Synthesis and reactions of some pyridazine derivatives

3,4-Diphenyl-5-cyanopyridazin-6-one 3 was prepared from the reaction of cyano-acetamide2 with benzilhydrazone in dry pyridine. A series of its derivatives was prepared. Tolyl and benzene sulphonyl derivatives6a and6b are also prepared. 3,4-Diphenyl-5-cyano-pyridazin-6-thione5 was obtained from3 by the action of P₂S₅ while 3,4-diphenyl-5-cyano-6-chloropyridazine4 was obtained from3 by the action of POCl₃. The reaction of4 with hydrazine hydrate directly afforded the pyrazolopyridazine derivative7. Compound4 also reacted with phenylhydrazine, aniline, thiophenol and anthranilic acid to yield pyridazine derivatives8, 9, 10 and11, respectively. On treatment of compound11 with acetic anhydride it cyclised to afford pyridazino pyrimidine derivatives12.     

Activated nitriles in heterocyclic synthesis: Syntheses of thiazole,pyrazole and 4H-1,4-benzothiazine derivatives

4-Arylazo-3-phenyl-5-aminopyrazoles (5a,b) and substituted hydroxythiazoles8a,b were synthesized from the reaction of4a,b with hydrazine hydrate and mercaptoacetic acid respectively. Compounds5a,b and8a,b were also obtained from coupling of2a,b with6 and7, respectively. 4H-1,4-Benzothiazine11 was prepared from1 and10. The reaction of the diazonium salts2a-c with diethyl 3-amino-2-cyanopent-2-en-1,5-dicarboxylate12 was also reported.     

Synthesis and antitumor evaluation ofcis-(1,2-diaminoethane) dichloroplatinum (II) complexes linked to 5- and 6-methyleneuracil and-uridine analogues

The search for platinum (II)-based compounds with improved therapeutic properties was prompted to design and synthesize a new family of water-soluble, third generation cis-diaminedichloroplatinum (II) complexes linked to uracil and uridine. Six heretofore unreported uracil and uridine-platinum (II) complexes are; [N-(uracil-5-yl-methyl)ethane-1,2-di-amine]dichloroplatinum (II) (3a), [N-(uracil-6-yl-methyl)ethane-1,2-diamine] dichloroplatinum (II) (3b), {[N-(2′,3′,5′-tri-O-acetyl)uridine-5-yl-methyl] ethane-1,2-diamine}dichloroplatinum (II) (6a), {[N-(2′,3′,5′-tri-O-acetyl) uridine-6-yl-methyl]ethane-1,2-diamine}dichloroplatinum (II) (6b), [N-(uridine-5-yl-methyl)ethane-1,2-diamine]dichloroplatinum (II) (7a), [N-(uridine-6-yl- methyl)ethane-1,2-diamine]dichloroplatinum (II) (7b). These analogues were prepared from the key starting materials, 5-chloromethyluracil (1a) and 6-chloromethyluracil (1b) which were reacted with ethylenediamine to afford the respective 5-[(2-aminoethyl)amino] methyluracil (2a) and 6-[(2-aminoethyl)amino]methyluracil (2b). The cis-platin complexes3a and3b were obtained through the reaction of the respective2a and2b with potassium tetrachloroplatiate (II). The heterocyclic nucleic acid bases1a and1b were efficiently introduced on the β-D-ribose ring via a Vorbruggen-type nucleoside coupling procedure with hexamethyldisilazane, trimethylchlorosilane and stannic chloride under anhydrous acetonitrile to yield the stereospecific β-anomeric 5-chloromethyl-2′,3′,5′-tri-O-acetyluridine (4a) and 6-chloromethyl-2′,3′,5′-tri-O-acetyluridine (4b), respectively. The nucleosides4a and4b were coupled with ethylenediamine to provide the respective 5-[(amino-ethyl)amino]methyl-2′,3′,5′-tri-O-acetyluridine (5a) and 6-[(aminoethyl)amino] methyl-2′,3′,5′-tri-O-acetyluridine (5b). The diamino-uridines5a and5b were reacted with potassium tetrachloroplatinate (II) to give the novel nucleoside complexes,6a and6b, respectively which were deacetylated into the free nucleosides,7a and7b by the treatment with CH₃ONa. The cytotoxic activities were evaluated against three cell lines (FM-3A, P-388 and J-82) and none of the synthesized compounds showed any significant activity.     

