test in mice. Compound 6 in which the Phenobarbital moiety was incorporated into the benzoxepin nucleus was the most active one.

Quantitative analysis of anti-inflammatory drugs using FTIR-ATR spectrometry

Four simple, accurate, sensitive and economic Attenuated Total Reflectance-Fourier Transform Infrared Spectroscopic (ATR-FTIR) methods have been developed for the quantitative estimation of some non-steroidal anti-inflammatory drugs. The first method involves the determination of Etodolac by direct measurement of the absorbance at 1716cm-1. In the second method, the second derivative of the IR spectra of Tolfenamic acid and its reported degradation product (2-chlorobenzoic acid) was used and the amplitudes were measured at 1084.27cm-1 and 1056.02cm-1 for Tolfenamic acid and 2-chlorobenzoic acid, respectively. The third method used the first derivative of the IR spectra of Bumadizone and its reported degradation product, N,N-diphenylhydrazine and the amplitudes were measured at 2874.98cm-1 and 2160.32cm-1 for Bumadizone and N,N-diphenylhydrazine, respectively. The fourth method depends on measuring the amplitude of Diacerein at 1059.18cm-1 and of rhein, its reported degradation product, at 1079.32cm-1 in their first derivative spectra. The four methods were successfully applied on the pharmaceutical formulations by extracting the active constituent in chloroform and the extract was directly measured in liquid phase mode using a specific cell. Moreover, validation of these methods was carried out following International Conference of Harmonisation (ICH) guidelines.