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Respiratory infection is one of the infections that can be transmitted in closed places due to the ease of transmission of pathogens from infected people to healthy people through droplets from coughing and sneezing, among these bacterial causes, Haemophilus influenza. Therefore, this study aimed to evaluate the prevalence of this type of bacteria among pilgrims coming from different geographical locations in the world and determine the antibiotic-resistant strains. Around 1226 nasopharyngeal swabs were collected from 613 pilgrims from several different nationalities before and after completing the Hajj. These specimens were cultivated on chocolate agar medium and the pathogens were identified according to Clinical Laboratory Standards Institute (CLSI) protocol and confirmed by an automated system machine (VITEK2). There is no H. influenzae was detected among pilgrims before performing Hajj and the rate of transmission of H. influenzae was 1% after performing Hajj. The most effective antibiotics against to H. influenza isolates from pilgrims was Rifampicin while all the isolates were resistant to ampicillin. The continuous monitorization of the rate of potentially pathogenic bacterial during the Hajj season is required in order to develop advanced strategies to confront any outbreak of any infectious disease among the pilgrims. Key words: Hajj season, nasopharyngeal swabs, ethnic group, Makkah.

We report an efficient synthesis of 10b-azachrysenes and 10a-azaphenanthrene derivatives via the Hantzsch-like reaction of heterocyclic aldehydes and 2-(6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)acetonitrile with either dimedone or 3-aminocrotononitrile in acetic acid.

Objective: Coupling of ethyl 2-(6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)acetate 2 with diazotized anilines in ethanol in the presence of sodium acetate yielded 2-(2-arylhydrazono)-2-(6,7- dimethoxy-3,4-dihydroisoquinolin-1-yl)acetate (4a-f). Methods: Treatment of 2 with α-bromoketones 6a-f in dry benzene at reflux gave the corresponding isoquinolinium bromides 7a-f. Refluxing of each of the salts 7a-f in dry benzene and in the presence of triethylamine yielded 2-arylpyrrolo-[2,1-a]isoquinoline structures 8a-f, that converted to ethyl (E)-8,9- dimethoxy-3-(phenyldiazen-yl)-2-(aryl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-1-carboxylate (9a-f) upon treatment with diazotized anilines 3 in ethanol in the presence of sodium acetate. Results and Conclusion: Cytotoxic assay was performed for in vitro antitumor screening against caucasian breast adenocarcinoma (MCF7), hepatocellular carcinoma (HepG2) and colorectal carcinoma (HCT-116) cell lines. The results were compared with the standard anticancer drug (doxorubicin). Molecular docking using MOE 2014.09 software was carried out for the most potent compound 4d, which showed the highest binding affinity towards the four tested proteins and thus initiated apoptosis of cancer cells.

Reaction of ethyl 2-(2-((methylthio)carbonothioyl)hydrazono)propanoate (2) and ethyl 2-(2-carbamothioyl-hydrazono)propanoate (3) with hydrazonoyl halides 4a-e afforded the corresponding thiadiazole...

A novel series of 9,10-dihydro-3H-10a-azaphenanthrene-2,4-dicarbonitrile derivatives that contain a bridgehead nitrogen were prepared by a three-component reaction of aldehydes, 2-(6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)acetonitrile, and 3-aminocrotononitrile in acetic acid.

Compound 1 condensed with benzaldehyde to produce styryl pyrimidine 2. Pyridopyrimidines 5, 8 and 10 resulted from [4 + 2] cycloaddition (condensation) of 1 with malononitrile, ethyl cyanoacetate and/or ethyl acetoacetate. Compound 1 was also concerted to pyridopyrimidine 14 through multistep reaction (hydrolysis, chlorination, isothiocyanate formation and intramolecular cyclization). Bromopyrimidine 15 transformed into thiazolopyrimidine 17. Cyclization of bromomethyl pyrimidine 15 resulted in imidazolopyrimidine 19. Upon reacting the compound 15 with ammonium acetate resulted in amination affording the amino derivative 20. Oxazolopyrimidine 21 was obtained as the result of the reaction of compound 1 with chloroacetic acid and p-nitrobenzaldehyde. Compound 21 was transformed into pyridopyrimidine 23 and pyridopyrimidine of type 25 when reacted with cyanoacetamide and/or phenylhydrazine, respectively. All of the tested compounds showed good microbial activity against pathogenic microorganisms especially pyridopyrimidine derivative 21.

