The Hypolipidemic Activity of a Series of 2,3-Dihydrophthalazine-l,4-dione Derivatives in Rodents

A series of substituted 2,3-dihydrophthalazine-l,4-dione derivatives as well as the corresponding N,N-diaminophthalamides were prepared and were demonstrated to have potent hypolipidemic activity, lowering both serum triglyceride and cholesterol levels significantly at 20 mg/kg/day after 16 days of dosing in CF₁ male mice. The parent compound, 2,3-dihydrophthalazine-l,4-dione, lowered serum cholesterol 51% and serum triglyceride 43%. 2-(2-Carboxyethyl)-2,3-dihydrophthalazine-l,4-dione demonstrated the best hypocholesterolemic activity, with a 66% reduction after 16 days. The 2-(p-chlorophenyl) derivative demonstrated good activity (>40% reduction) in both screens, as did the 6-methyl-2,3-dihydrophthalazine-l,4-dione derivative. Of the amides, 4-methyk N,N-diaminophthalamide demonstrated the best hypolipidemic activity, affording a greater than 40% reduction. 2,3-Dihydrophthalazine-l,4-dione was found to inhibit the enzyme activity of acetyl CoA synthetase, ATP-dependent citrate lyase, sn-glycerol-3-phosphate acyl transferase, phosphatidylate phosphohydrolase, and mitochondrial citrate exchange of liver. In mice after 16 days of dosing, there was a reduction of cholesterol, triglycerides, neutral lipids, and phospholipids in the liver. Cholesterol and neutral lipids were reduced in rat chylomicrons, very low-density lipoproteins, and low-density lipoproteins. The cholesterol content of the high-density lipoprotein fraction was slightly elevated, but reductions in the triglycerides and phospholipids were observed in this lipoprotein fraction. ³H-Cholesterol distribution studies showed a lower concentration in the major organs and plasma, with a higher ³H-cholesterol content in the stomach and large intestine.     

Synthesis and antiviral activity of quinoxalinedione 2,3(1H, 4H) derivatives

Syntheses and Antiviral Activities of Quinoxalinedione 2,3(1H,4H) Derivatives In our search for new virustatics, we have synthesized derivatives of quinoxaline-2,3(1H,4H)-dione and investigated their antiviral activities against various strains of herpes simplex virus types 1 and 2, vaccinia virus and vesicular stomatitis virus. None of the compounds showed antiviral activity comparable to that of 5-ethyl-2′-deoxyuridine (EtUdR).     

1,2,3,4-Tetrahydrophthalazine, 2. Mitt. 2,3,4,5,7,12-Hexahydro-1H-(1,2,5)triazepin[1,2-b]phthalazin-1,5-dion-Derivate

1,2,3,4-Tetrahydrophthalazines, II:Derivatives of 2,3,4,5,7,12-Hexahydro-1H-[1,2,5]triazepino[1,2-b]phthalazine-1,5-dione A series of derivatives of the new heterocyclic system 2,3,4,5,7,12-hexahydro-1H-[1,2,5]triazepino[1,2-b]-phthalazine-1,5-dione was obtained as a result of condensation of 2,3-bis(haloacetyl)-1,2,3,4-tetrahydrophthalazines with primary amines.     

Biological evaluation of novel 1,4-dithiine derivatives as potential antimicrobial agents

The preparation of twelve aminoalkanol derivatives of 2,3-dihydro-5H-[1,4]dithiino[2,3-c]pyrrole-5,7(6H)-dione was described. Newly obtained compounds, as well as their propyl and butyl analogues, were evaluated in vitro against selected viruses. Selected derivatives were tested for their antibacterial and antifungal activity. Compounds 3h, 3j, 4b and 5a–d showed moderate to significant protections against CVB-2, HSV-1 and YFV viruses. The molecular structures of 4a, 5c and 5g were determined by an X-ray analysis.     

