Thioglycolic acid and pyrazole derivatives of 4(3H)-quinazolinone: synthesis and antimicrobial evaluation.

New derivatives of 4(3H)-quinazolinone were synthesized and evaluated for their antibacterial and antifungal activity. The derivatives are: 3-Aryl-2-[3-aryl-1-(carboxymethylthio)-3-oxopropyl)]-4(3H)-quinazolinones 2a-f; 3-Aryl-2-(3-aryl-1H-pyrazol-5-yl)-4(3H)-quinazolinones 3a-f; 3-Aryl-2-(1,3-diaryl-1H-pyrazol-5-yl)-4(3H)-quinazolinones 4a-f; 3-Aryl-2-(3-aryl-1-thiocarbamoyl-1H-pyrazol-5-yl)-4(3H)-quinazolinones 5a-f; 3-Aryl-2-[3-aryl-1-(carboxymethylthio)-3-hydroxyiminopropyl)]-4(3H)- quinazolinones 6a-f; and 3-Aryl-2-[3-aryl-1-(carboxymethy- lthio)-3-thiocarbamoyliminopropyl)]-4(3H)-quinazolinones 7a-f. Some of the tested compounds showed activity comparable to that of the standard references used.

Synthesis and 5-HT2A antagonist activity of derivatives of the novel heterocycles indolo[3,2-d]pyrrolo[3,2-g]azecine and benzo[d]pyrrolo[3,2-g]azecine compared to the benz[d]indolo[2,3-g]azecine derivative LE 300.

An indolo[3,2-d]pyrrolo[3,2-g]azecine and a benzo[d]pyrrolo[3,2-g]azecine analogue of the potent dopamine receptor antagonist LE 300 (7-methyl-6,7,8,9,14,15-hexahydro-5H-benz[d]indolo[2,3-g]azecine) have been prepared in multi-step reactions via C-N bond cleavage of corresponding quaternary N-methylquinolizinium iodides. LE 300, the target compounds and two precursor quinolizines have been tested in vitro for antagonist activity at 5-HT2A receptors (rat tail artery) and H1 receptors (guinea-pig ileum), respectively. LE 300 and compound 19 (3,6-dimethyl-4,5,6,7,8,13-hexahydro-3H-benzo[d]pyrrolo[3,2-g]azecine) competitively inhibited 5-HT-induced contractions with similar nanomolar potency (pA2 = 8.32 and 8.01, respectively) but were less active than the reference antagonist ketanserin (pA2 = 9.55). Compound 19 displayed moderate H1-antihistaminic activity in the guinea-pig ileum assay (pA2 = 7.37).

Polysubstituted pyrazoles, Part 4: Synthesis, antimicrobial and antiinflammatory activity of some pyrazoles.

As a continuation of an earlier interest in polysubstituted pyrazoles, the synthesis of some derivatives of 1H-pyrazol-4-yl-2-oxo-but-3-enoic acid and ethyl 4-hydroxy-1H-pyrazole-3-carboxylates of potential antimicrobial and antiinflammatory activity is described. One compound showed in vitro antibacterial activity and two compounds displayed in vivo antiinflammatory potency in rats.

Parasitic causes of hepatomegaly in children.

Three hundred children with hepatomegaly were selected. They were subjected to full clinical and laboratory examinations. Also serum samples were examined to detect IgG using ELISA against SEA, chromatography purified hydatid cyst antigen, commercially available Toxoplasma antigen, partially purified adult Fasciola antigen and second-stage larvae Toxocara canis antigen. IFAT was used to detect IgG against Toxoplasma and T. canis. A commercially available IHAT kit for leishmaniasis was used. Based on immunological assays, 125 cases were suffering from various parasitic infections. Thirty cases with schistosomiasis (10%), 26 cases fascioliasis (8.7%), 18 toxocariasis (6%), 35 toxoplasmosis (11.7%), 3 cases hydatidosis (1%) and 13 cases mixed parasitic infections. No parasitic causes could be found in 175 cases (58.3%). Moderate or marked hepatomegaly favours the presence of schistosomiasis. Whereas, most cases with other parasites and those with non-parasitic infections fall in the category of mild hepatic enlargement. There was no associated splenomegaly in cases with Fasciola, Toxocara, hydatid disease and/or the non-parasitic group. Most of hepatomegalic cases with non-parasitic causes were found to be associated with fever (88.5%). Fever was found in nearly 50% of cases with either Toxoplasma or Toxocara infections. Mild eosinophilia was found in all cases with parasitic causes. Only 24 cases of non-parasitic group (13.7%) had easinophilia. Moderate and high eosinophilia were found in cases with fascioliasis and toxocariasis. Cases with fascioliasis had a statistically significant increase in enzymes activities specially alkaline phosphatase. It was concluded that parasitic infections should be considered as an important cause of liver enlargement in children. Serological methods using purified antigenic fractions are an important tool for diagnosis.