Arabian flora is a rich source of bioactive compounds. In this study, we investigated three aromatic plant species with the aim of finding valuable sources of antimicrobial agents against common pathogenic microorganisms. We focused especially on microorganisms, which cause outbreaks of infectious disease during mass gatherings and pilgrimages season in Saudi Arabia. The essential oils of three aromatic plant species were hydrodistilled from flowering aerial parts of Lavandula pubescens Decne. and Pulicaria incisa subsp. candolleana E.Gamal-Eldin, and from leaves, stems, ripe and unripe fruits of Juniperus procera Hochst. Ex Endl. They were subsequently analyzed by gas chromatography-mass spectrometry (GC-MS). The main constituents of L. pubescens were found to be carvacrol (55.7%), methyl carvacrol (13.4%), and β-bisabolene (9.1%). P. incisa subsp. Candolleana essential oil was rich in linalool (33.0%), chrysanthenone (10.3%), eugenol (8.9%), and cis-chrysanthenol (8.0%), the major components of J. procera essential oil were α-pinene (31.3–62.5%) and δ-3-carene (7.3–30.3%). These essential oils were tested against thirteen American Type Culture Collection (ATCC) strains of Gram-positive and Gram-negative bacteria using the agar diffusion assay. The only effective essential oil was that of L. pubescens and the most sensitive strains were Acinetobacter baumannii, Salmonella typhimurium, Shigella sonnei, Enterococcus faecalis and Staphylococcus epidermidis. Carvacrol, the major constituent of L. pubescens, was tested on these strains and was compared with vancomycin, amikacin, and ciprofloxacin. The Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) assays of L. pubescens essential oil and carvacrol revealed that Gram-negative strains were more susceptible than the Gram-positive ones.

We report an efficient synthesis of 4-aminotetrahydropyrazolo[3,4-b]quinolin-5-one derivatives via Friedländer-type reaction of dimedone with 5-aminopyrazole-4-carbonitriles in the presence of an acidic catalyst. We also report the synthesis of N-(1H-pyrazol-5-yl)- pyridine-3-carbonitrile via the reaction of pyrazol-5-ylcyanoacetamide with acetylacetone in the presence of basic catalyst.

A series of Schiff bases linked with heterocyclic moiety (6a–c, 7a–c, 11a–c, 12a–c, and 13a–c) and ferrocenyl Schiff bases (15a–c) were designed, synthesized, and confirmed based on the spectral data. Also, evaluations of their in vitro antibacterial and antifungal activities were performed and some Schiff bases (7a, 13a, b, and 15b) show moderate activities. Moreover, the physicochemical, pharmacokinetic, lipophilicity properties, druglikeness, ADME prediction, and toxicity properties of the newly Schiff bases (6a–c, 7a–c, 11a–c, 12a–c, and 13a–c) were predicted in silico. The results exhibited that some Schiff bases agree with druglikeness rules, inhibition of some CYP isoenzymes, and predicted as negative values on the carcinogenicity test. Also, all the Schiff bases exhibited more than 70% on the human intestinal absorption test, moderate permeation on the in vitro Caco-2 cell permeability test, and low permeability on the in vitro MDCK cell permeability test.

The prevalence of nosocomial infections due to multidrug resistant (MDR) bacterial strains is associated with high morbidity and mortality. Folk medicine and ethnopharmacological data can provide a broad range of plants with promising antimicrobial activity. Triphala, an Ayurvedic formula composed of three different plants: Terminalia chebula Retz., Terminalia bellirica (Gaertn.) Roxb. (Combretaceae), and Phyllanthus emblica L. (Phyllanthaceae), is used widely for various microbial infections. Various extraction techniques were applied in the extraction of the biologically active constituents of Triphala in order to compare their efficiency. Microwave-assisted extraction (MAE) was shown to be the most efficient method based on yield, extraction time, and selectivity. The Triphala hydroalcoholic extract (TAE) has been chemically characterized with spectroscopic and chromatographic techniques. Triphala hydroalcoholic extract was evaluated alone or with carvacrol. Different drug formulations including cream and nanoemulsion hydrogel were prepared to assess the antimicrobial activity against selected microorganism strains including Gram-positive and Gram-negative bacteria and fungi. We used a lipophilic oil of carvacrol (5 mg/mL) and a hydrophilic TAE (5 mg/mL) ingredient in a dosage form. Two solutions were created: hydrogel containing nanoemulsion as a lipophilic vector dispersed in the gel as a hydrophilic vehicle and a cream formulation, an oil-in-water emulsion. In both cases, the concentration was 250 mg of active ingredient in 50 mL of final formulation. The formulas developed were stable from a physical and chemical perspective. In the nanoemulsion hydrogel, the oil droplet size ranged from 124 to 129 nm, with low polydispersity index (PdI) 0.132 ± 0.013 and negative zeta potential −46.4 ± 4.3 mV. For the cream, the consistency factor (cetyl alcohol and white wax) induced immobilization of the matrix structure and the stability. Triphala hydroalcoholic extract in drug nanoformulation illustrated might be an adjuvant antimicrobial agent for treating various microbial infections.

