Synthesis and cycloaddition reactions of C-(2-Naphthoyl)-N-arylmethanohydrazonoylpyridinium bromides

Coupling of naphthacylpyridinium bromide2 [1-(2-naphthyl) ethanone-2-pyridinium bromide] with N-nitrosoacetarylamides afforded C-(2-naphthoyl)-N-arylmetha-nohydrazonoylpyridinium bromides3A-C. Treatment of3A-C with base afforded the corresponding tetrazines6A-C. Cycloaddition of nitrilimines5A-C to N-arylmaleimides, acrylonitrile, ethyl acrylate, acrylamide, fumaronitrile, α-cyanocinnamonitriles, ethyl α-cyanop-nitrocinnamates and α-cyano-p-nitrocinnamamide afforded the corresponding cycloadducts7–14, respectively. The cycloadducts11–14 undergo a facile thermal elimination of hydrogen cyanide to give the corresponding pyrazoles18–21, respectively.     

Reactions with activated nitriles: A new route for the synthesis of new pyridine and pyrazolopyridine derivatives

It has been found that α, β-unsaturated nitrile derivatives1–3 reacted with S-methylisothiourea to give the propene derivatives4–6 respectively. Cyclisation of4–6 using ethanolic hydrochloric acid afforded the pyridine derivatives7–9 in good yields. On the other hand, the reactions of hydrazine hydrate and of phenylhydrazine with each of7–9 gave the corresponding pyrazolopyridine derivatives10–15. The structures of the newly synthesised derivatives were assigned on the basis of elemental analyses, IR and¹H-NMR spectral data studies.     

Reactions with hydrazidoyl halides (V)1): synthesis of some amidrazones,hydrazides, pyrazoles and pyrazolo[3,4-d]pyridazine derivatives

2-Bromo (2′-benzofuryl)glyoxal-2-arylhydrazonesI reacted with nucleophiles displacing the bromide. Treatment ofI with active methylene compounds yield the pyrazole derivativesVIII–XI. CompoundsXII–XIV reacted with hydrazine to give pyrazolo[3,4-d]pyridazine derivativeXIV–XVI. The structures of the products were assigned and confirmed on the basis of their elemental analysis and spectral data.     

Perphenazine decanoate andcis(z)-flupentixol decanoate in maintenance treatment of schizophrenic outpatients

Two groups of schizophrenic outpatients were treated with perphenazine decanoate (N=20) andcis(z)-flupentixol decanoate (N=24) respectively. Every 3 months the dose was gradually reduced until symptoms appeared that were suggestive of a prodromal phase of a psychotic episode. A slightly higher dose was then promptly reinstituted (the minimum effective dose). At each dose level, two blood samples were drawn for determination of serum concentration. The mean minimum effective dose of perphenazine decanoate was 99.3 mg/2 weeks (range 21.6–270.5), while the mean minimum effective dose ofcis(z)-flupentixol decanoate was 60 mg/2 weeks (range 20–250). The corresponding mean serum level of perphenazine decanoate was 7.3 nmol/l (range 2.0–18.1) and ofcis(z)-flupentixol decanoate 7.8 nmol/l (range 1.2–37.0). There was a significant correlation between the administered doses and the corresponding serum levels for both drugs (r=0.87,P<0.01). A weak positive correlation was found between serum levels at the minimum effective dose and symptom intensity (BPRS total score) (r=0.53,P<0.02) for perphenazine, but notcis(z)-flupentixol. No correlation was found between serum levels and side effects or length of neuroleptic treatment. It is concluded that the serum drug concentrations corresponding to the lowest effective dose are so variable that routine serum level monitoring may be of limited value in the long-term maintenance treatment of schizophrenia.     

Synthesis of some substituted furan-2(5H)-ones and derived quinoxalinones as potential anti-microbial and anti-cancer agents

In search for novel anti-cancer and anti-microbial agents with promising pharmacotoxicological profile, the synthesis of some substituted 4-halofuran-2(5H)-ones (8a–l, 9, 11) and derived halogenated quinoxalin-2(1H)-ones (12a–d) is described. Some of the halogenated furanones were readily oxidized to the corresponding 2-bromo-2-propenoic acids (13a–c) with hydrogen peroxide in alkaline medium. Twenty-two compounds were preliminary tested for their in vitro activity against three bacteria and one fungus and revealed encouraging activity. On the other hand, three compounds were screened as anti-cancer agents using cell line panel protocol and 22 compounds were subjected to cycline-dependent kinases (CDKs) inhibition screening program but were inactive.     