Synthesis of several new isoxazole,imidazo[1,2-a]pyridine,imidazo[1,2-a]pyrimidine,benzoxadiazine and benzothiazine derivatives from hydroximoyl halides

Furoylhydroximoyl chloride3 reacted with 2-aminopyridine, 2-aminopyrimidine,O-aminophenol,O-phenylenediamine and aminothiophenol to afford imidazo[1,2-a]pyridine6, imidazo[1,2-a]pyrimidine8, benzoxadiazine10, nitrosobenzopyrazine13a and nitrosobenzothiazine13b, respectively. Isoxazoline18 and pyrrolidino[3,4-d]isoxazolin-4,6-dione derivatives19a and19b obtained by the reaction of3 with acrylonitrile and N-arylmaleimide. Hydroximoyl chloride3 reacted with thiophenol and sodium benzenesulfinate to yield furylglyoxaloxime16a and16b, respectively. Hydroximoyl chloride3 reacted also with some active methylene compound to give isoxazole derivatives20–23, respectively.     

Investigation of the reaction of 6-amino-3-methyl-4-oxo-3,4-dihydro-2-pyrimidinylhydrazine

The hydrazine derivative2 has been utilized for the synthesis of three different fused 1,2,4-triazolo [4,3-a] pyrimidine derivatives4, 5 &6 and a tetrazolo[1,5-a] pyrimidine derivative7. Reaction of2 with the chalcone analogue 2-thenylidene-2′-acetothienone, gave the pyrazoline derivative8.     

Synthesis of a series ofcis-diamminedichloro-platinum (II) complexes linked to uracil and uridine as candidate antitumor agents

The search for platinum (II)-based compounds with improved therapeutic properties was prompted to design and synthesize a new family of water-soluble, third generation cis-diamminedichloroplatinum (II) complexes linked to uracil and uridine. Six heretofore undescribed uracil and uridine-platinum (II) complexes are; [N-(2-aminoethyl)uracil-5-carboxamide]dichloroplatinum (II) (3a), [N-(2-aminoethyl)uracil-6-carboxamide]dichloroplatinum (II) (3b), [5-(2-aminoethyl)carbamoyl-2′,3′,5′,-tri-O-acetyluridine] dichloroplatinum (II) (6b), [5-(2-aminoethyl) carbamoylu-carbamoyl-2′,3′,5′,-tri-O-acetyluridine] dichloroplatinum (II) (6b), [5-(2-aminoethyl)carbamoyluridine]dichloroplatinum (II) (7a), [6-(2-aminoethyl)carbamoyluridine]dichloroplatinum (II) (7b). These analogues were prepared from the key starting materials, 5-carboxyuracil (1a) and 6-carboxyuracil (1b) which were reacted with ethylenediamine to afford the respective N-(2-aminoethyl)uracil-5-carboxamide (2a) and N-(2-aminoethyl)uracil-6-carboxamide (2b). The cisplatin complexes3a and3b were obtained through the reaction of the respective2a and2b with potassium tetrachloroplatinate (II). The heterocyclic nucleic acid bases1a and1b were efficiently introduced on the β-D-ribose ring via a Vorbruggen-type nucleoside coupling procedure with hexamethyldisilazane, trimethylchlorosilane and stannicchloride under anhydrous acetonitrile to yield the stereospecific β-anomeric 5-carboxy-2′,3′,5′-tri-0-acetyluridine (4a) and 6-carboxy-2′,3′,5′-tri-0-acetyluridine (4b), respectively. The nucleosides4a and4b were coupled with ethylenediamine to provide the respective 5-(2-aminoethyl)carbamoyl-2′,3′,5′-tri-0-acetyluridine (5a) and 6-(2-aminoethyl)carbamoyl-2′,3′,5′-tri-0-acetyluridine (5b). The diamino-uridines5a and5b were reacted with potassium tetrachloroplatinate (II) to give the novel nucleoside complexes,6a and6b, respectively which were deacetylated into the free nucleosides,7a and7b by the treatment with CH₃ONa. The antitumor activities were evaluated against three cell lines (K-562, FM-3A and P-388).     