Reaction of N,2-diaryldiazene-1-carbohydrazonoyl chlorides 1, 2 with 2-((methylthio)-carbonthioyl)hydrazones 7, 12 and 18–21 in absolute ethanol at room temperature in the presence of triethylamine afforded the corresponding 1,3,4-thiadiazole derivatives 10, 11, 13, 14 and 22–29. Stirring of N,2-diaryldiazene-1-carbohydrazonoyl chlorides 1–3 with thioanilides 31A–E in acetonitrile at room temperature in the presence of triethylamine gave the corresponding 1,3,4-thiadiazol-2(3H)-ylidene derivatives 34–36. The structures of all new compounds 10, 11, 13, 14, 22–29 and 34–36 were identified by elemental analysis and spectral data. Some new synthesized compounds were studied against Staphylococcus aureus and Escherichia coli and the most potent compounds were 3-phenyl-5-(phenyldiazenyl)-2-((1-(pyridin-2-yl)ethylidene)hydrazono)-2,3-dihydro-1,3,4-thiadiazole (13c), 2-((1-(pyridin-2-yl)ethylidene)hydrazono)-3-(p-tolyl)-5-(p-tolyldiazenyl)-2,3-dihydro-1,3,4-thia-diazole (14c) and 2-(benzo[d]thiazol-2-yl)-2-(3-(p-tolyl)-5-(p-tolyldiazenyl)-1,3,4-thiadiazol-2(3H)-ylidene)-acetonitrile (35C).

Reaction of N,N'-diphenyl-1,3-benzene-bis-carbohydrazonoyl bromide 3 with potassium thiocyanate, potassium selenocyanate, active methylene compounds and dipolarophilic alkenes were studied. Structu...

Depending on the reaction conditions, two alternative cyclizations are possible for [3 + 3] cyclocondensation of pyrazolone derivative 1a and ethyl cyanoacetate of type pyrano [2,3-c] pyrazol-6(1H)-one 2 and pyrano [2,3-c] pyrazol-4(1H)-one 3. Keeping of enaminic system 3 and benzylidene malononitrile in the presence of catalytic amount of trimethylamine resulted in pyridine cyclization affording pyrazolopyranopyridine derivative 4, not 5. The pyrazolone derivative 6a was obtained as a result of the acid-mediated addition reaction between compound 1a, urea and/or ammonium thiocyanate. In addition, the bispyrazolone of type 6b was obtained from the condensation reaction of urea and pyrazolone derivative. The spiro compound 7 was obtained from the double-addition reaction of pyrazolone to cinnamoyl isothiocyanate. A one-pot three-component condensation of a 3-hydroxybenzaldehyde, pyrazolone 1a, urea and/or thiourea under Biginelli conditions resulted in tetrahydropyrazolo pyrimidine derivatives 8a and 8b, respectively. The acid-mediated reaction of benzaldehyde and pyrazolone derivative 1a in the presence of Ac2O yielded styrylpyrazole derivative 9. The polyfunctionalized product 9 reacted with hydrazine to furnish pyrazolotriazoloe of type 10. Treatment of styrylpyrazole derivative 9 with aniline furnished the aniline derivative 11 and none of the expected polyheterocyclic derivative 12 was obtained. Compound 9 undergoes pyridine cyclization to produce 13 under the effect of urea. N-phenyl pyrazolone converted into pyrano-dipyrazolone derivative 14. Pyran of type 14 underwent a ring transformation upon treatment with urea and/or thiourea to give the same dipyrazolo pyrimidine derivative 15. The newly synthesized compounds were characterized by FT-IR, 1H-NMR, 13C-NMR, ESI/LC-MS and elemental analysis.

Novel tetrahydro-[1,2,4]triazolo[3,4-a]isoquinolin-3-yl)-3-arylprop-2-en-1-one derivatives were synthesized and their structures were confirmed by different spectral tools. Cytotoxicity test revealed that some compounds exhibited strong to moderate effect, while others showed weak action against different cancer cell lines (MCF7, A549, HCT116, and Hepg2). Breast carcinoma revealed higher sensitivity toward all derivatives especially compounds 5 and 8 which offered the lowest IC50 values (50.05, and 27.15 μg/ml) respectively, relative to the positive control 5-fluorouracil (5-FU) (IC50 = 178 μg/ml). In addition, the two compounds exhibited less toxic effect toward normal melanocytes (HFB4). Several theoretical and experimental studies were done to reveal the molecular mechanisms that control breast carcinoma metastasis using the two promising novels 5 and 8. Docking simulation studies against the two proteins EGFR and DHFR demonstrate that compound 8 showed higher binding affinity toward the two proteins more than compound 5, suggesting that trimethoxy groups may be responsible for this higher activity through the formation of five hydrogen bonding with the active domain (4r3r) and other four interactions with the active domain (1dls). Real time PCR assay illustrates that the two compounds up regulated BAX, p53, caspase-3 genes and down regulated BCL2, MMP1, CDK4 ones. In addition, it was noted that compound 8 was more effective in gene regulation and apoptotic induction than compound 5. Also, flow cytometer analysis demonstrates that both compounds 5 and 8 induced cell growth arrest at G1 phase and thus, inhibit G1/S transition and cell cycle progression. In addition, both compounds stimulate apoptotic death of breast cells significantly to reach 8.72%, and 17.28% respectively, compared to their control (0.55%). Apoptotic induction of breast cells was enhanced effectively through activation of caspase-3 by compound 8 using Elisa assay.