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 of 2-(2-fluorenyl)propanoic acid

Friedel-Crafts reaction of fluorene with methyl α-chloro-α-(methylthio)acetate1 gave methyl α-methylthio-2-fluoreneacetate2. Cicloprofen8, a potent antiinflammatory agent, was prepared by methylation of2 followed by reductive desulfurization of methyl 2-(2-fluorenyl)-2-(methylthio)propionate6 and hydrolysis of methyl 2-(2-fluorenyl)propionate7.     

Paracetamol (acetaminophen) esters of some non-steroidal anti-inflammatory carboxylic acids as mutual prodrugs with improved therapeutic index

Paracetamol (acetaminophen) esters [4a-f] of some acidic NSAIDs were synthesized and evaluated as mutual prodrug forms with the aim of improving the therapeutic index through prevention of the gastrointestinal toxicity. The structures of the synthesized esters were confirmed by IR and ¹H-NMR spectroscopy and their purity was established by elemental analyses and TLC. In-vitro stability studies revealed that the synthesized ester prodrugs 4a-f are sufficiently chemically stable in non-enzymatic simulated gastric fluid (hydrochloric acid buffer of pH 1.3 (t _1/2 ∼ 15–45 h)) and in phosphate buffer of pH 7.4 (t _1/2 ∼ 4–40 h). In 80% human plasma and 10% rat liver homogenate, the mutual prodrugs were found to be susceptible to enzymatic hydrolysis releasing the corresponding NSAID and paracetamol at relatively faster rates (t _1/2 ≈ 15–385 min and 1–140 min, respectively). Calculated log P values indicated that the prodrugs 4a-f are more lipophilic than the parent drugs. In-vivo experiments in rabbits showed higher plasma levels of ibuprofen after oral administration of its ester prodrug 4b compared with those resulting from an equivalent amount of the corresponding physical mixture. Moreover, significant improvement in latency of pain threshold in mice has been observed up to 4 h after po administration of 0.02 mmol/kg of the prodrugs, compared with the corresponding physical mixtures. Gross observations and scanning electromicrographs of the stomach showed that the prodrugs induced very little irritancy in the gastric mucosa of mice after oral administration for 4 days. These results suggest that the synthesized mutual ester prodrugs were characterized by a better therapeutic index than the parent drugs.     

Synthesis and anticonvulsant activity of 4-(2-phenoxyphenyl)semicarbazones

A new series of 4-(2-phenoxyphenyl)semicarbazones were synthesized as potential anticonvulsant agents. Thus, the reaction of 4-(2-phenoxyphenyl)semicarbazide with various benzaldehydes and acetophenones in ethanol yielded the corresponding semicarbazones 6a–k and 7a–i, respectively. Structures of the synthesized compounds were confirmed by spectral data and elemental analysis. All compounds were evaluated for their anticonvulsant activity in pentylenetetrazole (PTZ)-induced kindling model in adult male Wistar rats. The neurotoxicity of active compounds was also assessed using the rotorod method. The results showed that two compounds (6g and 6i) showed greater protection from seizure than sodium valproate at dose of 100 mg/kg. Compounds 6g and 6i showed no neurotoxicity at the maximum dose administered (300 mg/kg).     

Synthesis and antibacterial activity of some new 1-aroyl-3-(substituted-2-benzothiazolyl)thioureas

An efficient, synthesis of some new 1-aroyl-3-(substituted-2-benzothiazolyl)-thioureas is reported. Substituted anilines were treated with potassium thiocyanate and bromine in acidic medium to afford the corresponding 2-amino-benzothiazoles (2a–e). Treatment of the latter with suitably substituted aroyl isocyanates, produced in situ by reaction of corresponding aroyl chlorides with thiocyanate in acetone, afforded the 1-aroyl-3-(substituted-2-benzothiazolyl)thioureas (3a–k). The structures were confirmed by physical, IR, NMR, and mass spectral data. The synthesized compounds (2a–d, 3a–k) were assayed in vitro for their antimicrobial activity against Gram positive and Gram negative bacteria and were found to exhibit moderate to potent activity towards the tested microorganisms, as compared to the standard drugs.     