Detection of Giardia antigen in stool samples before and after treatment.

A double antibody sandwich ELISA technique, using a chromatography purified Giardia antiserum, was applied to detect faecal antigen in patients infected with Giardia lamblia before and after treatment. The assay could detect antigens in 98% of infected cases with false positive reactions in 3 cases infected with E. histolytica. There was a significant direct relation between the antigen level in stool samples and the number of Giardia cysts. The mean level of copro-antigen was slightly lower in children, below 10 years, than in older patients, without significant difference. On the other hand, the lowest cyst count was noticed in elder patients, over 20 years. The level of faecal antigens decreased significantly after successful treatment in patients with giardiasis. It was concluded that detection of Giardia antigens by ELISA technique in the stool samples was a highly sensitive (98%) and specific (91%) diagnostic method. It is also considered as a good monitor for treatment success.

Treatment of schistosomiasis with praziquantel among school children.

This study, as a part of the drug resistance project, one of the activities of the schistosomiasis research project, was carried out in 3 villages in lower Egypt. Its main objective is to assess the praziquantel cure rate and to identify infected persons not responding to praziquantel treatment. Among the studied population, the prevalence of S. mansoni among school children (age 6 to 18 years) was 21.8%, 32.7% and 32.4% in the 3 villages respectively. Those who were found infected were treated with praziquantel (40 mg/kg body weight). The cure rate after six weeks was 75.8%, 83.9% and 72.7% among school children respectively. This cure rate among school children was less than that of adults by 5-10%. Compared with that of preschool age, it showed variable results. A second dose after 6-8 weeks was given to those who were still infected. Those who remained infected even after this second treatment, received a third dose of 60 mg/kg body weight. After the third treatment, only 5 patients of school age remained infected compared to one among adults and one among preschool age. The failure rate was found to be 50%, 18.5% and 12.5% among preschool, school children and adults respectively after the third treatment regimen.

Laboratory induced resistance to praziquantel in experimental schistosomiasis.

To study the effect of praziquantel (PZQ) on successive generations of S. mansoni worms, infected mice were treated 6 weeks after infection with different doses of PZQ (300, 500 mg/kg.), the schistosome strain was originally obtained from an infected Egyptian patient. The eggs subsequently produced by worms that had survived the PZQ treatment were used to infect snails and mice of the following generations. The results were expressed as average number of worms and cure rates in comparison with control groups. It was found that the use of PZQ., especially in low subcurative dose may lead to the development of resistance to therapeutic dose of the drug in following generations.

Low avidity antibodies in diagnosis of recent experimental schistosomal infection.

ELISA test was used to measure both of low- and high-avidity specific IgG against soluble S. mansoni egg antigen, to differentiate between S. mansoni experimentally infected mice with recent and chronic infection. Mice were infected with 100 S. mansoni cercariae and serum samples were obtained and tested 4, 6, 8, 10, 12, 14 and 16 weeks after infection. The results showed that there was a statistically significant difference between low- and high-avidity specific IgG in experimentally infected mice at 4, 6, 8, and 10 weeks after infection (recent infection). On the other hand, no difference was found in those with chronic infection (12, 14 and 16 weeks after infection). From these results it was concluded that the comparison of low- and high-avidity specific IgG levels was able to differentiate between recent and chronic experimentally infected mice with S. mansoni.

Assessment of praziquantel therapy in treatment of Schistosoma mansoni infection.

The present study is the first report of the epidemiological survey carried out as a part of the Praziquantel resistance project which is one of the projects of Schistosomiasis Research Project (SRP) in Egypt. The results of the study, which has been carried out in 3 villages, revealed that praziquantel is effective as an antischistosomal drugs and reduced egg count significantly. However at the end of the study some cases remained infected in spite of the three treatment regimens. Several factors can be responsible, among them is the presence of resistance strains, which will only be elucidated in the subsequent steps of the project, when identification of resistant strains in experimental animals will be carried out.

Non-steroidal anti-inflammatory agents: novel pyrazolyl-, 1,2-oxazolyl-, and 1,3-diazinyl derivatives of 4(3H)-quinazolinones.

