Michael Reaction of 3-aAryl-2,4-Dicarboethoxy-5-Hydroxy-5-Methylcyclohexanones.

The reaction of 3-aryl-2,4-dicarboethoxy-5-hydroxy-5-methylcyclohexanones 1with benzalacetone, dibenzalacetone, benzalacetophenone, and 4-benzal-1-phenyl-3-methyl pyrazolone has been investigated to give Michael compounds 2-5. hydrolysis of the dioxo derivative 4 afforded1,5-dicarbonyl derivative 6which On condensation with hydrazine and/or substituted hydrazine and hydroxylamine produced1,2-diazepine and 1,2-oxazepine derivatives 7,8 respectively. Reaction of ß-Keto ester 1 with 1,3-diphenylacetone afforded 9. The structures of the hitherto unknown compounds have been confirmed by analytical and spectral data. The newly synthesized compounds have been screened to test their antimicrobial and antifungal activity.

Study of the population pharmacokinetic characteristics of nimorazole in head and neck cancer patients treated in the DAHANCA-5 trial.

AIMS: To study the pharmacokinetic characteristics of the hypoxic radiosensitiser nimorazole in patients with head and neck squamous cell carcinoma. MATERIALS AND METHODS: The pharmacokinetics of the hypoxic radiosensitiser nimorazole were studied in 63 patients treated in the DAHANCA-5 trial. After the first day of treatment, serial venous blood samples were taken and plasma concentrations of nimorazole measured by high pressure liquid chromatography (HPLC). Plasma concentration profiles were subjected to non-compartmental pharmacokinetic analysis using validated PC-based software. The different pharmacokinetic parameters were calculated and correlated with the different patient- and treatment-related variables. RESULTS: HPLC measurements showed a linear relationship between peak plasma concentration and administered dose. The mean peak concentration adjusted for dose (in g/m(2)) was 32.2 ± 0.9 µg/ml. The time of peak concentration ranged between 30 and 180 min (median 60 min). Plasma elimination occurred with a mean half-life of 3.35 ± 0.09 h and was not significantly altered as a function of dose. There was a well-established linear-linear relationship between area under the concentration-time curve (AUC; mean 191 ± 6 µg·h/ml) and administered dose, especially when expressed as g/m(2). The mean apparent volume of distribution was 0.77 ± 0.02 l/kg. A statistically significant longer elimination half-life in men relative to women (mean difference 0.40 h; 95% confidence interval 0.77-0.03; P 0.03) was detected. Nimorazole was well tolerated; with 67% of patients reporting no toxicity; nausea/vomiting was the most reported toxicity in the remaining patients. CONCLUSION: The study supports the current nimorazole dose scheduling in patients.

Incidence and predictors of hematological side effects in chronic HCV Egyptian patients treated with PEGylated interferon and ribavirin.

AIM: The aim of this paper was to study the incidence and predictors of hematological abnormalities during treatment of chronic hepatitis C virus (HCV) patients with interferon and ribavirin. METHODS: One thousand and eighty-one chronic HCV patients who were treated with PEGylated interferon α-2a 180 µg (n = 536) or α-2b 1.5 µg/kg (n = 545) plus ribavirin for 48 weeks were included. Baseline demographic, laboratory, and histopathological data and, during treatment, hematological data were collected and analyzed using univariate and multivariate analyses to identify independent predictors of hematological side effects. RESULTS: During therapy, 168 of 1,018 (15.5 %) had moderate anemia (Hb <10 and ≥8.5 g/dL) and 88 (8.1 %) had severe anemia (Hb <8.5 g/dL). Two hundred and six patients (19.1 %) had moderate neutropenia (absolute neutrophil count (ANC) <750 and ≥500/mm(3)); only 55 (5.1 %) had severe neutropenia (ANC <500/mm(3)). Forty-three patients (4 %) had moderate (platelet <50,000 and ≥25,000/mm(3)) and 5 (1.4 %) had severe thrombocytopenia (platelet <25,000/mm(3)). Fibrosis stage, week 4 Hb level, and week 2 and 4 reduction level in Hb were independent predictors of moderate and severe anemia (p < 0.001). Fibrosis stage and ANC at weeks 2 and 4 were predictors of neutropenia (p < 0.001, 0.001, and 0.004, respectively). Fibrosis stage and platelet count at weeks 2 and 4 were predictors of thrombocytopenia (p < 0.001, <0.001, and 0.005, respectively). There was no association between interferon type and anemia (p = 0.57), neutropenia (p = 0.6), or thrombocytopenia (p = 0.79). CONCLUSIONS: Fibrosis stage and week 2 and 4 hematological parameter reduction levels were independent predictors of hematological side effects, which are not related to interferon type.

