Showing papers in "Archiv Der Pharmazie in 2006"

Synthesis and molluscicidal activity of new cinnoline and pyrano [2,3-c]pyrazole derivatives

Abstract: 2-(3-Hydroxy-5,5-dimethylcyclohexylidene)malononitrile 5 undergoes an azo coupling reaction with aryldiazonium salts to afford 3-amino-2-aryl-6,6-dimethyl-8-oxo-2,6,7,8-tetrahydrocinnoline-4-carbonitriles 7. Upon reflux in acetic acid, these compounds were acetylated to give the cinnoline derivatives 9. The pyrazolones 10a, b react with 3-furfurylidene- and 3-thienylidene-malononitrile derivatives 11a, b to afford the pyrano[2,3-c]pyrazole derivatives 13a-d. These newly synthesized compounds show generally a moderate molluscicidal activity to Biomphalaria alexandrina snails.

Synthesis and antiviral evaluation of some sugar arylglycinoylhydrazones and their oxadiazoline derivatives.

Abstract: Sugar N-arylaminoacetylhydrazones 2-5 were prepared by the reaction of N-arylaminoacetylhydrazides 1 with equivalent amounts of the corresponding monosaccharides. Per-O-acetyl derivatives 6-9 of sugar hydrazones 2-5 were prepared by using acetic anhydride in pyridine at room temperature, while on boiling with acetic anhydride, cyclization had taken place to give the oxadiazolines 10-12. The prepared compounds were tested for antiviral activity against Herpes Simplex virus type-1 (HSV-1) and hepatitis-A virus (HAV, MBB-cell culture adapted strain). Plaque reduction infectivity assay was used to determine virus count reduction as a result of treatment with tested compounds.

Synthesis of some new quinoxalines and 1,2,4-triazolo[4,3-a]-quinoxalines for evaluation of in vitro antitumor and antimicrobial activities.

Abstract: Two novel series of quinoxalines derived from 3-phenylquinoxalin-2(1H)-one and 2-hydrazino-3-phenylquinoxaline, namely 1-substituted-3-phenylquinoxaline-2(1H)-ones, 2a-c, 3a-d, and 4; 2-(3-oxo-3,3a,4,5,6,7-hexahydroindazol-2-yl)-3-phenylquinoxaline 6; N- cyclopentylidene or benzylidene-N'-(3-phenylquinoxaline-2-yl)hydrazines, 7 and 18; 1-substituted-4-phenyl-1,2,4-triazolo[4,3-a]quinoxalines, 9, 10, 12, 13, 14, and 16 have been synthesized in order to evaluate their antitumor and antimicrobial activities. Preliminary screening at NCI showed that compounds 2b, 2c, 3b, 3c, and 9 exhibited a moderate to strong growth inhibition activity on various tumor panel cell lines between 10(-6) to 10(-5) molar concentrations. Compound 3b was the most active with a broad spectrum of activity. Compound 3c showed selectivity towards CNS-cancer SF-639, leukemia CCRF-CEM, and melanoma SK-MEL-5 (GI(50) = 4.03, 6.46, and 4.17 microM, respectively). On the other hand, the in vitro microbiological data revealed that the prepared compounds showed mild antimicrobial activity.

Synthesis, anticonvulsant, and anti-inflammatory activities of some new benzofuran-based heterocycles.

Abstract: Treatment of 2-bromoacetylbenzofuran (2) with pyridine afforded its corresponding pyridinium bromide 3. The latter salt reacted with some activated alkenes and acetylenes to give the corresponding indolizine derivatives. Treatment of the salt 3 with benzylidenemalononitriles 9 afforded polysubstituted aniline derivatives, however with arylidenecyanothioacetamides 15 it gave the corresponding 4,5-dihydrothiophenes. Bromide 3 also coupled with p-chlorobenzenediazonium salt followed by ammonium acetate to give the corresponding 1,2,4,5-tetrazine derivative. The biological activity of the newly synthesized compounds was examined and some of them were found to possess anticonvulsant and anti-inflammatory activities.