Four novel series of 4(3H)-quinazolinone derivatives have been prepared by cyclization of the key intermediates 3-aryl-2-(3-aryl-3-oxopropenyl)-4-(3H)-quinazolinones with different reagents: 3-aryl-1-iminocarbamoyl-1H-pyrazol-5-yl)-4(3H)-quinazolines, 3-aryl-2-(3-aryl-1-thiocarbamoyl-1H-pyrazol-5-yl)-4(3H)-quinazolines, 3-aryl-2-(3-aryl-4,5-dihydro-1,2-oxazol-5-yl)-4(3H)-quinazolinones , and 3-aryl-2-(4-aryl-2-thioxo-1,2,5,6-tetrahydro-1,3-diazin-6-yl )-4(3H)- quinazolinones. The antiinflammatory activity of representatives of these compounds is comparable to or higher than that of proquazone.

Experimental schistomiasis: the effect of chemotherapy on concomitant immunity and resistance to reinfection.

To study the effect of chemotherapy on concomitant immunity, mice infected with Schistosoma mansoni were treated after either 8 or 16 weeks of primary infection and challnged at different periods after treatment. Results were compared with infected un-treated groups of mice. It was found that in mice treated 8 weeks after infection the degree of protection decreased gradually with time and 16 weeks after treatment no significant degree of protection was obtained. On the other hand, mice infected for 16 weeks prior to treatment showed higher degrees of protection and there was still significant degree of resistance to challenge infection after 16 weeks of treatment. It was concluded that in schistosomiasis mansoni there is a certain degree of resistance to reinfection after successful treatment of primary infection prior to treatment.

Alternate chemotherapy in experimental schistosomiasis.

Schistosoma mansoni infected mice were treated with a single oral dose of either praziquantel (400 mg/kg) or oxamniquine (100 mg/kg). The uncured mice, after the first dose, were given a second dose of the same drug or alternatively with the other drug. The drug efficacy was monitored by stool examination and egg count using Kato-thick smear technique. Praziquantel was found to be more effective, it gave 60% cure rate after the first dose, increased to 100% after the second dose, than oxamniquine which had 37% and 74% cure rates respectively. Furthermore, in uncured mice praziquantel resulted in more egg count reduction than oxamniquine. Treatment with the alternate drug of mice not cured with the first treatment gave 100% cure rate with praziquantel and 83% with oxamniquine. It was concluded that praziquantel is generally more effective than oxamniquine and cases not cured with a single dose of either drugs may be effectively treated with a second dose of the other.

Topical niclosamide as a protective agent against schistosome infection.

Niclosamide, as a semisolid pharmaceutical form suitable for external use, was used in 4 different concentrations (0.5%, 1%, 2% & 4%) to paint albino mice tails at different periods before exposure to infection with S. mansoni cercariae. Complete protection (100%) was achieved in all mice painted on the same day, the previous day and 3 days before exposure to cercariae irrespective to the niclosamide concentrations. Neither eggs nor worms were detected. Also, no pathological changes were found in livers, spleens or intestines of those mice. On the other hand, no protection against infection was achieved in mice painted with, 0.5% or 1%, 7 days before exposure to cercariae. Partial protection (25% and 40%) was gained in mice painted with 2% or 4% concentration of the drug respectively. It can be concluded that locally application of niclosamide as an ointment can completely prevent the infection with S. mansoni for three days. So, testing the promising drug for human trials to evaluate its efficacy specially for those at high risk is recommended.

Testicular changes in rats after Trichinella spiralis infection.

Infection of rats with Trichinella spiralis was found to be associated with testicular enlargement. A paucity of Leydig cells with marked oedema of interstitial areas were observed. Most of the seminiferous tubules were lined by spermatogonia and primary spermatocytes. T. spiralis larvae were not detected in the testes. Using the indirect immunoperoxidase procedure, T. spiralis antigen was detected as weak brown staining. The antigen was diffusely distributed in the cytoplasm of spermatogenic cells, Sertoli cells and focally around the tubular basement membrane of the infected rats. The significance of the results was discussed.

Synthesis, antimicrobial, inotropic, and chronotropic activities of novel 1,2,4-triazolo[4,3-a]quinolines.

Starting from the 2-quinolylhydrazine 1 the title compounds were prepared according to Schemes 1 and 2. Some of them show activities described in the title of this paper.

Interaction of butorphanol, with monoamine oxidase inhibitor, tranylcypromine.