The synthesis and antimicrobial activities of some 1,4-naphthoquinones (II)

In order to evaluate the antimicrobial effect of 2,3-disubstituted-1,4-naphthoquinone derivatives we newly synthesized several 2-chloro and 2-bromo-3-(substituted)-1,4-naphthoquninones. Amination reaction of 2,3-dihalo-1,4-naphthoquinones with aryl and aliphatic amines in ethanol gave 2-halo-3-(N-alkyl or N-aryl)-1,4-naphthoquinone derivatives (1a,b–10a,b) in 60%–90% yield. These derivatives subjected to antibacterial and antifungal activities,in vitro, againstBacillus subtilis ATCC 6633, Candida albicans 10231 and local, Pseudomonas aeruginosa NCTC10490, Staphylococcus aureus ATCC 6538p, Escherichia coli NIHJ, Aspergillus niger KCTC 1231. Tricophyton mentagrophytes KCTC 6085. Among these derivatives,1b, 6b and7a showed the potent antibacterial activities.1b, 8b and9b have the antifungal activities.1b is most effective in preventing the growth ofBacillus subtilis and Pseudomonas aeruginosa, Candida albicans, Aspergillus niger. Tricophyton mentagrophytes. The several of these compounds demonstrated a broad spectrum of activitiesin vitro.     

Synthesis and antiviral activity of 2′-fluorohexopyranosyl nucleosides

2′-Fluorohexopyranosyl nucleosides1a and1b which contained a bioisosteric double bond and a fluorine were synthesized in 12 steps, starting from D-galactose. During diethylaminosulfur trifluoride (DAST) fluorination, retention of stereochemistry was observed through the participation of methoxy or chloro group at the 6-position of the purine base. The final nucleosides1a and1b were found to be inactive against HIV-1 and HSV-1,2.     

Ketoketene gem-dithiols: Synthesis of some sulphur heterocycles as antimicrobial agents

A convenient method for the preparation of N-aryl thiazolines4a,b, 2,2-dichlorothiophene5, thiazolinones6 and8, and 2,6-dihydrothiopyran 2-thione9 derivatives is described. This depends on interaction of 3,3-dimercapto-1-(4-biphenyl)-2-propen-1-one1 with dichloroethane, amines, trichloroacetylchloride, chloroacetamide, ethylene oxide and epichlorohydrin. Antimicrobial activity of the obtained products was studied.     

A facile synthesis of some 3-cyano-1,4,6-trisubstituted-2(1H)-pyridinones and their biological evaluation as anticancer agents

The synthesis of some new 3-cyano-1,4,6-trisubstituted-2(1H)-pyridinones supported with various pharmacophores and functionalities at positin-1 is described. The in vitro anticancer activity of 24 of the newly synthesized compounds was evaluated according to the protocol of the NCI in vitro disease-oriented human cells screening panel assay. The results revealed that five compounds 4a–c, 7b, and 12b were able to display moderate antitumor potential against some of the tested subpanel tumor cell lines at the GI₅₀ and TGI levels, however, with marginal or no cytotoxic (LC₅₀) activity. The obtained data suggested that better antitumor activity was linked to derivatives with either 4-bromophenyl or 3,4-dimethoxyphenyl moieties, together with a 1-methyl-1H-pyrrol-2-yl counter part at positions 6 and 4, respectively. Consequently, the 3-cyano-4-(1-methyl-1H-pyrrol-2-yl)-6-(4-bromophenyl or 3,4-dimethoxyphenyl)-2(1H)-pyridinones 4a and 4b, could be considered as the most active members identified in this investigation as evidenced from their relative higher growth inhibitory (GI₅₀ (MG-MID) 77.6 and 67.6 μM, respectively) and cytostatic (TGI (MG-MID) 85.1 and 95.5 μM, respectively) activities, when compared with the substituted thiocarbamoyl analog 7b and the bicyclic [1,2,4]triazolo[3,4-a]pyridine derivative 12b.     

Antiangiogenic and growth inhibitory effects of synthetic novel 1, 5-diphenyl-1,4 pentadiene-3-one-3-yl-ethanone pyridine curcumin analogues on Ehrlich ascites tumor in vivo

In the present investigation we have synthesized novel substituted dienone pyridine ethanone curcumin analogues 3a and 3b by nucleophilic substitution reactions with 2-bromo-1-pyridine-3-yl ethanone and characterized by ¹H nuclear magnetic resonance (NMR), infrared IR, mass, and CHNS analysis. The compounds demonstrated tumor growth inhibition and antiangiogenic effects against mouse Ehrlich ascites tumor in vivo and suppressed neovascularization in a chorio allantoic membrane model.     