Synthesis,cytotoxicity, and antibacterial studies of 2,4,5,6-substituted hexahydro-1H-isoindole-1,3(2H)-dione

In this study, synthesis of novel isoindole-1,3-dione analogues bearig halo, hydroxy, and acetoxy groups at the position 4,5,6 of the bicyclic imide ring was performed to examine their potential anticancer effects against some cell lines. A multistep chemical pathway was used to synthesize the derivatives. The cytotoxic effect of trisubstituted isoindole derivatives were evaluated by determining cellular viability using the MTT assay against A549, PC-3, HeLa, Caco-2, and MCF-7 cell lines. The C-2 selective ring-opening products were obtained from the ring-opening reaction of 5-alkyl/aryl-2-hydroxyhexahydro-4H-oxireno[2,3-e]isoindole-4,6(5H)-diones with nucleophiles such as chloride (Cl⁻) and bromide (Br⁻) ions. In addition, the ring-opening products halodiols were converted to their related acetates. The anticancer activity of synthesized isoindole-1,3-dione derivatives was investigated against HeLa, A549, MCF-7, PC3, and Caco-2 cells in vitro and resulted in varies cytotoxic effect depend on the group attached to the isoindole molecule. Furthermore, the evaluation of the antimicrobial action of trisubstituted isoindole derivatives against Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria was assessed and found out selective inhibition of the both bacterial growth via different trisubstituted isoindole derivatives. The results of this work encourage further research on the potential utilization of trisubstituted isoindole derivatives as cytotoxic and antimicrobial agents.     

Benzo[4,5]thieno[2,3-d]pyrimidine phthalimide derivative,one of the rare noncompetitive inhibitors of dipeptidyl peptidase-4

A small library of benzo[4,5]thieno[2,3-d]pyrimidine phthalimide and amine derivatives was evaluated for inhibitory activity against dipeptidyl peptidase-4 (DPP-4). The phthalimide derivatives exhibited better activity than the amine precursors, with 2-(2-(3-chlorobenzyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)isoindoline-1,3-dione (compound 14 ) as the most effective inhibitor (IC₅₀ = 34.17 ± 5.11 μM). The five most potent selected inhibitors did not show cytotoxicity to a greater extent on Caco-2 cells, even at a concentration of 250 μM. Compound 14 is considered as a novel representative of the rare noncompetitive DPP-4 inhibitors. Molecular docking and dynamics simulation indicated the importance of the Tyr547, Lys554, and Trp629 residues of DPP-4 in the formation of the enzyme–inhibitor complex. These observations could be potentially utilized for the rational design and optimization of novel (structurally similar, with phthalimide moiety, or different) noncompetitive DPP-4 inhibitors, which are anyway rare, but favorable in terms of the saturation of substrate competition.     

Relationships Between the Chemical Structure of Antimycobacterial Substances and Their Activity Against Atypical Strains. Part 14: 3-Aryl-6,8-dihalogeno-2H-1,3-benzoxazine-2,4(3H)-diones

A set of eight derivatives of 6,8-dichloro-3-phenyl-2H-benzoxazine-2,4(3H)-dione and nine derivatives of 6,8-dibromo-3-phenyl-2H-1,3-benzoxazine-2,4(3H)-dione, substituted on the phenyl ring, was prepared by the reaction of the corresponding salicylanilides with ethyl chloroformate. The compounds were evaluated in vitro for antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii, and Mycobacterium avium. Their activity increases with increasing hydrophobicity and electron-withdrawing ability of the substituents on the phenyl ring.     

Synthesis of new series of pyrazolo[4,3-d]pyrimidin-7-ones and pyrido[2,3-d]pyrimidin-4-ones for their bacterial and cyclin-dependent kinases (CDKs) inhibitory activities

Two series of pyrazolo[4,3-d]pyrimidin-7-ones and pyrido[2,3-d]pyrimidin-4-ones were designed, synthesised, and evaluated for their antibacterial activities and CDKs inhibitory activities. The pyridazine derivative: 6-phenyl-5-phenylhydrazono-2,3,4,5-tetrahydropyridazine-3,4-dione (3a) revealed activity against Staphylococcus aureus as Gram-positive bacteria while compound 2-(2-Ethoxyphenyl-5-Phenylpiperazinosulfonamido)-3H-pyrido[2,3-d]pyrimidin-4-one (13c) was showing moderate antifungal activity against Candida albicans.     