The target compounds 6,6′-(1,4-phenylenedimethylene)-bis(3-thioxo-1,2,4-triazin-5(1H)-one) 4,5 were prepared from reaction of oxazolone 1 with thiosemicarbazide and 4-phenylthiosemicarbazide, in potassium hydroxide solution, respectively. Reaction of 4 with hydrazonoyl halides 6 afforded triazolotriazine derivatives 7. Also, 5 reacted with 6 to give the corresponding substitution products 8. Antimicrobial and antitumor activities for some compounds were studied.

Background: Chalcones are naturally occurring compounds found in various plant species which are widely used for the traditional popular treatments. Chalcones are distinguished secondary metabolites that are reported to display diverse biological activities such as antiviral, antiplatelet, anti-inflammatory, anticancer, antibacterial and antioxidant agents. The presence of a,ß-unsaturated carbonyl group in chalcones is assumed to be responsible for their bioactivity. In addition, heterocyclic compounds having nitrogen such as isoquinolines are of considerable interest as they constitute the core structural element of many alkaloids that have enormous pharmacological activities. Objective: The objective of this study is the synthesis and biological activity of novel chalcones incorporating thiadiazolyl isoquinoline as potential anticancer candidates. Different genetic tools were used in an attempt to know the mechanism of action of this compound against breast cancer. Methods: An efficient one pot synthesis of novel chalcones incorporating thiadiazolyl isoquinoline has been developed. The cytotoxic activity of the novel synthesized compounds was performed against four different kinds of cancer cell lines. Results: Among all the tested derivatives, chalcone 3 has the best cytotoxic profile against A549, MCF7, and HeLa cell lines, with IC50s (66.1, 51.3, and 85.1μM, respectively). Molecular docking studies for chalcone 3 revealed that CDK2, and EGFRTK domains have strong binding affinities toward the novel chalcone 3, while tubulin-colchicine-ustiloxin, and VEGFRTK domains illustrated moderate mode of binding. Conclusion: We have developed an efficient method for the synthesis of novel chalcones incorporating thiadiazolyl isoquinoline. All compounds showed better cytotoxicity results against four kinds of cancer cell lines (A549, MCF7, HCT116, and HELA cells). The results depicted that chalcone 3 has a high and promising cytotoxic effect against HELA cell line and the mechanism of cytotoxicity was widely studied through different theoretical and experimental tools. Thus, the newly synthesized derivative 3 can be utilized as a novel chemotherapeutic compound for cervical carcinoma.

Reactions of bis-hydrazonoyl bromide 1 with each of phenyl-5-arylidene-2-thioxo-thiazol-4-one, triazinethiones and 4,6-dimethyl-2,6-dioxocyclohexane-1-thiocarboxanilide as sulfur dipolarophilic reagents led to the formation of the hitherto unreported 1,3-phenylene bis-heterocycles 4, 8 and 10, respectively. The structures of the isolated products were established on the basis of their elemental and spectral analyses. The mechanism and the site selectivity in the studied reactions are discussed.

Background:Isobutyrohydrazonoyl bromide 1 was used as a precursor for the synthesis of 4-imino-3-isopropyl-1-(4-nitrophenyl)-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-amine 4, which was converted into hydrazino derivative 5 by heating with hydrazine hydrate at reflux. Hydrazino, as well as imino-amino derivatives, underwent condensation and cyclization reactions to give pyrazolo[ 3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[3,4-c]pyrimidine derivatives, respectively.Method:Antimicrobial studies are performed using two-gram positive bacteria and two-gram negative bacteria.Results:Data revealed that compound 9a is the most promising antibacterial agent with high efficiency (low MIC value (48 μg/ml)). The cytotoxic assay was investigated for in vitro antitumor screening against Caucasian breast adenocarcinoma MCF7, hepatocellular carcinoma HepG2 and colon carcinoma HCT-116 cell lines.Conclusion:The results are compared with doxorubicin standard anticancer drugs as well as normal cell lines like MCF10 and MCF12. Molecular docking was carried out for the highest potent compound 8c with the binding site of dihydrofolate reductase enzyme DHFR PDB:ID (1DLS).

Two series of metronidazole derivatives (ester derivatives and ether derivatives) were prepared reacting metronidazole and its acetic acid oxidized form with menthol, thymol, carvacrol, and eugenol. Both series of compounds were tested in vitro against two strains of Helicobacter pylori (the ATCC 26695 and P12), and one strain of Clostridium (Clostridium perfringens). Most of the prepared compounds showed biological activity against the targeted bacteria. Compound 11 was highly active against all tested bacterial strains, especially against P12 with IC50 0.0011 μM/ml. Compound 6 was highly active against C. perfringens with MIC 0.0094 nM/ml. Viability test was conducted for compound 11 to test its selectivity for normal human fetal lung fibroblasts (MRC5), and it was found to be non-toxic with IC50 more than 50 μM/ml.