Synthesis, antitumor, cytotoxic and antioxidant evaluation of some new pyrazolotriazines attached to antipyrine moiety.

Iminopropanehydrazonoyl cyanide 4 was achieved upon reaction of antipyrine diazonium salt 2 with 3-iminobutanenitrile (3) in EtOH/AcONa. 3-Aminopyrazole derivative 5 was obtained upon reaction of 4 with hydrazine hydrate. Diazodization of 5 afforded the diazonium salt 6 which coupled with active methylene compounds 7-10, 19, 20, 25, 29 and 32 in pyridine to give aryl hydrazone derivatives 11-14, 21, 22, 26, 30 and 33, respectively. Refluxing of compounds 11-14, 21, 22, 26 and 33 in acetic acid afforded the pyrazolotriazines 15-18, 23, 24, 28 and 35, respectively. The newly synthesized compounds were screened for their cytotoxic and antioxidant activities. The results showed clearly that compounds 4, 5, 13, 22, and 24 displayed promising in vitro anticancer activity against four different cell lines (HepG2, WI 38, VERO and MCF-7). Compounds 4 and 22 are the more potent antioxidant and anticancer agents. On the other hand, most of the compounds exhibited good cytotoxic activity toward (EAC).

Alleviation of the harmful effects of soil salt stress on growth, yield and endogenous antioxidant content of wheat plant by application of antioxidants.

Two field experiments were carried out during the two growing seasons (2005/2006; 2006/2007) to investigate the role of some plant antioxidant materials such as ascorbic acid, glutathione, alpha-tocopherol and spermine in alleviating the harmful effects caused by soil salt levels (3840 and 6080 mg L(-1)) on wheat plant. The grains were pre-soaked then the plants sprayed with any of antioxidants used. Moreover, the data showed that 6080 mg L(-1) soil salt level alone or in combination with any of applied antioxidants increased the activity of total peroxidase, ascorbic peroxidase, superoxide dismutase and catalase in wheat leaves. In addition, salinity level (6080 mg L(-1)) alone or in combination with any of applied antioxidants increased the endogenous contents of ascorbic acid and glutathione and total phenols but decreased carotenoids. It could be concluded that salt soil stress depressed all of growth parameters and yield components. The data also revealed that the different antioxidants could partially alleviate the harmful effect of salinity stress which reflected on growth and yield of wheat plant.

Induce systemic resistance in lupine against root rot diseases.

Root rot caused by soil borne pathogenic fungi is the most sever disease attacks lupine plants. Isolation trials from diseased plants in some areas of Dakahlia Province (Egypt) was carried out. Rhizoctonia solani and Fusarium solani proved to be the most dominant isolates. Meanwhile, Fusarium oxysporum and Sclerotium rolfsii were less frequent. Efficacies of some plant resistance elicitors viz.: chitosan (CHI), Salicylic Acid (SA) and hydroquinone (HQ) in comparing to the fungicide Rhizolex T-50 as seed treatments showed significant reduction in the fungal growth in vitro. Chitosan at 8 g L(-1) and fungicide completely inhibited the growth of all isolated fungi, while SA at 1.4 g L(-1) and HQ at 1.2 g L(-1) inhibited the growth of Fusarium solani and F. oxysporum, respectively. The greenhouse experiments showed that S. rolfesii (No. 6) and R. solani (No. 2) followed by F. solani (No. 5) and F. oxysporum (No. 9) were the most aggressive root rot fungi. Soaking susceptible lupine seeds (Giza 1) in each one of the three selected elicitors showed a significant reduction in seedlings mortality. CHI at 8 g L(-1) was superior in increasing the percentage of healthy plants to record 72.5, 80.9, 62.7and 64.3%, when seeds were grown in soil infested with of F. solani, F. oxysporum, R. solani and S. rolfesii, respectively. These results were confirmed under field conditions in two different locations i.e., Tag El-Ezz and El-Serow Research Stations. CHI 8 g L(-1) proved to be the best elicitor after fungicide, in reducing lupine root rot disease. It showed 41 and 60% reduction in the plants mortality comparing to 56.37 and 69.13% in case of Rhizolex-T in Tag El-Ezz and El-Serow locations, respectively. The treatments were accompanied with a significant increase in lupine growth parameters, yield components and physiological aspects. Application of CHI at 8 g L(-1) or HQ at 1.2 g L(-1) was the most potent in this respect as compared to check treatment.

