Riham F. George

Synthesis, antitumor and antibacterial activities of some novel tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives.

Two series of new tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines namely 2,3-disubstituted derivatives 3a-z and 2,4-disubstituted ones 6a-c were prepared and tested for their antitumor and antibacterial activities. The structures of the prepared compounds were confirmed by spectral and elemental analyses. Compound 3z exhibited the highest antitumor activity against breast MCF-7 with IC50 = 0.19 μM compared to Doxorubicin (IC50 = 5.46 μM), while 3r was the most active one against liver HEPG-2 cancer cell line with IC50 = 1.29 μM as regard to Doxorubicin (IC50 = 7.36 μM). Concerning the antibacterial activity, compounds 3m and 3z exerted remarkable activity against the tested bacterial species compared to Ampicillin, whereas compound 6c showed good activity against only Gram positive species.

Synthesis, analgesic and anti-inflammatory activities evaluation of some bi-, tri- and tetracyclic condensed pyrimidines.

Novel series of bicyclic pyrrolo[1,2-c]pyrimidines 3a-g, 5, 6a, b, and 7a, b, tricyclic pyrimido[5,4-e]pyrrolo[1,2-c]pyrimidines 8a-c, 9a-g, 13a-c, 17, 18a, b, 19, 20a,b and 21 and tetracyclic condensed pyrimidines 14, 22 and 23 were synthesized through different chemical reactions. Structures of all synthesized pyrimidine derivatives were supported by spectral and elemental analyses. Analgesic activity evaluation was carried out using acetic acid-induced writhing assay, and all compounds exerted comparable activity to indomethacin. The anti-inflammatory activity evaluation was performed using carrageenan-induced paw edema in rats, the potency of the bicyclic derivatives 3a-f and 7b revealed comparable activity to indomethacin without gastric ulceration. The tricyclic derivatives 13a and 20a exerted good activity, however, they induced gastric ulcers while 13b and 13c showed moderate activity without ulceration. In case of tetracyclic derivatives, compound 14 exhibited the highest potency and safety profile.

Synthesis, hypnotic properties and molecular modeling studies of 1,2,7,9-tetraaza-spiro[4.5]dec-2-ene-6,8,10-triones.

1,3-Dipolar cycloaddition reaction of nitrilimines with 5-arylidene-1,3-dimethyl-2,4,6-pyrimidinetriones 1a-i afforded 7,9-dimethyl-1,3,4-triaryl-1,2,7,9-tetraaza-spiro[4.5]dec-2-ene-6,8,10-triones 3a-k in a high regioselective manner. Single crystal X-ray study of 3d added a conclusive support for the assigned structure. Potentiating effects of the synthesized compounds 3a-k (at a dose of 25 mg/kg body weight) on hypnotic action of sodium thiopental (at a dose of 75 mg/kg body weight i.p.) were investigated in vivo using Albino mice according to the standard method. Most of the tested compounds revealed promising hypnotic potentiating effects especially compounds 3k and 3e that could be nominated as short-acting hypnotics. A hypothesis of molecular modeling study, including fitting of the synthesized compounds into 3D-pharmacophore using Discovery Studio 2.5 software and their docking into optimized homology model of GABA(A)-α(1) showed good results consistent with the observed pharmacological properties.

Synthesis and QSAR study of novel anti-inflammatory active mesalazine-metronidazole conjugates.

Novel, mesalazine, metronidazole conjugates 6a-e with amino acid linkers were synthesized utilizing benzotriazole chemistry. Biological data acquired for all the novel bis-conjugates showed (a) some bis-conjugates exhibit comparable anti-inflammatory activity with parent drugs and (b) the potent bis-conjugates show no visible stomach lesions. 3D-pharmacophore and 2D-QSAR modeling support the observed bio-properties.

Stereoselective synthesis and QSAR study of cytotoxic 2-(4-oxo-thiazolidin-2-ylidene)-2-cyano-N-arylacetamides.

(2Z,5Z) 2-[(5-Arylidene-4-oxo-3-phenyl)-thiazolidin-2-ylidine]-2-cyano-N-arylacetamides 4a-l were stereoselectively prepared via condensation of aromatic aldehydes with 4-thiazolidinones 3a-c. The latters were obtained via electrophilic attack of phenylisothiocyanate on 2-cyano-N-arylacetamides 1a-c followed by reaction with chloroacetyl chloride under basic condition. Single crystal X-ray study of 3a allows good confirmation for the assigned structure. Additionally, 5-arylhydrazono analogs 5a-e were prepared via condensation of the appropriate diazonium salts with 4-thiazolidinones 3a,b. Many of the synthesized compounds exhibited promising antitumor properties against colon HCT116, breast MCF7 and liver HEPG2 cell lines. 3D-Pharmacophore modeling and QSAR analysis were combined to explain the observed antitumor properties.