Synthesis and anticoagulant activities of substituted 2,4-diketochromans, biscoumarins, and chromanocoumarins.

Abstract: Different substituted 2,4-diketochromans, biscoumarins, and chromanocoumarins are the final products when 4-hydroxycoumarin and aromatic aldehydes containing hydroxyl group in o-, m,- or p-position condense in boiling ethanol. We synthesized 14 compounds. Three of them are described for the first time. The X-ray crystal structure analysis of 3-[6-oxo-(6H, 7H)-benzopyrano[4,3-b]benzopyran-7-yl]-4-hydroxy-2H-1-benzopyran-2-one 1 confirmed the structure of this compound. Acute toxicity studies of the compounds were performed on mice by oral and intraperitoneal administration. A comparative pharmacological study of the in vivo anticoagulant effect of the derivatives with respect to warfarin showed that the synthesized compounds have different anticoagulant activities. The most prospective compounds are 3-(3'-hydroxybenzylidene)-2,4-diketochroman 4 and 3,3'-(2-pyridylmethylene)-bis-4-hydroxy-2H-1-benzopyran-2-one 11 with low toxicity and dose-dependent anticoagulant activity in vivo.

Synthesis of Tyrosinase Inhibitory Kojic Acid Derivative

Abstract: Kojic acid derivative 2 was synthesized by joining two pyrone rings through an ethylene linkage by Horner-Emmons reaction of phosphonate 6 with aldehyde 7. The intermediates 6 and 7 were derived from kojic acid. The tyrosinase inhibitory activity of 2 was about 8 times more potent (IC(50) = 3.63 microM) than that of kojic acid (IC(50) = 30.61 microM). Compound 2 also exhibited potent melanin synthesis inhibitory activity (19.53% inhibition at 5 mug) indicating that the connection of two pyrone rings of kojic acid through a suitable linker can be an useful strategy for identification of potent tyrosinase inhibitors.

Synthesis and anti-tumor activities of novel pyrazolo[1,5-a]pyrimidines.

Abstract: A series of novel pyrazolo[1,5-a]pyrimidines were designed and synthesized in order to find novel potent anti-tumor compounds. The structures of all the compounds were confirmed by IR, (1)H-NMR, elemental analysis, and MS. Their anti-tumor activities against cancer cell lines were tested by the MTT method in vitro. Compound 19 displayed potent anti-tumor activity.

Cyanoacetic acid hydrazones of 3-(and 4-)acetylpyridine and some derived ring systems as potential antitumor and anti-HCV agents.

Abstract: Two new acetylpyridinehydrazones derived from cyanoacetic acid hydrazide have been synthesized namely: cyanoacetic acid (1-pyridin-3 or 4-yl-ethylidene) hydrazides (1a,b). and some derived ring systems: 2-imino or 2-oxo-2H-chromenes (2a,b and 3a,b), substituted 2-thioxo-2,3-dihydrothiazoles (4a-d), substituted 2-thioxo-2,3-dihydro-6H-thiazolo[4,5-d]pyrimidin-7-ones (5a-d), substituted dihydrothiazoles (7a,b), and substituted 2-oxo-1,2-dihydropyridines (8a-d and 9a,b). Fifteen compounds were evaluated for their anticancer activity using the USA-NCI in-vitro screening program. Among the tested compounds, 8d exhibited a high value of percent tumor growth inhibition at concentrations of 10(-5) to 10(-7) M in all cancer cell lines, while 8b exhibited a significant value of percent tumor growth inhibition at concentration 1b = 3a > 4c > 7a > 5c.

Curcumin analogs as potent aldose reductase inhibitors.