Involvement of alpha-receptors and potassium channels in the mechanism of action of sildenafil citrate.

Modulation of the adrenergic activity and interfering with channels such as potassium channels may affect relaxation and contraction of the corpus cavernosum. Sildenafil is a selective phosphodiesterase-5 inhibitor, proven effective in treating erectile dysfunction. In this study, the effect of sildenafil citrate on alpha-receptors modulation and potassium channels was tested. The direct relaxant effect of sildenafil citrate was studied by measuring changes in isometric tension in isolated strips of rabbit corpus cavernosum and rat aortic ring precontracted with phenylephrine or KCl compared to that of diazoxide in the presence and absence of tetraethylammonium. The inhibitory effect of sildenafil on electrical field stimulation-induced contraction of rabbit corpus cavernosum and rat anococcygeus muscle was also studied compared to that of phentolamine. Muscle relaxant effect of sildenafil (1 x 10(-9)-1 x 10(-6) M on phenylephrine-precontracted rabbit corpus cavernosum strips was not attenuated by N(G)-nitro-L-arginine (3 x 10(-5) M). Cumulative addition of sildenafil (1 x 10(-9)-1 x 10(-6) M) and phentolamine (1 x 10(-9)-1 x 10(-6) M) to the organ bath dose-dependently inhibited electrical field stimulation-induced contraction of rabbit corpus cavernosum and rat anococcygeus muscle, with almost similar EC(50) values. Sildenafil (1 x 10(-7) M) also inhibited phenylephrine-induced contraction of rat aortic rings by 39.83+/-3.01%. In addition, tetraethylammonium (1 x 10(-3) M) significantly attenuated the muscle relaxant effect of sildenafil (1 x 10(-9)-1 x 10(-6) M) on phenylephrine-precontracted strips of rabbit corpus cavernosum. Sildenafil citrate is capable of producing cavernosal smooth muscle relaxation by an additional mechanism that may involve alpha-receptors and potassium channel opening.

Effect of sildenafil on the isolated rat aortic rings.

Sildenafil, a highly selective inhibitor of PDE 5, is effective in the treatment of erectile dysfunction. Penile erection involves relaxation of smooth muscle of corpus cavernosum and its associated arterioles. The objective of this study was to investigate the effect of sildenafil on nitric oxide/cyclic guanosine monophosphate (NO/cGMP)-dependent relaxation of rat aortic rings. The contribution of sildenafil to the vasorelaxation of rat aortic rings was also investigated. Sildenafil produced significant potentiation of acetylcholine (ACh, 2 x 10(-6) m)-induced relaxation at concentration > or =1 x 10(-8) m. Addition of sildenafil (1 x 10(-7) m) to aortic rings failed to alter the effect of N(G)-nitro-L-arginine (l-NNA, 3 x 10(-5) m) or methylene blue (MB, 3 x 10(-5) m) on ACh response. Similarly, sildenafil (1 x 10(-7) m) augmented significantly the vasorelaxation induced by sodium nitroprusside over the range of 1 x 10(-9)-1 x 10(-8) m. When added to phenylephrine (3 x 10(-6) m)-precontracted rat aortic rings, sildenafil (1 x 10(-9)-1 x 10(-4) m) induced concentration-dependent relaxation reaching a maximum of 96.48 +/- 1.44%. These relaxations were not significantly attenuated by previous incubation with L-NNA (3 x 10(-5) m) or MB (3 x 10(-5) m). Denudation did not significantly affect the vasorelaxant effect of sildenafil. Sildenafil may act in the rat aortic rings through the amplification of NO/cGMP pathway. It may augment both basal endothelial NO function and exogenous NO-dependent vasodilatation. However, sildenafil may act by a mechanism independent of NO/cGMP pathway and this mechanism contributes to its smooth muscle relaxant effect.

Comparative effects of sildenafil, phentolamine, yohimbine and L-arginine on the rabbit corpus cavernosum.