Bacteriocins are natural metabolites produced by many strains of Lactic acid bacteria that used in foodpreservation. They have potential healthy role in suppressing the growth of some spoilage andpathogenic bacteria. The aim of the current study was to demonstrate the stability of the bacteriocinextracted from Lactobacillus acidophilus at different pH values, heat treatments and proteinase Kenzyme. The obtained results revealed that the inhibitory effectiveness of bacteriocins was higher onGram-positive bacteria than Gram-negative bacteria. Further, the largest inhibition zone was obtainedby L. acidophilus bacteriocin against Bacillus subtilis while the smallest one was against E.coli. Theextracted bacteriocin exhibited broad spectrum of inhibition at concentration 6400AU/ml against Staph.aureus, Bacillus subtilis and E.coli. The antimicrobial activity of crude supernatant fluid was stableafter heating at 100°C for 30 min and declined thereafter. Stability of antimicrobial activity was observedat pH ranged from 2.0 to 8.0. Its active principle was proteinaceous in nature since the bacteriocin wasinactivated by proteinase K enzyme

Refluxing of (E)-5-amino-1-phenyl-3-styryl-1H-pyrazole-4-carbonitrile 2 with triethylor-thoformate in acetic anhydride afforded the corresponding formimidate 3. Treatment of 3 with hydrazine hydrate in ethanol afforded amino imino compound 4. Reaction of 4 with diethyl dicarbonate at reflux gave (E)-7-phenyl-9-styryl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine 7. Refluxing of 4 with hydrazine hydrate afforded (E)-4-hydrazinyl-1-phenyl-3-styryl-1H-pyrazolo[3,4-d] pyrimidine 8. Treatment of the latter compound 8 with aldehydes in boiling ethanol in the presence of acetic acid afforded the corresponding hydrazone 10. Oxidative cyclization of the hydrazone 10 led to the formation of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidine 11. The latter products re-arranged to pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines 13. The structures of the new products were established on the basis of elemental analysis and spectral data.

A new series of 4,4-dimethyl-2,6-dioxocyclohexane-thiocarboxamides were prepared by reaction of aryl isothiocyanate with dimedone. Reaction of N-aryl-4,4-dimethyl-2,6-dioxocyclohexane- thiocarboxamides with hydrazonoyl halides led to th e formation of the corresponding thiadiazoles. Treatment of 2-(5-acetyl-3-phenyl-1,3 ,4-thiadiazol-2(3 H)-ylidene)-5,5- dimethylcyclohexane-1,3-dione with dimethylformamide dimethylacetal (DMF-DMA) in refluxing dioxane afforded (E)-2-(5-(3-(dimethylamino)acryloyl)-3-phenyl-1,3,4-t hiadiazol- 2(3H)-ylidene)-5,5-dimethylcyclohexane-1,3-dione. Reaction of the latter enaminone with hydrazonoyl halides yielded the corresponding 2-(1- aryl-3-substituted-pyrazol-4-carbonyl)-5-(3- phenyl-5-(5,5-dimethylcyclohexane-1,3-dione)-(1,3,4)-thiadiazole) derivatives. The structures of the new compounds were elucidated on the basis of t heir elemental analyses and spectral data.

Herein, we report the first synthesis of 10b-azachrysenes via the Hantzsch-like reaction of aldehydes with 2-(6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)acetonitrile and dimedone in the presence of acetic acid. The regioselectivity was established using X-ray crystallography and 2D-HMBC spectroscopy.

The reaction of 1,2-dihydro-6-(phenylamino)-2-thioxopyrimidin-4(3H)one (16) with N-arylhydrazonoyl halides 15 in CHCl3 in the presence of Et3N under reflux afforded the corresponding 1,2,4-triazolo[4,3-a]pyrimidin-5-ones of type 20 in good yields (Scheme 3). The structure of one of the derivatives, 20d, has been established by X-ray crystallography. Conceivable reaction mechanisms are discussed in Schemes 3 and 4. The products of type 20 easily undergo reactions with electrophiles such as benzenediazonium chloride, chloroacetyl chloride, and NaNO2 in AcOH to give 6-phenylazo, 6-chloroacetyl, and 6-nitroso derivatives 21, 23, and 25, respectively (Scheme 5).

Phenacylmalononitriles 8a, 8b react with hydrazines under dry conditions to afford the pyrazole derivatives 9a, 9b, 9c, 9d and in refluxing dioxane to afford the pyrazolo[3,4-c]pyridazine derivatives 11a, 11b, 11c, 11d and the pyridazine-6-imine derivatives 12a, 12b, 12c, 12d. Compounds 12a, 12b were transformed into their oxo analogs 13a, 13b upon reflux in ethanolic HCl, whereas 12c, 12d were transformed into the furan derivatives 14a, 14b under the same reaction conditions (reflux in ethanolic HCl). Compounds 8a, 8b could be transformed directly into the benzoyl-pyrazole derivatives 16a, 16b, 16c, 16d upon coupling with diazotized aromatic amines in pyridine. The structures of the new compounds were substantiated by elemental analyses and spectral data as well as x-ray crystallographic analysis. Plausible mechanisms for the unexpected transformations are suggested.

