Synthesis and pharmacological studies of some pyrone and benzodifuran derivatives

The michael adducts2a,b were obtained from the reaction of the phenylacetyl derivative1 with benzaldehyde and p-anisaldehyde respectively.2a and2b were subjected to react with cyanoethanoic acid hydrazide, malononitrile, cyanothioacetamide, cyanoacetamide and 1,1,3-tricyano-2-amino propene to yield4a-h and5a,b respectively. Hydrogen peroxide oxidation of2a,b gave the aurone derivative6a,b. The pyrone derivatives8a,b were obtained from2a,b by addition of chloroacetyl chloride followed by dehydrochlorination.     

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.     

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.     

Synthesis of some new 4-substituted antipyrines as potential antipyretic analgesics

4-Acetylantipyrine1 underwent condensation with 4-formyl-antipyrine2 to give3. Condensation of either3 with1 or1 with2 in a molar ratio of (2∶1) afforded4. Cyclization of4 in the presence of PPA and ammonium acetate or 4-aminoantipyrine in the presence of glacial acetic acid gave5–7, respectively. Claisen condensation of1 with ethyl acetate and diethyl oxalate afforded compounds8–10. The reaction of1 and2 with indole in ethanol/conc. hydrochloric acid was also investigated.     

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 C-(2-furyl)-N-(4-nitrophenyl)methanohydrazonyl bromide. Reactions with nucleophiles and active methylene compounds

Synthesis of C-(2-furyl)-N-(4-nitrophenyl)methanohydrazonyl bromide2 is described. Treatment of2 with nucleophiles affords the corresponding substitution products3–7. Also, compound2 reacts with selenocyanate anion and thiocyanate anion and give the corresponding selenadiazoline and thiadiazoline8 and9, respectively. Moreover, reaction of2 with enolates of various active methylene compounds afforded the pyrazole derivatives17–20.     

Benzoin in heterocyclic synthesis: Synthesis and reactions of 2,3-Diphenyl-4-cyanopyrrole-5-thione

2,3-Diphenyl-4-cyano-pyrrole-5-thione (4) was prepared either by the reaction of benzoin (1) and cyanothioacetamide (3) followed by cyclization using AcOH/sodium acetate or by refluxing a mixture of benzoin (1) and cyanothioacetamide in pyridine to afford directly4. Several new pyrrole and pyrazole derivatives were synthesised using4 as synthon. The structure of the newly synthesised derivatives were based on celemental and spectral data studies. Methylation of the SH group in4 afforded5. Reaction of4 with ethyl bromo acetate afforded (6). Treatment of (5) and (6) with hydrazine hydrate afforded the same pyrazole derivative (10) through the intermediate (9). Treatment of6 with aniline and phenylhydrazine afforded the pyrrole derivatives8a,b respectively. Treatment of6 while dil HCl gave 2,3-diphenyl-4-cyano-pyrrole-5-one (7). Treatment of6 with NH₃/EtOH afforded the amidic derivatives (11) with treatment of6 with NH₃/heat then acidification it gave the carboxylic derivatives (12).     

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 cycloaddition reactions of N-aryl-2-furohydrazonyl chlorides

The novel N-phenyl-2-furohydrazonyl chloride4A and its p-nitro analog4B have been prepared and identified. The cycloaddition reactions of nitrilimines5A and5B, derived by base catalyzed dehydrochlorination of4A and4B respectively, to a variety of dipolarophiles were investigated. The results showed that4A and4B are useful precursors for synthesis of differently substituted 3-(2-furyl)-2-pyrazoline derivatives and their pyrazoles and analogs.     

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).     

Reactions with acetoacetanilide: Synthesis and antibacterial activity of some new pyran,pyrano[2,3-c]pyrazole and pyrano[2,3-c]-pyridine derivatives

The reaction of acetoacetanilide (1) with the α-cyanocinnamonitrile derivatives2 yielded the Michael adducts4 which could be converted into the pyrano[2,3-c] pyrazole derivatives5 via their reaction with hydrazine hydrate. Cyclisation of4 afforded the cyanoaminopyrans9 which could in turn be converted into the corresponding pyridine derivatives10. The pyranopyrazoles9 reacted with different activated nitrile derivatives (3a-c) to give the pyrano[2,3-c]pyridine derivatives13, 16 and19 respectively. The biological activity of the synthesised heterocyclic derivatives was investigated and discussed.     

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.     

Synthesis and biological activity studies of new hybrid molecules containing tryptamine moiety

The synthesis of N′-(4-substitutedphenylsulfonyl)-2-{4-[2-(1H-indol-yl)ethyl]-3-(4-chlorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetohydrazides (3a–c), 2-{4-[2-(1H-indol-3-yl)ethyl]-3-(4-chlorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N′-aryl methylidene acetohydrazides (4a–f) and 4-[2-(1H-indol-3-yl)ethyl]-5-(4-substitutedbenzyl)-2-[(5-sulfanyl-1,3,4-oxadiazol-2-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-ones (5a, b) was performed starting from the corresponding acid hydrazides (2a, b) which was reported earlier. The treatment of 1,3,4-oxadiazole derivatives (5a, b) with hydrazine hydrate produced 4-amino-5-sulfanyl-4H-1,2,4-triazol-3-yl derivatives (6a, b). Then, compound 6b was converted to the corresponding Schiff base (7) by the treatment with anisaldehyde. The synthesis of 5-(4-chlorobenzyl)-4-[2-(1H-indol-3-yl)ethyl]-2-[(4-benzyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (8) and 5-(4-methylbenzyl)-4-[2-(1H-indol-3-yl)ethyl]-2-[(4-benzyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (10) was carried out by the reaction of acid hydrazides (2a, b) with aryl iso(thio)cyanates either via the formation of the intermediates (9a, b) (for 10) or direct cyclization (for 8). 1,3-Oxa(thia)zol-2(3H)-ylidene]acetohydrazide derivatives (11a, b) were obtained by the reaction of 9a, b with 4-chlorophenacyl bromide. All newly synthesized compounds were screened for their antimicrobial activities and some of which was found to be active against the test microorganisms.     