Penile erection involves relaxation of smooth muscle of corpus cavernosum and associated arterioles. Sildenafil, a highly selective inhibitor of phosphodiesterase type 5, is effective in the treatment of erectile dysfunction. The aim of this study is to investigate the effect of sildenafil on smooth muscle of the rabbit corpus cavernosum (RCC) and to compare its effect with those of phentolamine, yohimbine and L-arginine. The effects of sildenafil, phentolamine, yohimbine and L-arginine were studied on the response of the RCC to electrical field stimulation (EFS) as well as on the phenylephrine (PE, 3 x 10(-6) M)-induced tone. EFS caused transient, frequency-dependent relaxation of the RCC that was inhibited by the nitric oxide synthase inhibitor NG-nitro-L-arginine (3 x 10(-5) M). Sildenafil (1 x 10(-9)-1 x 10(-6) M) and phentolamine (1 x 10(-9)-1 x 10(-6) M) enhanced the EFS-induced relaxation in a concentration-dependent manner with ED50 of 0.056 +/- 0.004 and 0.572 +/-0.035 microM at 8 Hz, respectively, yohimbine (3 x 10(-7)-3 x 10(-5) M) and L-arginine (3 x 10(-6)-3 x 10(-4) M) did not show significant effects (ED50 at 8 Hz = 35.84 +/-2.24 and 2.164 +/- 0.174 microM, respectively). Sildenafil (1 x 10(-9) and 1 x 10(-8) M) potentiated the EFS-induced relaxation caused by L-arginine (3 x 10(-5) m). Sildenafil, phentolamine, yohimbine and L-arginine reduced the PE-induced tone to different extents; the ED50 values were 0.81 +/- 0.097, 0.49 +/- 0.025 and 13.97 +/- 1.10 microM, respectively. Maximum concentration of L-arginine used failed to produce 50% relaxation (ED20 = 221.82 +/- 15.71 microM). The muscle relaxant effects of different combinations of sildenafil and L-arginine on PE-induced tone did not differ significantly from the sum of the individual effects. The results demonstrate that sildenafil, when compared to other drugs used in penile erection dysfunction, shows the highest potency on the nitrergic transmission in the RCC. On the other hand, phentolamine was found to possess the highest potency in inducing relaxation of RCC proving that its action is independent on the stimulated neurogenic system. In addition, the combination of less effective doses of sildenafil and L-arginine has a potential advantage on erectile functions. The importance of this combination remains to be solved clinically.

Synthesis of some new phenylthiocarbamoyl 2-pyrazolin-5-ones of pharmaceutical interest.

Thiocarbamoylation reaction of 3-methyl-2-pyrazolin-5-one (1a) with two equivalents of PhNCS, resulted in the formation of 1,4-di(alpha-phenylthiocarbamoyl)-3-methylpyrazolone 3, which underwent cleavage of the thiocarbamoyl group at position 4 when coupled with aromatic diazonium salts affording 4-arylhydrazono-1-phenylthiocarbamoylpyrazolone (4a-j). Reactions of 4a with chloroacetyl chloride, benzenesulphonyl chloride, piperidine and hydrazine hydrate, resulted in the formation of 8.

2-Pyrazolin-5-ones structurally related to certain analgesics and antipyretic drugs and their anti-inflammatory activity.

The anti-inflammatory activity of twenty six 2-pyraxolin-5-one derivatives (Ia-z) was studied using carrageenin induced paw edema in male albino rats. Compounds 1(1)-Ip exhibited moderate anti-inflammatory activity, while the rest were devoid of significant anti-inflammatory activity.

Synthesis and antibacterial testing of some new quinolines, pyridazinoquinolines and spiroindoloquinolines.

3-Dicyanomethylideneindole derivatives were involved in (i) ring expansion reactions in alcoholic piperidine to form new quinolines from which a new pyridazinoquinoline was synthesised; and (ii) formation of new spiroindoloquinolines by reactions with cyclohexanone and beta-tetralone. The suggested structures of the new products were confirmed by IR, 1H-NMR, 13C-NMR and mass spectral analyses. Some of the new derivatives were active against the bacteria Escherichia cell.

Aminoazoles in heterocyclic synthesis. Synthesis of some new pyrimidobenzimidazoles and pyrazolonopyridines as well as triazolo-, tetrazolo- and pyrazolo-pyrimidines of pharmaceutical interest.

The reactivity of 3-cinnamoylindole, 3-cinnamoylantipyrine and 1-(3-methyl-1-phenyl-5-pyrazolon-4 yl)-4-antipyrin-4-yl)-prop-2-ene-1- one(la-c) towards 2-aminobenzimidazole, 3-amino-1,2,4-triazole, 5-aminotetrazole monohydrate, 5-amino-3-phenylpyrazole and 3-amino-1-phenyl-2-pyrazolin-5-one to give the fused heterocycles 2a-c, 4a,b, 5a,b, 8a,b, and 10a-c has been investigated. Structures of the synthesized compounds were confirmed by both the analytical and the spectral data (IR, UV and 1H NMR).