Abstract: In the present study, curcuminoids isolated from curcuma longa were demonstrated to possess inhibitory activities on bovine lens aldose reductase. In order to find more potent aldose reductase inhibitor, curcumin analogs were synthesized and evaluated for their ability to inhibit bovine lens aldose reductase enzyme. The results indicated that the compounds with tetrahydroxyl groups, 2,6-bis(3,4-dihydroxybenzylidene)cyclohexanone (A(2)), 2,5-bis(3,4-dihydroxybenzylidene)cyclopentanone (B(2)), 1,5-bis(3,4-dihydroxyphenyl)-1,4-pentadiene-3-one (C(2)), and 3,5-bis(3,4-dihydroxybenzylidene)-4-piperidone (D(2)) showed remarkably potent inhibitory effects on aldose reductase with IC(50) of 2.9 microM, 2.6 microM, 3.4 microM, and 4.9 microM, respectively. The structure-activity relationship revealed that the curcumin analogs with ortho-dihydroxyl groups could form a more tight affinity with aldose reductase to exert more potential inhibitory activities.

Synthesis of some oxime ether derivatives of 1 2 naphthyl 2 1 2 4 triazol 1 yl ethanone and their anticonvulsant and antimicrobial activities

Abstract: In this study, oxime and oxime ether derivatives of [1-(2-naphthyl)-2-(1,2,4-triazol-1-yl)ethanone] were prepared as potential anticonvulsant and antimicrobial compounds. The oxime was synthesized by the reaction of ketone and hydroxylamine hydrochloride. O-Alkylation of the oxime by various alkyl halides gave the oxime ether derivatives. Anticonvulsant activity of the compounds was determined by maximal electroshock and subcutaneous metrazole tests in mice and rats according to procedures of the Anticonvulsant Screening Program of National Institutes of Health. Neurotoxicity was determined by the rotorod test in mice and the positional sense test, gait and stance test in rats. In addition to anticonvulsant tests, all compounds were also evaluated against the following microorganisms: S. aureus, E. coli, P. aeruginosa, E. faecalis, C. albicans, C. parapsilosis, and C. krusei using microdilution broth method for possible antibacterial and antifungal activities. Although most of the O-alkyl substituted oxime ethers exhibited both anticonvulsant and antimicrobial activities, the O-arylalkyl substituted compounds were found to be inactive in both screening paradigms.

Inhibitory effects of triterpenes and flavonoids on the enzymatic activity of hyaluronic acid-splitting enzymes.

Abstract: The effect of triterpenes and flavonoids on the activity of several hyaluronic acid-splitting enzymes was investigated. Studies showed that the inhibitory effect of the triterpenes glycyrrhizin and glycyrrhetinic acid is dependent on the source of hyaluronate lyase. Hyaluronate lyase from Streptococcus agalactiae (Hyal B) and recombinant hyaluronate lyase from Streptococcus agalactiae (rHyal B) demonstrated strongest inhibition. In contrast, hyaluronate lyases from Streptomyces hyalurolyticus (Hyal S), Streptococcus equisimilis (Hyal C) and hyaluronidase from bovine testis (Dase) showed only reduced inhibition action. A non-competitive dead end inhibition with Ki=3.1+/-1.8x10(-6) mol/mL and Kii=6.7+/-2.4x10(-6) mol/mL was found for glycyrrhizin on recombinant hyaluronate lyase from Streptococcus agalactiae. The inhibitory effect of flavonoids on Hyal B, rHyal B and Dase was determined depending on the number of hydroxyl groups and side chain substituents in the molecule. Flavonoids with many hydroxyl groups inhibited hyaluronate lyase stronger than those with only a few. Native hyaluronate lyase (Hyal B) showed a more extensive inhibition than the recombinant protein (rHyal B). Accordingly, the inhibition by triterpenes and flavonoids is presumably specific for each hyaluronic acid (HA)-splitting enzyme.

Synthesis of 5-phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3-carboxylic acid derivatives of potential anti-inflammatory activity.