(E)-2-Chloro-3-(2-cyanovinyl)-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrido[2,1-a] isoquinoline- 1-carbonitrile (5) was obtained by treatment of the 2-chloro-3-formylpyrido[2,1-a]isoquinoline derivative 3 with 2-(triphenylphosphoranylidene)acetonitrile (4). Treatment of 5 with sodium azide afforded the corresponding azido compound 6 which could be reduced by sodium dithionite to compound 7. A novel isoquinolino[2,1-g][1,6]naphthyridine derivative 11 was obtained by the reaction of phenyl isothiocyanate with the phosphorane compound 8, which was prepared by the reaction of compound 6 with triphenylphosphine. Treatment of 5 with amines 12a-c and thiophenols 14a-c in refluxing ethanol afforded the corresponding substitution products 13a-c and 15a-c, respectively. Also, the reaction of 1 with a-oxo hydroxamoyl chlorides 16 was reinvestigated, and the synthesized pyrazoloisoquinolines 19a-f and pyridazinopyrazoloisoquinolines 20a, e were screened for their in vitro antitumor activities.

Treatment of 6,7-diethoxy-3,4-dihydroisoquinoline (8) and its 1-methyl derivative 12 with hydrazonoyl halides 10 in the presence of Et3N in THF under reflux afforded the corresponding 5,6-dihydro-1,2,4-triazolo[3,4-a]isoquinolines 11 and 13, respectively, in high yield (Schemes 2 and 3). The products are formed via regioselective 1,3-dipolar cycloaddition of the intermediate nitrilimines 9 with the isoquinoline C=N bond. Reaction of 6,7-diethoxy-3,4-dihydroisoquinoline-1-acetonitrile (4a) with ethyl alpha-cyanocinnamates 15 in the presence of piperidine in refluxing MeCN yielded benzo[a]quinolizin-4-ones 16 (Scheme 4). Under the same conditions, 12 and arylidene malononitriles 19 reacted to give benzo[a]quinolizin-4-imines 20 (Scheme 5). Instead of 15 and 19, mixtures of an aromatic aldehyde, and ethyl cyanoacetate or malononitrile, respectively, can be used in a one-pot reaction.

Electrochemical corrosion behavior and hydrogen evolution reaction of 316L stainless steel has been investigated, in 0.5 M sulfuric acid solution containing four novel organic inhibitors as derivatives from one family, using potentiodynamic polarization, electrochemical impedance spectroscopy (EIS) measurements and surface examination via scanning electron microscope (SEM) technique. The effect of corrosion inhibitors on the hydrogen evolution reaction was related to the chemical composition, concentration and structure of the inhibitor. The inhibition efficiency, for active centers of the four used compounds, was found to increase in the order: –Cl

3-Acetyl[1,2,4]triazolo[3,4-a]isoquinolines were prepared using chitosan as a catalyst. These compounds were used to prepare a novel series of enaminones 5, and their reactions with hydrazonoyl halides 1 and 11 gave triazoloisoquinolines 8 and 13, respectively, with a carbonylpyrazole side chain. Hydrazinolysis of 8 and 13 gave the pyrazolopyridazines 10 and pyrazolopyridazinones 14. Reaction of 5 with hydroximoyl halides 15 led to triazoloisoquinoline 16 with a carbonylisoxazole side chain. Antibacterial effects of compounds 8 and 10 were studied.

Regioselective 1,3-dipolar cycloaddition of nitrilimines (generated in situ from dehydrohalogenation of the corresponding hydrazonoyl halides by the action of triethylamine) with 4-arylidene-1-aryl-2-phenyl-1H-imidazol-5(4H)-one 3 afforded the corresponding spiro[4,4]nona-2,8-dien-6-one 4. The reaction was carried out in dry benzene under reflux temperature. Refluxing in acetic acid, 4a was converted to its respective N-phenylpyrazole-5-carboxamide 8. The structures of prepared compounds were established by elemental analyses and spectral data (IR, MS, 1H, and 13C NMR). © 2011 Wiley Periodicals, Inc. Heteroatom Chem 22:131–136, 2011; View this article online at wileyonlinelibrary.com. DOI 10.1002/hc.20666

The reaction of 1-methylisoquinoline 1 with hy-drazonoyl halides 2 in ethanol in the presence of chitosan under microwave irradiation affords triazoloisoquinoline 4. Product 4 reacts with dimethylformamide-dimethylacetal to give ena- minones 7 which react with hydrazonoyl halides to give pyrazolyl triazoloisoquinoline 13. Also, 1-methylisoquinoline 1 reacts with arylisothio-cyanate to give thioanilide 15 which reacts with hydrazonoyl halides to give the corresponding thiadiazolyl isoquinoline derivatives 20, 24.