Behaviour of hexahydrobenzodipyrazolones towards chloroacetylation, aminoalkylation, Grignard reagent and their antimicrobial activity.

Treatment of 2,3a,4,6,7a,8-hexahydrobenzo [1,2-c; 4,5-c] dipyrazole-3,7-dione (1) with chloroacetyl chloride gave the 2,6-bis (chloroacetyl) derivative (2), which on treatment with acetic anhydride pyridine afforded (3). Compound (2) when heated with pyridine afforded (1). Compound (1) underwent Mannich reaction with piperidine or morpholine and formaldehyde to give the 2,6-bis (piperidino or morpholinomethyl) derivatives (4a,b). Hydroxymethylation of (1) with formaldehyde gave the 2,6-bis (hydroxylmethyl) derivative (4), which on heating with piperidine afforded (4a), Reaction of 2,3a,4,6,7a,8-hexahydro- 2,6-bis (phenylsulphonyl) benzo [1,2-c; 4,5-c] dipyrazole-3,7-dione (7) with phenylmagnesium bromide gave dodecahydro-3,3,4a,7,7,8a-hexaphenyl-2,6- bis (phenylsulphonyl) benzo [1,2-c; 4,5-c] dipyrazole (8). Derivatives of hexahydrobenzodipyrazolone (9a-g) have been subjected to general screening for their antimicrobial activity.

Synthesis and antimicrobial activity of some new carbazoles, indazoles, quinolines, quinazolines and naphthalenes from 3-methyl-5-phenyl-6-benzylidene-2-cyclohexene-1-one.

Reaction of the title compound (1) with phenylhydrazine using the Fisher indole synthesis, resulted in the formation of the carbazole derivative (2). Condensation of (1) benzaldehyde afforded the 6-benzylidene derivative (3). Treatment of compound (3) with some hydrazines and hydrazides resulted in the formation of the indazoles (4). Michael addition of some active methylene components with (3) gave quinolines (5) and naphthalenes (7). The reaction of (3) with urea and thiourea gave the uraciles (6). The newly synthesized compounds were screened for antibacterial activity.

Synthesis of condensed heterocycles from 3-aryl-2,4-dicarbethoxy-5-methylcyclohexanones and their testing for antimicrobial activity.

Condensation of the title compounds (1) with hydroxylamine hydrochloride, hydrazines and/or aromatic amines resulted in the formation of the benzisoxazoles 2, oximes 3, indazolines 4 and beta-keto anilides 6. The oxime derivatives and anilides underwent cyclization to compounds 2. The interaction between 1 and thiourea gave the benzothiazines 7 and thiouracils 8. Compounds 8 on treatment with monochloroacetic acid gave the dioxo compounds 9, while their reaction with hydrazine hydrate afforded the hydrazino derivatives 10, which upon treatment with nitrous acid gave the azido or tetrazolo derivatives 11 and 12. Treatment of 1 with 2,3-diaminopyridine and/or 2-amino-3-hydroxy-pyridine gave the pyrimidoquinazolines 13 or 14. Some of the synthesized compounds were screened to test their antimicrobial properties.

Synthesis of certain heteroaryl-fused pyrimidines and pyridines and selena- and thia-diazoles with naphthyl substituent as potential antifungal agents.

A convenient route is reported for the synthesis of 1,2,3-selenadiazole, 1,2,3-thiadiazole, 1,2,4-triazolo[4,3-a]pyrimidine, tetrazolo[4,5-a]pyrimidine, benzimidazolo[1,2-a]pyrimidine and pyrazolo[3,4-b]pyridine derivatives in which the naphthyl nucleus is incorporated. The preliminary results of antifungal testing are reported.

Synthesis of some heterocycles of pharmaceutical interest.

The condensation of 2-aminobenzimidazole (2), 3-amino-1,2,4-triazole (3), 5-aminotetrazole (4), 1-phenyl-3-aminopyrazolone (5), 2-aminobenzothiazole (6) and 2-amino-5-ethylthiadiazole (7) with 3-aryl-2,4-dicarboethoxy-5-hydroxy-5-methylcyclohexanones (1) has been investigated. Oxazepines 19 and 21 has been obtained from 1 and o-aminophenol. Cyclization of the carboxanilides 22 with polyphosphoric acid (PPA) gave the phenanthridinecarboxylates 23, while the cyclization of the arylhydrazones 26 gave the cinnoline carboxylate 27. The structures of the hitherto unknown ring systems have been confirmed by analytical and spectral methods. Some of the synthesized compounds were screened to test their antimicrobial and antifungal properties.