A facile synthesis and neuroprotective role of novel quinoxaline-2,3-bis hydrazones in ethidium bromide-induced demyelinated rats

There is a growing interest in the design and synthesis of the quinoxaline-2,3-dione derivatives and hydrazones due to their neuroprotective activity, anticancer, anti-inflammatory, analgesic, anticonvulsant, antiviral, antibacterial and antifungal activity, and hydrazone-based coupling methods are used in medical biotechnology to couple drugs and also to target antibodies. Different series of α-amino-3-hydroxy-5-methylisoxazole propionate receptor antagonists are described to be effective in the therapy of neurodegenerative disorders in the literature, one of which is based on the quinoxaline-2,3-dione structure, which has a high affinity and selectivity over receptors. Quinoxaline-2,3-bis hydrazone(s) were prepared by the nucleophilic addition reaction at the second and third position of quinoxaline-2,3-dione using different hydrazines (a–f) in conventional and microwave oven methods successfully with the good percentage of yields. The six synthesized compounds showed satisfactory analytical results. The oral administration of the synthesized drugs (20 mg/kg body weight) showed its curative and preventive effect against intracranial administration of ethidium bromide-induced demyelination in rats proved by the battery of behavioral and histological studies. The synthesized drugs are useful to counteract various demyelinating disorders which will be a great relief for our society. Further studies are needed on the molecular mechanisms of these compounds with neuroprotective activity.     

The anti-neoplastic activity of 2,3-dihydrophthalazine-1,4-dione and N-butyl-2,3-dihydrophthalazine-1,4-dione in human and murine tumor cells.

2,3-Dihydrophthalazine-1,4-dione derivatives demonstrated potent cytotoxicity against the growth of murine leukemia cells and human single cell suspension, i.e. Tmolt3 leukemia and HeLa-S3, as well as colon adenocarcinoma and KB nasopharynx. However, only select compounds demonstrated activity against bronchogenic lung, osteosarcoma and glioma growth. 2,3-Dihydrophthalazine-1,4-dione was active in vivo against L1210 leukemia, Lewis lung and Ehrlich ascites carcinoma growth. In L1210 cells the agents inhibited both DNA and RNA synthesis, and a few of the compounds were capable of inhibiting protein synthesis at 3 times their ED50 values. When 2,3-dihydrophthalazine-1,4-dione and N-butyl-2,3-dihydrophthalazine-1,4-dione were examined for their mode of action in the L1210 lymphoid leukemia cells, the sites of inhibition by the agents appear to be the de novo purine pathway at the enzymes IMP dehydrogenase and PRPP amido transferase. IMP dehydrogenase activity was inhibited at least 45% by 45 min at 100 microM concentration of drugs whereas the remaining enzymes that were affected by the drugs were not inhibited as early. Secondary sites were dihydrofolate reductase and thymidylate synthetase. The d(NTP) levels were also reduced specifically dATP and dCTP levels.     

Rapid and efficient ultrasound-assisted method for the combinatorial synthesis of spiro[indoline-3,4'-pyrano[2,3-c]pyrazole] derivatives

An efficient one-pot synthesis of spiro[indoline-3,4'-pyrano[2,3-c]pyrazole] derivatives by four-component reaction of hydrazine, β-keto ester, isatin, and malononitrile or ethyl cyanoacetate catalyzed by piperidine under ultrasound irradiation is described. This synthesis was confirmed to follow the group-assistant-purification chemistry (GAP) chemistry process, which can avoid traditional chromatography and recrystallization purifications.     

Naphthannelated azepinones: synthesis and antitumor activity.