The coupling reaction of 3-cyanoacetyl-2-methylindole 1a with the aromatic diazonium salts gave the corresponding arylhydrazones 2a-e. Compounds 2 were used for synthesis of 4-aminopyrazole-5-carbonitrile 4a-e and 5-amino-4-arylazo-3-pyrazoles 5a-e derivatives. Also, treatment of 3-cyanoacetyl-2-phenylindole 1b with phenyl isothiocyanate gave the corresponding thioacetanilide 7. The later compound 7 was utilized as the key intermediate for the synthesis of some new thiadiazole derivatives 9a-r. The structures of all new compounds were elucidated on the basis of elemental analysis and spectral data.

Diazonium chlorides of 5-amino-3-methypyrazole 1a and 5-amino-4-phenylpyrazole 1b coupled with 1,3-indanedione 2 and led to the formation of acyclic hydrazone 3a and a cyclic product indenopyrazolotriazine 4b respectively. Cyclization of the hydrazone 3a by boiling in acetic acid afforded the corresponding 4a. The hydrazone 3a reacted with malononitrile in boiling ethanol in the presence of piperidine and gave indeno[2,1-c]pyridazine-4-carbonitrile derivatives 5a,b. Also, coupling of 6 with aryl diazonium chlorides gave the corresponding indenopyridazine derivatives 8a-e. Acetylation, benzoylation and hydrolysis of compound 8a afforded the corresponding substitution products 10-12, respectively. The structures of the newly synthesized compounds were established on the basis of chemical and spectral evidences.

Two series of aldose N-(3-substituted-4-oxo-3,4-dihydroquinazolin-2-yl)hydrazones were prepared by the reaction of each of the aldoses with the appropriate 2-hydrazino-3-substituted-quinazolin-4(3H)-ones. Oxidative cyclisation of these aldose hydrazones with ferric chloride in ethanol yielded the title acyclo C-nucleosides.

Hydrazonyl bromides 2a,b reacted with active methylene compounds (dibenzoylmethane, acetylacetone, ethyl acetoacetate, phenacyl cyanide, acetoacetanilide, ethyl cyanoacetate, cyanoacetamide and malononitrile) to afford the corresponding 1,3,4,5- tetrasubstituted pyrazole derivatives 5-12a,b. Reaction of 12a,b with formamide, formic acid and triethyl orthoformate give the pyrazolo[3,4-d]pyrimidine, pyrazolo[3,4- d]pyrimidin-4(3H)one and 5-ethoxymethylene-aminopyrazole-4-carbo-nitrile derivatives 13-15a,b, respectively. Compounds 15 a,b reacted with benzhydrazide and hydrazine hydrate to afford pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine and [4-iminopyrazolo- [3,4-d]pyrimidin-5-yl]amine derivatives 16 a,b and 17 a,b. Reactions of compounds 17 a,b with triethyl orthoformate and carbon disulfide give the corresponding pyrazolo[4,3-e]- [1,2,4]triazolo[1,5-c]pyrimidine derivatives 18a,b and 19 a,b, respectively.

Several 1,3-diaryl-5-(cyano-, aminocarbonyl- and ethoxycarbonyl-)-2-pyrazoline, pyrrolo[3,4-c]pyrazole-4,6-dione and 1,3,4,5-tetraaryl-2-pyrazoline derivatives were prepared by the reaction of nitrilimine with different dipolarophilic reagents. The new compounds were characterized using IR, (1)H-NMR, (13)C-NMR and mass spectra. Biological screening of some compounds is reported.

Azolopyrimidines are biologically interesting molecules as indicated by the large number of recent papers dealing with synthesis, chemistry, and pharmacology of these molecules [1 – 9]. For example, zaleplon (1), a pyrazolopyrimidine, is a hypnotic agent licensed for treatment of insomnia [10], and allopurine (2), a 4-hydroxypyrazolopyrimidine used in the treatment of hyperuricemia and gout, inhibits de novo purine biosynthesis and xanthine oxidase [11] (Fig. 1). The triazolopyrimidine trapidil and its derivatives are coronary vasodilating and potential antiatherosclerotic drugs [12 – 14]. Also, pyrimidobenzimidazoles have been found to be of pharmacological interest; for example, pyrimido[1,2-a]benzimidazoles have been described as anti-hypertensive [15], anti-diabetic [16] and anti-inflammatory [17].

Glyoxalbis(phenylhydrazone) 1a reacts with aromatic aldehydes and secondary amines to yield either propan-1,2-dialdiphenylhydrazones 2 or arylazopyrazoles 7 depending on the nature of utilised aldehyde. The reactivity of 1a with phosphorus oxychloride (POCl3) and dimethylformamide (DMF) (Vilsmeier reaction) afforded the cinnolin-3-carbaldehyde phenylhydrazone 11. Compound 1a afforded also the tribenzoyl derivative 16 on treatment with benzoyl chloride. Only the diacetyl derivative 17 was produced on refluxing 1a in acetic anhydride. The diphenylhydrazone 20 was produced on treatment of 19, prepared via coupling 18 with benzenediazonium chloride followed by phenylhydrazine. This cyclised into pyrazole 21 on reflux in acetic acid.