Abstract: A series of 5-phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3-carboxylic acid derivatives 4-10 were synthesized by rearrangement of 4-(3-pyridyl)-hydrazono-2-phenyl-2-oxazolin-5-one 3 in the presence of different nucleophiles to afford derivatives 4, 7, and 8, while hydroxamic acid derivative 6 was prepared from reaction of methyl ester 4 with hydroxylamine hydrochloride. Semicarbazide 9 and thiosemicarbazide 10, derivatives of the 5-phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3-carboxylic acid, were synthesized via hydrazide 8 with potassium cyanate and appropriate isothiocyanate, respectively. The structures of the synthesized compounds were confirmed by elemental analyses, IR, (1)H-NMR, and mass spectra. The results of the anti-inflammatory activity of the synthesized derivatives showed that most of the tested compounds 4-10 showed significant inhibition against carrageenan-induced rat paw edema in albino rats. Derivatives 4 and 8 showed promising results and were found to be equipotent or more potent than Indomethacin and Celecoxib as reference drugs at two dose levels, 5 and 10 mg/kg, and they have no ulcerogenic activity.

Synthesis and Molluscicidal Activity of Some 1,3,4‐Triaryl‐5‐chloropyrazole, Pyrano[2,3‐c]pyrazole, Pyrazolylphthalazine and Pyrano[2,3‐d]thiazole Derivatives

Abstract: 2-(5-Chloro-1,3-diphenyl-1H-pyrazol-4-ylmethylene)-malononitrile 1a reacts with the arylidenes of malononitrile 2a–d to afford the triaryl-5-chloropyrazoles 3a–d, respectively. 1a reacts with the active methylene pyrazolinones 5a, b and 12a, b to afford different products 8, 9, 10, 11, and 14a, b – depending on the substitution in the pyrazole ring. Compound 1a reacts also with the pyridazinone derivative 15 to afford the phthalazinone 16, and with the thiazolinones 17a–c to afford the pyrano[2,3-d]thiazoles 20a–c, respectively. It reacts also with the malononitrile dimer 21a and with ethyl cyanoacetate dimer 21b to yield the pyrazolyl pyridines 22a, b, respectively. The synthesized compounds showed a moderate molluscicidal activity towards Biomphalaria alexandrina snails.

Synthesis of new 3-(substituted phenacyl)-5-[3'-(4H-4-oxo-1-benzopyran-2-yl)-benzylidene]-2,4-thiazolidinediones and their antimicrobial activity.

Abstract: Synthesis of 3-(3-nitrophenacyl)thiazolidine-2,4-dione 2g and 3-(substituted phenacyl)-5-[3'-(4H-4-oxo-1-benzopyran-2-yl)-benzylidene]-2,4-thiazolidinediones 4a-g are reported in this paper. These compounds 4a-g were prepared from 3'-flavone carboxaldehyde and 3-substituted phenacyl-2,4-thiazolidinediones using Knoevenagel reaction. The structures of all compounds were confirmed by IR, 1 H-NMR, mass spectral data, and elemental analyses. The molecules 4a-g were evaluated for in-vitro antimicrobial activity against Staphylococcus aureus, Candida albicans, Candida krusei, Candida glabrata, and Candida parapsilosis. Compounds 4c and 4f showed better inhibitory activity when compared to fluconazole against Candida krusei and Candida glabrata.

Synthesis and anti-inflammatory activities of new cyanopyrane derivatives fused with steroidal nuclei.

Abstract: Thirteen new heterocyclic derivatives containing a cyanopyrane ring fused to a steroidal moiety were conveniently synthesized and screened for their anti-inflammatory potencies comparable to that of the glucocorticoid prednisolone. Four compounds 5a, 5b, 6b, and 8 exhibited superior anti-inflammatory indices (in rats, protection against carrageenan induced edema and inhibition of plasma PGE). All the candidates were less toxic than the reference drug concerning LD(50) values. Synthetic steroidal structures fused to a substituted cyanopyrane ring seem to be a promising approach in search for novel leads for potent anti-inflammatory agents.

Antileishmanial and antibacterial activity of a new pyrazole derivative designated 4-[2-(1-(ethylamino)-2-methyl- propyl)phenyl]-3-(4-methyphenyl)-1-phenylpyrazole.