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.     

Synthesis of certain mercapto-and aminopyrimidine derivatives as potential antimicrobial agents

Reaction of ethyl 4-chloro-2-phenylpyrimidine-4-carboxylate (4) with 5-chloro-2-methylthiophenol or 3-aryl-4-phenyl-1,2,4-triazole-5-thiol yielded the corresponding thioethers (5) and (8a, b), respectively. Careful alkaline hydrolysis of (5) yielded the corresponding carboxylic acid (6). Reaction of (4) withp-aminoacetophenone yielded compound (10) which was reacted with certain aromatic aldehydes to afford the α, β-unsaturated ketones (11a–d). Condensation of (11a–d) with malononitrile or phenylhydrazine yielded the 2-amino-3-cyanopyridines (12a–f) or the 2-pyrazolines (13a, b), respectively. Seven representative compounds were tested for theirin vitro antimicrobial activity against some pathogenic micro-organisms, some of them were proved to be active.     

Synthesis and antibacterial activity of N-[5-chlorobenzylthio-1,3,4-thiadiazol-2-yl] piperazinyl quinolone derivatives

A series ofN-[5-(chlorobenzylthio)-1,3,4-thiadiazol-2-yl] piperazinyl quinolone derivatives (4a-1) have been synthesized by reaction of piperazinyl quinolones with 5-chloro-2-(chloroben-zylthio)-1,3,4-thiadiazoles. Their structures were confirmed by elemental analysis, IR and NMR spectra. The antibacterial activities of4a-1 against a variety of Gram-positive and Gram-negative bacteria were determined. Several compounds showed a good antibacterial activity against Gram-positive bacteria among which, compound 4e with a 2-chlorobenzylthio moiety in ciprofloxacin derivative, exhibited high activities againstStaphylococcus aureus andStaphylococcus epidermidis (MIC=0.06 μg/mL). The structure-activity relationship (SAR) study revealed that the position of chlorine atom on benzyl moiety would dramatically affect the antibacterial activities of the synthesized compounds.     

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).     

Saponins from the fructus ofKochia scoparia

Two new triterpenoidal saponins,B(1) andC(2) were isolated from the fruccus ofKochia scoparia. On the basis of chemico-spectral evidences, the structures of1 and2 were elucidated as oleanolic acid 3-O-β-D-ribopyranosyl-(1→2)-β-D-glucuronopyranoside and 3-O-β-D-xylopyranosyl-(1→3)-β-D-glucuronopyranosyl-olean-12-en-28-O-β-D-glucopyranosyl ester, respectively.     

Synthesis andin vitro antitumor activity of isoazamitosene and isoiminoazamitosene derivatives

Seven isoazamitosene derivatives, mitomycin analogues, were synthesized and tested for cytotoxicities against leukemia and gastric cancer cell lines. Preparation of a pyrrolo[1,2-a]benzimidazole (3) (azamitosene ring system) was completed by utilizing the Lewis acid-catalized cyclization, witho-chloronitrotoluene as the starting material. Nitration of3 produced a mixture of two isomers (5-nitro isomer (4) and 7-nitro isomer (5)) in product ratio of 36∶52.4 was directly converted into quinone (7) by reduction and Fremy oxidaton. Finally, quinone derivatives (8, 9, 10, and11) were synthesized by 1,4-addition of7 with cyclic secondary amines. From above-mentioned5, 8-nitro compound (15) was prepared in 4 steps. At pH 3, Fremy oxidation of15 produced quinone (16), whereas iminoquinone derivatives (17a and17b) at pH 7. Isoazamitosene derivatives (8, 9, 10, and11), containing cyclic amino groups at the 7-position, showed potent cytotoxicity on P388, SNU-1, and KHH tumor cell lines. Among them,8 had stronger cytotoxicity against SNU-1 cell line than mitomycin and adriamycin. Considering these results, isoazamitosene derivatives may had unique cytotoxicity profiles. However, isoiminoazamitosene derivatives (17a and17b) revealed very weak cytotoxicity.     

Synthesis of 6-[1-[4-(benzoxazol-2-yl)thiobuthyl]-1,2,3-triazole-4-yl]methylenepenam as β-lactamase inhibitors

The 6,6-dibromopenam6 was treated with CH₃MgBr and carbaldehyde5 to afford the 6-bromo-6-(1-hydroxy-1-methyl)penicillanate7, which was reacted with acetic anhydride to give acetoxy compound8. The deacetobromination of8 with zinc and acetic acid gave 6-exomethylenpenams, Z-isomer9 and E-isomer10, which were oxidized to sulfones11 and12 by m-CPBA. The p-methoxybenzyl compounds were deprotected by AlCl₃ and neutralized to give the sodium salts13, 14, and15.