5H-Benzo[b]naphth[2,3-e]azepine-6,13-diones 4a, 4b and 4H-naphtho[2,3-e]thieno[3,2-b]azepine-5,12-dione (6) were prepared by aldol condensation of phthalic dialdehyde (3) with the fused azepinediones 2a, 2b and 5, respectively. The Schmidt reaction of naphthacene-5,12-quinone (7) yielded 6H-benzo[e]naphth[2,3-b]azepine-7,12-dione (10). Several derivatives of the heterocyclic basic scaffolds 4, 6 and 10 were prepared by standard procedures, e.g. Grignard reaction, deoxygenation with triethylsilane, and sodium borohydride reduction. Evaluation of the synthesized compounds in the NCI in vitro cell line screening revealed a modest antitumor activity without marked cell line selectivity for the majority of the derivatives. The 2-bromo-5H-benzo[b]naphth[2,3-e]azepin-6(13H)-one (19) was the only representative in this series exhibiting a noteworthy growth inhibitory effect for human tumor cells.     

邪蒿素及其衍生物的合成及镇痛活性

本文报道了合成天然产物邪蒿素及其衍生物的新方法，以7-羟基-8-乙酰基香豆素或取代香豆素为原料，经与丙酮缩合、还原、脱水得到单一的角型三环邪蒿素类化合物。三步反应条件温和，各步收率均>80%。12个邪蒿素类衍生物的小鼠醋酸扭体镇痛试验结果表明合成的邪蒿素(4a)和4，8，8-三甲基-9，9-二氢-吡喃［2，3-f］色烯-2，10-二酮(2b)具有明显的镇痛活性，抑制率分别为85%和50%，明显优于或相当于同试验中的对照药阿司匹林。     

Synthesis and properties of 7-methyl-5-oxo-1,5-dihydro-8-[1,2,4]-triazolo [4,3-c]pyrimidinecarboxylic acid derivatives

The synthesis of the new triazolo[4,3-c]pyrimidines is described, starting from derivatives of 5-carboxy-2-hydroxy-4-hydrazino-6-methylpyrimidine. The 4-methyl-2,3-dihydropyrazolo[3,4-d]pyrimidine-3,6-dione was also obtained. Some of triazolo[4,3-c]pyrimidines tested for biological activity were found inactive.     

Synthesis,Properties, and Antimicrobial Activity of 3-Hydrazones of 1-Aryl-5-methyl-1,5-ethoxycarbonylpyrrolidine-2,3-diones

Reactions of 5-methyl-1-aryl-ethoxycarbonylpyrrolidine-2,3-diones (I, II, III, IV) with hydrazine hydrate, phenylhydrazine, isoniazid, benzoylhydrazine, and thiosemicarbazide were used to synthesize a series of 3-hydrazones of 1-aryl-5-methyl-5-ethoxycarbonylpyrrolidine-2,3-diones (V – VIII), 3-phenylhydrazones of 1-aryl-5-methyl-5-ethoxycarbonylpyrrolidine-2,3-diones (IX – XII), 3-isonicotinoylhydrazones of 1-aryl-5-methyl-5-ethoxycarbonylpyrrolidine-2,3-diones (XIII – XV), 3-benzoylhydrazone of 5-methyl-1-phenyl-5-ethoxycarbonylpyrrolidine-2,3-dione (XVI), and 3-thiosemicarbazone of 5-methyl-1-phenyl-5-ethoxycarbonylpyrrolidine-2,3-dione (XVII). All target products were obtained with a yield of 51 – 90%. The reactions of 3-hydrazone of 1-phenyl-5-methyl-5-ethoxycarbonylpyrrolidine-2,3-dione (V) with 5-aryl-2,3-dihydro-2,3-furandiones yielded 3-N-aroylpyruvoylhydrazones of 5-methyl-1-phenyl-5-ethoxycarbonylpyrrolidine-2,3-dione (XVIII, XIX), and the heating of 3-hydrazone of 5-methyl-1-(4-chlorophenyl)-5-ethoxycarbonylpyrrolidine-2,3-dione (VI) with 4-methoxybenzaldehyde yielded 5-methyl-3-N-4-methoxybenzylidene-hydrazino-1-(4-chlorophenyl)-5-ethoxycarbonyl-3-pyrrolidin-2-one (XX). The synthesized compounds are characterized by physicochemical constants and the parameters of IR and ¹H NMR spectra. Some compounds were tested for antimicrobial activity. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 8, pp. 19 – 22, August, 2005.     