One pair of new cyclopentaisochromenone enantiomer from Alternaria sp. TNXY-P-1 and their cytotoxic activity

One pair of new cyclopentaisochromenone derivatives, (+)-(S)-6-hydroxy-1,8-dimethoxy-3a-methyl-3,3a-dihydrocyclopenta[c]isochromene-2,5-dione (1a) and (-)-(R)-6-hydroxy-1,8-dimethoxy-3a-methyl-3,3a-dihydrocyclopenta[c]isochromene-2,5-dione (1b), together with seven known analog 2?8, were isolated from a rice solid culture of the endophytic fungus Alternaria sp. TNXY-P-1, obtained from fresh leaf of Arisaema heterophyllum. Their structures were elucidated on the basis of detailed 1D, 2D NMR, and HRESIMS analysis. Among them, compounds 1a and 1b were enantiomers separated from 1 by chiral HPLC. The absolute configurations of 1a and 1b were assigned by quantum chemical calculations of the electronic circular dichroic spectra. All isolated compounds were evaluated for cytotoxic activities. Interestingly, enantiomers (+)-1a and (?)-1b showed distinct selective antitumor activities against HL-60 cell lines with IC₅₀ values of >200, 75.3 μM, respectively.     

Isolation of 3-O-(4′-Hydroxybenzyl)-β-sitosterol and 4-[4′-(4″-Hydroxybenzyloxy)benzyloxy]benzyl methyl ether from fresh tubers ofGastrodia elata

Two new 4-hydroxybenzyl alcohol derivatives (1 and2) were isolated from the methanol extract obtained from fresh tubers ofGastrodia elata together with 4-hydroxybenzyl methyl ether, 4-hydroxybenzyl alcohol, bis(4-hydroxyphenyl)methane, 4-hydroxybenzaldehyde, β-sitosterol and palmitic acid.1 and2 were identified as 3-O-(4′-hydroxybenzyl)-β-sitosterol and 4-[4′-(4″-hydroxybenzyloxy) benzyloxy)benzyl methyl ether, respectively, according to the spectroscopic data.     

Potential antitumor α-methylene-ψ-butyrolactone-bearing nucleic acid bases. 2. Synthesis of 5′-methyl-5′-[2-(5-substituted uracil-1-yl)ethyl]-2′-oxo-3′-methylenetetrahydrofurans

Ten, heretofore unreported, 5′-methyl-5′-[2-(5-substituted uracil-1-yl)ethyl)]-2′-oxo-3′-methylenetetrahydrofurans (H, F, Cl, Br, I, CH₃, CH₃, CH₂CH₃, CH=CH₂, SePh) (7a-j) were synthesized and evaluated against four cell lines (K-562, FM-3A, P-388 and U-937). For the preparation of α-methylene-γ-butyrolactone-linked to 5-substituted uracils (7a-j), the convenient Reformasky type reaction was employed which involves the treatment of ethyl α-(bromomethyl)acrylate and zinc with the respective 1-(5-substituted uracil-1-yl)-3-butanone (6a-j). The 5-substituted uracil ketones (6a-j) were directly obtained by the respective Michael type reaction of vinyl methyl ketone with the K₂CO₃ (or NaH)-treated 5-substituted uracils (5a-j) in the presence of acetic acid in the DMF solvent. The α-methylene-γ-butyrolactone compounds showing the most significant antitumor activity are7e, 7f, 7h and7j (inhibitory concentration (IC₅₀) ranging from 0.69 to 2.9 μg/ml), while7b, 7g and7i have shown moderate to significant activity. The compounds7a, 7c and7d were found to be inactive. The synthetic intermediate compounds6a-j were also screened and found marginal to moderate activity where compounds6b and6g showed significant activity (IC₅₀:0.4∼2.8 μg/ml).     

Regioselective synthesis of [1]benzopyrano[4,3-c]pyrazol-4-(1H)-one and [1]benzopyrano[3,4-c]pyrazol-4(3H)-one derivatives

The cycloaddition reaction of N-phenyl-C-cinnamonitrilimine4 to coumarin leads to the formation of 3-styrylbenzopyrano[4,3-c]pyrazole derivative6, whereas 3-phenylsulfonylcoumarin 0163 0181 V 39 or 3-bromocoumarin10 or 3-cyanocoumarin11 gives 1-styrylbenzopyrano[3,4-c]pyrazole derivative7. Also, the cycloaddition of4 to 3-acetylcoumarin15 and 3-benzoylcoumarin16 gives the corresponding dihydropyrano[3,4-c]pyrazole adducts17 and18 respectively. Oxidation of17 and18 gives7.     