Hydrazidoyl halides 1a reacted with diethylphosphonoacetonitrile (2a) in sodium ethoxide to yield the hydrazine derivative 4a which readily cyclized to form the corresponding diazaphosphole 5 . The latter was hydrolyzed to form the final product 6, with the formation of a low yield of a second product 7a . Similarly 1b, c reacted with diethylphosphonoacetonitrile and triethylphosphonoacetate 2a, b to produce the corresponding diazaphospholes 6b–d . Interaction of hydrazidoyl halides 1b, d–g with Lawesson's reagent in dry toluene produced 1,3,4-thiadiazaphosphole derivatives 10b, d, e and 11f, g respectively.

2-Thioxopyrimidinyl-5-(N,N-dimethylamino)formamidine ( 5 ) and 1,3-diphenyltriazolo[3,4-d]pyrimidinyl-N,N-dimethylformamidine ( 14 ) were prepared by condensation of 6-amino-2-thioxo-1,3-dihydropyrimidin-4-one ( 2 ) and 7-amino-1,3-diphenyl-1,2,4-triazolo[4,3- a ]pyrimidin-4-one ( 13 ) with dimethylformamide dimethyl-acetal (DMFDMA). Compound 5 reacts with acetophenone and 2-acetylthiophene to give the 2-thioxo-1,3-dihydropyridino[2,3-d]pyrimidin-4-ones 3a and 3b, respectively. Compounds 3a,b react with hydrazonoyl halides 6,7 to give pyridino[2,3- d ]triazolo[4,5- a ]pyrimidin-4-ones 11a-d and not the isomeric structures 12a-d . Formamidines of type 14 react with ethyl cyanoacetate, malononitrile and benzoyl acetonitrile to give the 1,3-diphenyl-3a-hydropyridino[2,3- d ]1,2,4-triazolo[4,5- a ]pyrimidin-4-one derivatives 15a,b and 18 , respectively. The structures of the newly synthesized compounds are established on the basis of chemical and spectroscopic evidences as well as their synthesis by alternative methods.

A novel synthesis of thiadiazoline derivatives 12 and 14via treatment of indane-1,3-dione-2-thiocarboxanilides (5) with hydrazonoyl halides 1 and 2 is reported. Also, active chloromethylene compounds 15 react with 5 to give thiazole derivatives 19. © 2002 Wiley Periodicals, Inc. Heteroatom Chem 13:585–591, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10132

1-Methylisoquinoline 1 reacts with arylidine malononitrile 2 in the presence of piperidine to give the corresponding Michael adducts pyridinoisoquinolines 5. The structures of the products 5 were established on the basis of elemental and spectral analyses and studies of their chemical behaviours.

Sonogashira coupling of trimethylsilylacetylene with 4-alkyloxy-1-iodobenzenes gave 2-(4-(alkyloxy)phenyl)ethynyltrimethylsilanes which undergo deprotection via removal of TMS-group using tetrabutylammonium fluoride (TBAF) in THF at room temperature to afford the corresponding terminal 2-(4-(alkyloxy)phenyl)acetylenes. Regiocontrolled Sonogashira cross-coupling of 1,3,5-tribromobenzene with the terminal arylacetylenes in aqueous medium resulted in the formation of mono-, di- and tri-alkynylated benzene derivatives in moderate to good yields. Factors affecting the regioselective alkynylation were also examined. O acoplamento de Sonogashira do trimetilsililacetileno com 4-alcóxi-1-iodobenzenos resultou em 2-(4-(alquilóxi)fenil)etiniltrimetilsilanos, que sofrem desproteção pela retirada do grupo TMS usando fluoreto de tetrabutilamônio (TBAF) em THF à temperatura ambiente, resultando nos 2-(4-(alquilóxi)fenil)acetilenos terminais correspondentes. O acoplamento cruzado de Sonogashira do 1,3,5-tribromobenzeno com os arilacetilenos terminais em meio aquoso resultou na formação de derivados de benzeno mono-, di- e tri-alquinilados com rendimentos de moderados a bons. Os fatores que afetam a regiosseletividade da alquinilação também foram examinados.

Reactions of malononitrile derivatives of type (I) with hydrazine hydrate and phenyl hydrazine and some related reactions are described.

1,2-Dihydro-2-thioxopyrimidin-4(3H)ones 6 react with C-ethoxycarbonyl-N-arylhydrazonoyl chlorides 1 to give 1,2,4-triazolo[4,3-a]pyrimidines 11 in good yield. The latter products 11 react with benzenediazonium chloride, nitrous acid, acetyl chloride and chloroacetyl chloride to give the corresponding substitution products 16–18. The structures of the newly synthesized compounds are established on the basis of chemical and spectroscopic evidence.