Abstract: Here, we report for the first time the synthesis and the antileishmanial activity of a new pyrazole derivative, namely 4-[2-(1-(ethylamino)-2-methylpropyl)phenyl]-3-(4-methyphenyl)-1-phenylpyrazole). Micromolar concentrations of this compound were found to inhibit the in vitro multiplication of Leishmania tropica, Leishmania major, and Leishmania infantum, three species causing different forms of leishmaniasis. Furthermore, the 50% inhibitory concentration (IC50) values for the compound are only slightly higher than those of amphotericin B, one of the most active antileishmanial agents used as a satisfactory substitute in cases not responding to pentostam. The IC50 values after 48 h for L. tropica, L. major, and L. infantum promastigote growth were 0.48 microg/mL, 0.63 microg/mL and 0.40 microg/mL, respectively for the compound, while they were 0.23 microg/mL, 0.29 microg/mL and 0.24 microg/mL, respectively for amphotericin B. We also tested this compound for its antibacterial activity against several bacteria. The strongest antibacterial activity was observed against Entrococcus feacalis and Staphylococcus aureus with a minimal inhibitory concentration (MIC) of 60 microg/mL.

Potential Tuberculostatic Agent: Micelle-forming Pyrazinamide Prodrug

Abstract: Pyrazinamide was condensed with the poly(ethylene glycol)-poly(aspartic acid) copolymer (PEG-PASP), a micelle-forming derivative was obtained that was characterized in terms of its critical micelle concentration (CMC) and micelle diameter. The CMC was found by observing the solubility of Sudan III in Poly(ethylene glycol)-poly(pyrazinamidomethyl aspartate) copolymer (PEG-PASP-PZA) solutions. The mean diameter of PEG-PASP-PZA micelles, obtained by analyzing the dynamic light-scattering data, was 78.2 nm. The PEG-PASP-PZA derivative, when assayed for anti-Mycobacterium activity, exhibited stronger activity than the simple drug.

The oriented development of antituberculotics: salicylanilides.

Abstract: On the basis of our previous results 22 salicylanilides were synthesized. The compounds were tested for in vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii, and Mycobacterium avium. The Free-Wilson method was used to evaluate structure-antimycobacterial activity relationships. 4-Chloro-N-(4-propylphenyl)salicylamide and 5-chloro-N-(4-propylphenyl)salicylamide were selected for preclinical studies.

Synthesis of β-Hydroxypropanoic Acid Derivatives as Potential Anti-inflammatory, Analgesic and Antimicrobial Agents

Abstract: A series of new 3-(substituted) 3-hydroxy-propanoic acid ethyl esters 1a-c, hydrazides 2a-c, thiosemicarbazides 3a-f, and semicarbazides 3g, 3h has been synthesized. Cyclization of compounds 3a-d in basic medium yielded 1,2,4-triazole-5-thiones 4a-d. On the other hand, reaction of hydrazides 2a-c with CS(2 )in basic medium afforded 1,3,4-oxadiazole-5-thiones 5a-c. All the synthesized compounds were characterized by their physical and spectral analyses data. The newly synthesized compounds were evaluated for their anti-inflammatory, analgesic, and antimicrobial activities. Compounds 1c, 3g, 4a, 4b, 4c, and 5c exhibited comparable anti-inflammatory activity to that of indomethacin and compounds 1c, 4c, and 5c were more analgesics than acetyl salicylic acid. Compounds 4b, 4c, and 5c showed superior GI safety profile (33.3%, 33.3% and 50.0% ulceration) than that of indomethacin (100% ulceration) at 100 mg/kg oral dose. Compounds 4b, 4c, and 5c were also non-toxic with a median lethal dose (LD(50)) up to 200 mg/kg. The antibacterial and antifungal screenings identified compounds 3c, 4b, 4d, 5a, and 5b as the most effective against a variety of tested microorganisms.