This investigation examines the possibility of interaction between tranylcypromine and butorphanol in comparison to pethidine. The LD50 of pethidine and butorphanol were determined in mice pretreated with the non-selective monoamine oxidase (MAO) inhibitor, tranylcypromine orally for 8 days or with oral saline solution. Tranylcypromine decreased the LD50 of both pethidine and butorphanol by 78% and 41%, respectively. Anesthetized rabbits with halothane pretreated with tranylcypromine or saline were given pethidine (5 mg/kg i.v.) or butorphanol (0.5, 1 and 2 mg/kg i.v.). Pethidine produced a marked increase in blood pressure in rabbits pretreated with tranylcypromine and did not affect significantly the heart rate. Butorphanol did not affect either blood pressure or heart rate at doses of 0.5 or 1 mg/kg. However, the largest dose of butorphanol (2 mg/kg) produced hypotension and tachycardia in rabbits pretreated with tranylcypromine. Neither pethidine nor butorphanol affected the temperature of anesthetized rabbits pretreated with tranylcypromine or saline.

Synthesis of some thiazole-, 1,3,4-thiadiazole-, and 4H-1,2,4-triazole derivatives of pyrazolo[3,4-b]quinoline.

Three novel series of pyrazolo[3,4-b]quinolines were prepared, namely: 1-(3-substituted-4-phenylthiazolin-2-ylidene)hydrazinocarbonylm ethyl-1H-pyrazolo[3,4-b]quinolines 3a-d; 1-(5-substituted amino-1,3,4-thiadiazol-2-yl)methyl-1H-pyrazolo[3,4-b]quinolines 4b-d, and 1-(4-substituted-4H-5- thioxo-1,2,4-triazole-3-yl)methyl-1H-pyrazolo[3,4-b]quinolines 5a-d. These compounds were prepared by cyclization of the new key intermediates 1-(substituted thiocarbamoylhydrazinocarbonyl)methyl-1H- pyrazolo[3,4-b]quinolines 2a-d. The alkylthio, aralkylthio 6a-f as well as the Mannich bases 8a-f derived from compounds 5a-d were also prepared. The structures of the new compounds were elucidated by elemental analyses, IR, 1H-NMR-, and mass spectra. The antimicrobial as well as inotropic and chronotropic activities were studied.

Non-steroidal antiinflammatory agents. Synthesis of novel 2-pyrazolyl-4(3H)-quinazolinones.

Four novel series of pyrazolyl-4(3H)-quinazolinones have been prepared through the reaction of 3-aryl-2-hydrazino-4(3H)-quinazolinones with antipyrylazo-derivatives of ethyl acetoacetate, acetylacetone or diethyl malonate. These series of compounds are 3-aryl-2-[1-ethoxycarbonyl-1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H - pyrazol-4-yl)hydrazono-2-propylidene]hydrazino-4(3H)-quinazo linones; 3-aryl-2-[4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) hydrazono-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]-4(3H)-quinaz olinones; 3-aryl-2-[4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)azo -3,5- dimethyl-1H-pyrazol-1-yl]-4(3H)-quinazolinones and 3-aryl-2-[4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) hydrazono-3,5-dioxo-pyrazolidin-2-yl]-4(3H)-quinazolinones. The antiinflammatory activity of some representatives of the prepared compounds was studied.

Non-steroidal antiinflammatory agents, II: Synthesis of novel pyrazole and pyrazoline derivatives of 4(3H)-quinazolinone.

Antiinflammatory and/or analgesic activities have been ascribed to compounds containing the 4(3H)-quinazolinone or pyrazole moiety. Continuation to the previous work in the field of the synthesis of non-steroidal antiinflammatory 4(3H)-quinazolinones, the present investigation deals with the synthesis of new compounds having the pyrazole or pyrazoline and 4(3H)-quinazolinone moieties in one molecule, hoping that such combination might improve their antiinflammatory activity. alpha,beta-unsaturated ketones when treated with hydrazine hydrate achieve cyclization to the corresponding pyrazoline derivatives, whereas, when arylhydrazines are used, pyrazole derivatives are formed.

Synthesis of novel 2-substituted quinoline derivatives: antimicrobial, inotropic, and chronotropic activities.

Three novel series of quinoline derivatives have been prepared by cyclization of the intermediate 3-(1,3-dioxolan-2-yl)-2-substituted thiocarbamoyl-hydrazinoquinolines with different alpha-halocarbonyl compounds. These series are: 3-(1,3-dioxolan-2-yl)-2-(3-substituted-4-phenylthiazolin-2-y lidene) hydrazinoquinolines; 3-(1,3-dioxolan-2-yl)-2-(3-substituted-5-ethoxycarbonyl- 4-methylthiazoline-2-ylidene)hydrazinoquinolines and 3-(1,3-dioxolan-2-yl)-2- (3-substituted-4-thiazolidinon-2-yl)hydrazinoquinolines. The active methylene group of the latter series was used for the preparation of their arylidene derivatives. The antimicrobial as well as inotropic and chronotropic activities of the prepared compounds were studied.