Synthesis and DFT studies of an antitumor active spiro-oxindole

An anti-oncological active spiro-oxindole 7 was synthesized regioselectively via a [3+2]-cycloaddition reaction of azomethine ylide to exocyclic olefinic linkage of 4-piperidone 6, exhibiting properties against diverse tumor cell lines including leukemia, melanoma and cancers of the lung, colon, brain, ovary, breast, prostate, and kidney. Compound 7 crystallizes in the monoclinic system and P21/c space group with four molecules in the unit cell. The structure was also studied by AM1, PM3 and DFT techniques. DFT studies support the stereochemical selectivity of the reaction and determine the molecular electrostatic potential and frontier molecular orbitals.

Synthesis, bioassay, and QSAR study of bronchodilatory active 4H-pyrano[3,2-c]pyridine-3-carbonitriles

A statistically significant QSAR model describing the bioactivity of bronchodilatory active 4H-pyrano[3,2-c]pyridine-3-carbonitriles (N = 41, n = 8, R(2) = 0.824, R(2)cv = 0.724, F = 18.749, s(2) = 0.0018) was obtained employing CODESSA-Pro software. The bronchodilatory active 4H-pyrano[3,2-c]pyridine-3-carbonitriles 17-57 were synthesized through a facile approach via reaction of 1-alkyl-4-piperidones 1-4 with ylidenemalononitriles 5-16 in methanol in the presence of sodium. The bronchodilation properties of 17-57 were investigated in vitro using isolated guinea pig tracheal rings pre-contracted with histamine (standard method) and compared with theophylline (standard reference). Most of the compounds synthesized exhibit promising bronchodilation properties especially, compounds 25 and 28.

Synthesis and molecular modeling studies of indole-based antitumor agents

Indole-based compounds 30–63 were synthesized by the multi-component 1,3-dipolar cycloaddition reaction of 1-alkyl-3,5-bis(arylidene)-4-piperidones 11–25 with azomethine ylides (generated by the condensation of isatins 26–28 with sarcosine 29). The single crystal X-ray studies of 46 and 48 supported the regio- and stereoselectivity of the reaction. Most of the synthesized spiro-indoles exhibited potent antitumor properties against the HeLa (cervical cancer) cell line through in vitro sulfo-rhodamine-B bioassay, higher than that of cisplatin. Only compound 54 showed bio-potency against the HepG2 (hepatocellular cancer) cell line, comparable to that of doxorubicin hydrochloride (standard reference). 3D-Pharmacophore and 2D-QSAR studies were used to validate the observed biological data and determine the most important parameters controlling activity. The estimated bio-properties from the computational studies showed high approximations to the experimental data.

Synthesis and cytotoxic activities of some pyrazoline derivatives bearing phenyl pyridazine core as new apoptosis inducers

The cyclization of chalcones 3a-3u with 3-hydrazinyl-6-phenylpyridazine 7 under basic condition led to the formation of new pyrazoline derivatives 8a-8u. All final compounds were characterized by spectral and elemental analyses. They were screened for their antiproliferative activities against A549 (lung), HepG-2 (liver), CaCo-2 (intestinal) and MCF-7 (breast) cancer cell lines. Some of the synthesized compounds exhibited promising antiproliferative activities especially compound 8k with IC50 values of 8.33, 1.67 and 10 μM against HepG-2, MCF-7 and CaCo-2 cancer cell lines, respectively. Moreover, their antiproliferative activity was due to apoptosis rather than necrosis induction except compound 8h which exhibited equal apoptotic and necrotic properties. Compound 8k showed 5 fold increase in caspase-3 activity indicating that the apoptosis proceeds via caspase-3 activation.

Synthesis, Bioassay, and Molecular Field Topology Analysis of Diverse Vasodilatory Heterocycles

A diverse training set composed of 76 in-house synthesized and 61 collected from the literature was subjected to molecular field topology analysis. This resulted in a high-quality quantitative structure-activity relationships model (R² = 0.932, Q² = 0.809) which was used for the topological functional core identification and prediction of vasodilatory activity of 19 novel pyridinecarbonitriles, which turned out to be active in experimental bioassay.