Synthesis and antitumor activity of 3-arylisoquinoline derivatives

In order to study the structure-activity relationship of 7,8-dimethoxy-2-methyl-3-(4,5-methylen-edioxy-2-vinylphenyl)isoquinoline-1 (2H)-one (2), which has exhibited significant antitumor activity, chemical modifications of2 were performed to yield the corresponding products (3–7). Further systematic uses of an efficient procedure for the synthesis of 3-arylisoquinoline derivatives produced the substituted compounds (9a−9g), which were tested forin vitro antitumor activity against five different human cancer cell lines.     

Synthesis and antiviral activity of new 4-(phenylamino)/4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acids derivatives

The synthesis of new 4-(phenylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (3a-l) derivatives and the new 4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (5a–c) derivatives was achieved with an efficient synthetic route. Ethyl 4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (1) on fusion with appropriate substituted anilines or aminopicolines gave the required new ethyl 4-(phenylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylates (2a–l) (52–82%) or new ethyl 4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylates (4a–c) (50–60%), respectively. Subsequent hydrolysis of the esters afforded the corresponding carboxylic acids (3a–l) (86–93%) and (5a–c) in high yield (80–93%). Inhibitory effects of 4-(phenylamino)/4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acids. Derivatives on Herpes simplex virus type 1 (HSV-1), Mayaro virus (MAY) and vesicular stomatitis virus (VSV) were investigated. Compounds 2d, 3f, 3a, and 3c exhibited antiviral activity against HSV-1, MAY, and VSV virus with EC₅₀ values of 6.8, 2.2, 4.8, 0.52, 2.5, and 1.0. None of these compounds showed toxicity for Vero cells.     

Kaempferol glycosides and cardenolide glycosides,cytotoxic constituents from the seeds of <Emphasis Type="Italic">Draba nemorosa</Emphasis> (Brassicaceae)

Bioassay-directed fractionation of a methanolic extract from the seeds of Draba nemorosa (Brassicaceae) led to isolation of a new flavonol glycoside, drabanemoroside (5, kaempferol 3-O-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranose) along with four known flavonoid derivatives (1–4), four cardenolide glycosides (6–9). Kaempferol glycosides 2 and 5 showed strong cytotoxicity against human small lung cancer cell line A549 and melanoma SK-Mel-2 with an IC₅₀ of 0.5 μg/mL and 1.9 μg/mL, respectively. Cardenolide glycosides 6–9 showed potent cytotoxicity (A549) in the range of 0.01–0.032 μg/mL. Their structures were characterized based on spectroscopic data (2D NMR, HRTOFMS, IR, and UV) and comparison of literature values. The carbohydrate units were also confirmed by comparing the hydrolysate of 5 with authentic monosaccharides.     

Synthesis and bioactivity of some new 1-tolyl-3-aryl-4-methylimidazole-2-thiones

Three series of new 1-(isomeric methyl)benzoyl-3-arylthioureas (1–3a–i) were prepared from 2-, 3-, and 4-methylbenzoyl chlorides via isothiocyanate formation followed by treatment with various substituted anilines. The base-catalyzed condensation of thioureas (1–3a–i) with acetone was carried out in the presence of bromine to afford the corresponding 1-(isomeric methyl) benzoyl-3-aryl-4-methyl-imidazole-2-thiones (4–6a–i) in good yield. Thioureas and the corresponding thiones were characterized by spectroscopic data and elemental analyses. The mass fragmentation pattern of thiones is also discussed. The thiones were evaluated for antibacterial, antifungal, and insecticidal activities and exhibit significant antibacterial activity and slight but not significant antifungal and insecticidal properties.     

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 antitumor activity of (4-hydroxyphenyl)[5-substituted alkyl/aryl)-2-thioxo-1,3,4-thiadiazol-3-yl]methanone and [(3,4-disubstituted)-1,3-thiazol-2ylidene]-4-hydroxybenzohydrazide

To examine new drug leads with potential anticancer activity, some (4-hydroxyphenyl)[5-substituted alkyl/aryl)-2-thioxo-1,3,4-thiadiazol-3-yl]methanone (4.a–4.c) and [-(3,4-disubstituted)-1,3-thiazol-2ylidene)]-4-hydroxybenzohydrazide (6.a–6.d) were synthesized using appropriate synthetic route. The newly prepared compounds 4.a–4.c and 6.a–6.d demonstrated inhibitory effects on the growth of a wide range of cancer cell lines especially on leukemia (HL-60), non-small lung cancer (HOP-92), renal cancer (ACHN) at the range of GI₅₀ −4.23 to −7.23.     