Microbial transformation and bioactivation of isoflavones from <Emphasis Type="Italic">Pueraria</Emphasis> flowers by human intestinal bacterial strains

The flowers from Pueraria, which are called Puerariae Flos, have been used since ancient times for recovery from alcohol intoxication. We elucidated the microbial transformation of the main isoflavones (1, 1a and 2) by using 29 commercially available human intestinal bacterial strains together with the bioactivation of the hepatoprotective activity of their metabolites. Tectoridin (1a), which contains only one glucosyl moiety, was metabolized to its aglycone 1b by various bacterial strains. On the other hand, the metabolism of 1 and 2, which both have disaccharide groups, was limited to specific bacterial strains. The metabolites 1c and 2c obtained from the Peptostreptococcus productus strain were completely different from those produced by the other strains. These metabolites were identified as 6-hydroxygenistein and 6-hydroxybiochanin A, respectively. The glycosides 1, 1a and 2 did not show any hepatoprotective activity, whereas aglycones 1b and 2b showed moderate activity. Furthermore, the hepatoprotective activity of the demethylated metabolites 1c and 2c was extremely potent. Although not all people have P. productus in their gastrointestinal tract, the O-demethylated compounds might become one of the bioactivated metabolites when Puerariae Flos is administered orally.     

Synthesis and Anti-proliferative Activity of 2-Hydroxy-l,2-dihydroacronycine Glycosides

Purpose. Combination of the acronycine pharmacophore with various sugar units appeared of interest, since numerous anticancer agents possess a sugar moiety, which strongly influence both their bioavailability and their selective toxicity towards tumor cells. Methods. A series of 2-hydroxy-1,2-dihydroacronycine glycosides were synthetized, by condensation of the racemic aglycone with appropriate glycoside donors. Their effect on the inhibition of L1210 cell proliferation were evaluated. Results. Compounds 6a, 6b, 11a, 11b, and 12a, 12b, including a halogenated sugar moiety displayed activities of the same order of magnitude as acronycine itself. Compounds 7a, 7b, and 8a, 8b, bearing a 2,3,6-trideoxy-3-azido-L-lyxo- and L-arabino-hexopyranose unit respectively, were significantly more potent than acronycine in inhibiting cell proliferation. Conclusions. The activity of 2-hydroxy-1,2-dihydroacronycine glycosides seems to be related to the lipophilicity of the sugar unit.     

Isolation and structure elucidation of halymeniaol,a new antimalarial sterol derivative from the red alga Halymenia floresii

A new mono-hydroxy acetylated sterol derivative: 12β-hydroxy-3β, 15α, 16β-triacetoxy-cholest-5-en-7-one (halymeniaol) (1), and cholesterol (2) were isolated from the marine red alga Halymenia floresii. The structure of the compound 1 (halymeniaol) was established from its spectral data, derived from HRMS/MS and 2D NMR. Compound 1 exhibited growth inhibitory activity against chloroquine-resistant Plasmodium falciparum 3D7 strain with an IC₅₀ of 3.0 μM.     

A modified alkaline hydrolysis of total ginsenosides yielding genuine aglycones and prosapogenols

To improve the yield of genuine aglycones from glycosides, the conditions of alkaline hydrolysis were investigated, and a modified method was established. The modified method employed pyridine as an aprotic solvent. To complete the hydrolysis and obtain 20(S)-protopanaxadiol (1) and 20(S)-protopanaxatriol (2), which are the genuine aglycones of ginsenosides, total ginsenosides were refluxed with sodium methoxide in pyridine. Addition of methanol, a protic polar solvent to the reaction mixture, led partial hydrolysis yielding a mixture of the genuine prosapogenols. Of the prosapogenols compound3 and6 characteristically possessed D-glucopyranosyl moiety attached at the sterically hindered C-20 hydroxyl group.3 and6 were not obtained by other hydrolysis methods except by the soil bacterial hydrolysis.     

Design and synthesis of some thiazolotriazolyl esters as anti-inflammatory and analgesic agents

In order to develop potent analgesic/anti-inflammatory compounds with reduced ulcerogenic risk, a series of thiazolotriazolyl-carboxylic and acetic acid esters were synthesized and characterized by spectral and elementary analysis. All synthesized compounds were screened for in vivo anti-inflammatory activities in mice by carregeenan-induced paw edema model. The compounds showing 20% reduction in paw edema were also evaluated for their analgesic activities by acetic acid-induced writhing test and the gastric ulceration risk by determining the lipid peroxidation level in stomachs. Among the compounds tested, compounds 1, 4, 6, 7, 8, 1a, 2a, 3a, 4a, 7a, 2b, and 8b showed moderate-to-good anti-inflammatory activity at various doses in any of the measurement intervals. Compounds 7a, 2b, and 8b were the most actives of the series in analgesic activity test. Moreover, compounds 1, 4, and 8 were found to be safe in stomach in respect of free radical production.