Anti-inflammatory 2,3-dihydro-1H-pyrrolizines. 3. Aminomethylation and arylthiolation of 6,7-diaryl-2,3-dihydro-1H-pyrrolizines

Antiinflammatory 2,3-Dihydro-1H-pyrrolizines, III: Aminomethylation and Arylthiolation of 6,7-Diaryl-2,3-dihydro-1H-pyrrolizines Electrophilic substitution of the title compounds leads to the 5-aminomethyl and 5-arylthio derivatives 1 and 3 , respectively. The thioethers 3 show significant antiinflammatory activity, whereas the aminomethyl compounds are less active.     

Synthesis and cytotoxic activity of certain 2,3,4,9-tetrahydrofuro [2,3-b] quinolin-3,4-dione and ethyl 2-(substituted aniline) -4-oxo-4,5-dihydrofuran-3-carboxylate derivatives in murine leukemia WEHI-3 cells

A series of 2,3,4,9-tetrahydrofuro[2,3-b]quinolin-3,4-dione and ethyl 2-(substituted aniline) -4-oxo-4,5-dihydrofuran-3-carboxylate were synthesized and evaluated for cytotoxicity on murine leukemia WEHI-3 cells. The cytotoxic effects of most compounds tested were dose-dependent and the structure-activity relationships indicated that N-substituted benzyl derivatives displayed a stronger inhibitory activity against murine leukemia WEHI-3 cells compared to non-N-substituted benzyl substituted derivatives.     

Synthesis of heterocyclic quinones containing bridgehead nitrogen atom from 2-aminonaphtho[2,3-d]thiazole-4,9-dione

Imidazonaphthothiazole derivatives 3-6 were prepared by treatment of 2-aminonaphtho[2,3-d]-thiazole-4,9-dione(1) with phenacyl bromide, chloroacetic acid, diethyl oxalate and 2,3-dichloroquinoxaline respectively. The reaction of 1 with ethyl acrylate, ethyl acetoacetate and diethyl malonate gave the corresponding naphthothiazolopyrimidine derivatives 8-11.     

Three new and two rare furanoeremophilanes from senecio asirensis

Three new furanoeremophilanes have been obtained from the aerial parts of Senecio asirensis (N. O. Asteraceae), and characterized as 6-hydroxylmethyl-9-methoxyl-4,11-dimethylnaphtho[2,3-b]furan, designated asirensane-a (1), 6-hydroxyl-1,2-dimethoxyl-4,6,11-trimethyl-6-hydronaphtho[2,3-a]furan-7-one, named asirensane-b (2), and (6,12-dihydroxyl-9-methoxyl-4-methyl-11-acetyl-3,4-dihydronaphtho[2,3-b]furan-3-yl)methyl (2′Z)-2′-methylbut-2′-enoate, designated asirensane-c (3). In addition, two rare furanoeremophilanes have also been isolated and characterized from this source, namely 9-methoxyl-4,11-dimethylnaphtho[2,3-b]furan, named 14-nordehydrocalohastine (4), and 4,11-dimethylnaphtho[2,3-b]furan-6,9-dione, designated as maturinone (5). Their structures have been elucidated on the basis of spectral analysis. The alcoholic extract was also tested for anti-inflammatory activity, which decreased edema by 22% at a dose of 500?mg?kg^-1 after 3?h with respect to the control group treated only with carrageenan, while the standard drug phenylbutazone showed a 50% decrease at a dose of 100?mg?kg^-1, indicating that the extract has moderate anti-inflammatory activity.     

Ring transformation of pyrrolidine-enaminothiones to 4,5-dihydro-6H-thieno[2,3-c]azepines

Transformation of Pyrrolidine Enaminothiones to 4,5-Dihydro-6H-thieno[2,3-c]azepines Addition of the pyrrolidine enaminothiones 1 with a semicyclic C? C bond to α-bromocarbonyl derivatives leads to the 4,5-dihydro-6H-thieno[2,3-c]azepines 6 which were characterized by their spectroscopic data. The thienozepine system is formed under basic conditions from a spiro intermediate. Three of the dihydrothienoazepines 6 and the thienoazocine 10 where tested for antiinflammatory activity.