Inhibitory effect of the rhizomes of<Emphasis Type="Italic"> Alpinia officinarum</Emphasis> on TPA-induced inflammation and tumor promotion in two-stage carcinogenesis in mouse skin

The methanol extract of galangal (the rhizomes of Alpinia officinarum L.) exhibited remarkable antitumor-promoting activity on an in vivo two-stage carcinogenesis test of mice using 7,12-dimethylbenz[a]anthracene as an initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as a promoter. Seven diarylheptanoids (1–7) were isolated and identified from the active fraction of the methanol extracts of the galangal. These compounds, 1–7, were evaluated for their inhibitory effects on TPA-induced inflammation (1 μg/ear) in mice. These compounds (1–7) tested showed marked anti-inflammatory effects, with a 50% inhibitory dose of 0.8–2.7 μmol/ear.     

Synthesis of 6-aziridlnylbenzimidazole derivatives and theirin vitro antitumor activities

In search for new antitumor agents, twelve 6-aziridinylbenzimidazole derivatives were synthesized and their cytotoxicities were tested against three cancer cell lines (mouse lymphocytic leukemia P388 and B16, and human gastric carcinoma SNU-16). From 4-amino-3-nitrotoluene as the starting material, 2-(acetoxymethyl)benzimidazoles (5a–d) were obtained by Phillips reaction. These benzimidazoles were then reacted with Fremy's salt to give a mixture of three 2-(acetoxymethyl) (8a–c) and four 2-(hydroxymethyl)benzimidazole-4,7-diones (9a–d). Addition of these quinones with aziridine afforded 6-aziridinyl-2-(acetoxymethyl) (10a–c) and 6-aziridinyl-2-(hydroxymethyl)benzimidazole-4,7-diones (11a–d). Utilizing 2-(hydroxymethyl)benzimidazole-4,7-diones (9b,d), esters10d and13e–h were prepared by the sequential reactions of esterification and addition. The synthesized compounds show potent cytotoxicity against all of three cell lines tested. The cytotoxicities of10a–d or11a–d against SNU-16 were superior to those of13e–h, and were equal to or slightly higher than that of mitomycin C. Compounds11a–d were slightly more cytotoxic than10a–d in all cell lines tested.     

Inhibitory effect of 2-arylbenzofurans from the Mori Cortex Radicis (Moraceae) on oxygen glucose deprivation (OGD)-induced cell death of SH-SY5Y cells

Three known 2-arylbenzofurans, moracin P (1), moracin O (2) and mulberrofuran Q (3) were isolated from the MeOH extract of the Mori Cortex Radicis. These compounds 1–3 enhanced cell viability in dose-dependent manner against oxygen-glucose deprivation (OGD)-induced cell death in neuroblastoma SH-SY5Y cells, which was measured by MTT reduction assay. (EC₅₀ values of 10.4, 12.6, and 15.9 μM, respectively). In addition, the compounds 1–3 were examined for their inhibitory effect on OGD-induced ROS production by FACS analysis. We observed these compounds reduced ROS production in OGD-induced cell death (IC₅₀ values of 1.9, 0.3 and 12.1 μM, respectively). Consequently, reactive oxygen species (ROS) were overexpressed in OGD-induced cells and all three compounds reduced ROS induced by OGD in dosedependent manner. Taken together, compounds 1–3 might protect neuronal cell death against the oxidative stress induced by OGD, though further studies in vitro and in vivo models are necessary.     

Synthesis of new hydantoin-3-ethanethiol derivatives

5-sec-Butylthiomethyl-5-alkyl (methyl or phenyl) hydantoins (3−x) were prepared by the reaction of sec-butylthiomethyl alkyl (methyl or phenyl) ketone (1–2), potassium cyanide and ammonium carbonate. 3-(2-Bromoethyl) hydantoins (5–6) were the reaction products of 5-sec-butylthiomethyl-5-alkyl (methyl or phenyl) hydantoin and 1,2-dibromoethane in the presence of potassium hydroxide. Alkylation of5 and6 with an excess of alkyl (methyl or ethyl) iodide in THF with sodium hydride as base gave three 1-alkyl (methyl or ethyl)-3-(2-bromoethyl) hydantoins (7–9). Treatment of the 2-bromoethyl group with potassium thioacetate and triethylamine gave three 1-alkyl (methyl or ethyl)-3-(2-acetylthioethyl) hydantoins (10–12). Hydrolysis of the 2-acetylthioethyl group with sodium hydroxide in methanol afforded the three 1-alkyl (methyl or ethyl)-3-(2-mercaptoethyl) hydantoins.