A Study of Anti‐inflammatory Activity of Some Novel α‐Amino Naphthalene and β‐Amino Naphthalene Derivatives

Abstract: In the present study, some naphthalene derivatives have been synthesized by incorporating azetidinyl and thiazolidinyl moieties at its alpha- or beta-positions such as alpha-(3-chloro-2-oxo-4-substituted)aryl-1-azetidinyl)naphthalenes 6-10, alpha-((substituted)aryl-4-oxo-1,3-thiazolidin-3-yl)naphthalenes 11-15, beta-(3-chloro-2-oxo-4-substituted aryl-1-azetidinyl)naphthalenes 21-25, and beta-(substituted aryl-4-oxo-1,3-thiazolidin-3-yl)naphthalenes 26-30. These compounds have also been screened for acute toxicity and anti-inflammatory and analgesic activities. Compounds which showed better anti-inflammatory and analgesic activities were also examined for their ulcerogenic liability and underwent a cyclooxygenase assay. Two compounds, 12 and 28, were found to exhibit potent anti-inflammatory activity as compared to the standard drugs phenylbutazone and naproxen.

The role of the HPA axis in psychiatric disorders and CRF antagonists as potential treatments.

Abstract: An overview of the links between the Hypothalamic-Pituitary-Adrenal (HPA) axis and psychiatric disorders is presented. The current treatments are outlined, indicating that they are insufficient to meet the needs of those that suffer from these affective disorders. Therefore, there is an urgent need for the generation of new therapeutics, in particular, against new targets. The association of the corticotrophin releasing factor (CRF) and the HPA axis indicates that CRF antagonists should be beneficial as potential therapeutics.

Novel Pirfenidone Analogues: Synthesis of Pyridin-2-ones for the Treatment of Pulmonary Fibrosis

Abstract: A new series of polysubstituted 1-aryl-2-oxo-1,2-dihydropyridine-3-carbonitriles and pyrazolo[3,4-b]pyridine-5-carbonitriles and pyrido[2,3-d]pyrimidine-6-carbonitriles have been synthesized and tested for their antifibrotic activity. Among the tested compounds, compounds IIc and IVb exhibited higher antifibrotic activity than the standard pirfenidone PD with a reduction of the hydroxyproline level to 50 and 140 micromol/lung, respectively. However, bicyclic pyridone VIIIb displayed a high mortality rate. Detailed syntheses, spectroscopic and biological data are reported.

Synthesis and biological evaluation of some hydroxypyrazole derivatives as anti-inflammatory-antimicrobial agents.

Abstract: Some hydroxypyrazole derivatives 2-7 were synthesized by cyclocondensation of the keto-ester 1 with hydrazines hydrate or substituted hydrazines followed by reduction and acylation with acetic anhydride or trifluoroacetic anhydride. The newly synthesized compounds were evaluated for their anti-inflammatory, antimicrobial activities. In addition, the ulcerogenic and acute toxicity profiles were determined. Compounds N-(4-(5-hydroxy-1-trifluoroacetyl-1H-pyrazol-3-yl)phenyl) trifluoroacetamide 4b, 3-(4-nitrophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-ol 5b, and N-(4-(5-hydroxy-1-methyl-1H-pyrazol-3-yl)phenyl)trifluoroacetamide 7b were proved to be the most active anti-inflammatory, antimicrobial agents in the present study with a good safety margin and minimal or no ulcerogenic effect.

4-chloro-2,2-disubstituted chromen-3-carboxaldehyde : Synthesis of some fused polycyclic heterocycles as anti-inflammatory, analgesic, anticonvulsant, and antiparkinsonian agents

Abstract: Some new aldazino 4, pyrazolo 5, thieno 8, and thiooxopyrimidino chromenes 10 were prepared via reaction of the corresponding β-chlorocarboxaldehyde 3 with hydrazine hydrate, mercaptoacetic acid, and thiourea, respectively. Wherever, 4-chlorochromene derivatives 2 along with 4-chlorochromen-3-carboxaldehyde derivatives 3 were prepared from the corresponding ketone 1 with Vilsmeier-Haack reagent. Some of the new products showed good anti-inflammatory, analgesic, anticonvulsant, and antiparkinsonian activities comparable to indomethacin, diclofenace, carbamazepine, and benztropine.

Synthesis of Some Novel Azo Derivatives of 3,5-Dimethly-1-(2-hydroxyethyl)pyrazole as Potent Analgesic Agents

Abstract: A series of 1-(2-hydroxyethyl)-3,5-dimethylpyrazolylazo derivatives, incorporating thiosemicarbazide 2a-c, 1,3,4-thiadiazole 3a-c, and 1,2,4-triazole-3-thione 4a-c were synthesized. The structure of these novel synthesized compounds 2a-c, 3a-c, and 4a-c was confirmed by spectral analysis. All these compounds were screened for their analgesic activity. Hot-plate and tail-immersion tests were used for the determination of the analgesic activity. Morphine, an analgesic through both spinal and supraspinal pathways, was used as a standard test drug. All compounds were administered at a dose of 100 mg/kg i.p. Among the compounds, 2-(butylamino)-5-[((1-(2-hydroxyethyl)-3,5-dimethylpyrazole-4-yl)azo)phenyl]-1,3,4-thiadiazole 3a and 4-[((1-(2-hydroxyethyl)-3,5-dimethylpyrazole-4-yl)azo)phenyl]-4-(2-phenethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione 4c showed analgesic effects in both tests. Especially 4c exerted strong analgesia starting at 30 min after injection.

3D pharmacophore models for 1,2,3,4-tetrahydroisoquinoline derivatives acting as anticonvulsant agents.

Abstract: A 3D pharmacophore model predicting anticonvulsant activity was obtained for a series of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives recently disclosed as a new class of noncompetitive AMPA receptor antagonists The training set included 17 compounds with varying potency against audiogenic seizures in DBA/2 mice The best statistical hypothesis, generated with the HypoGen module of Catalyst 49, consisted of five features: two hydrogen bond acceptors, two hydrophobic features, and one hydrophobic aromatic region, providing a model with a correlation coefficient of 0919 The obtained model was an efficient tool in the design of some new anticonvulsant agents containing the tetrahydroisoquinoline scaffold Moreover, in order to explain the different degree of efficacy of the newly designed N-substituted derivatives, excluded volumes were also considered

Synthesis and in vitro-anticancer and antimicrobial evaluation of some novel quinoxalines derived from 3-phenylquinoxaline-2(1H)-thione.

Abstract: Two novel series derived from 3-phenylquinoxaline-2(1H)-thione 2 and 2-(hydrazinocarbonylmethylthio)-3-phenylquinoxaline 6 have been synthesized. Eight out of twenty six new compounds were selected at the National Cancer Institute for evaluation of their in vitro-anticancer activity. Among them, compounds 3b, 3c, 4b, and 4c displayed moderate to strong growth inhibition activity against most of the tested sub-panel tumor cell lines with GI(50) 10(-5) to 10(-6 )molar concentrations. Compound 4b exhibited a significant value of percent tumor growth inhibition against breast cancer at concentration < 10(-8) M. Compound 4c showed moderate selectivity towards leukemia cell lines with GI(50) of 1.8 to 3.8 microM (selectivity ratio = 5.7). Preliminary antimicrobial testing revealed that compounds 7a, 7b, 8a, 11a, and 11b were as active as ampicillin against B. subtilis (MIC = 12.5 microg/mL). Compounds 7b and 8a were also nearly as active as ampicillin against E. coli (MIC = 12.5 microg/mL). In addition, compounds 4a, 7b, 10b, and 11a were as active as ampicillin against P. aerugenosa (MIC = 50 microg/mL). However, compounds 7b, 8a, and 10b showed mild activity against C. albicans (MIC = 50 microg/mL). The values of minimum bactericidal concentrations indicated that compounds 4a and 7b were bactericidal against B. subtilis and P. aerugenosa, respectively, while compound 10b was bactericidal against both organisms. However, compound 11a was bactericidal against E. coli, P. aerugenosa, and S. aureus.

Antinociceptive effects of synthetic chalcones obtained from xanthoxyline.

Abstract: A wide variety of noxious stimuli are known to induce a sensation of pain evoked in a remote region of the body. Here, we show that chalcones can inhibit the pain provoked by the administration of an intraperitoneal acetic acid (AA). This study investigates the effects of 17 synthetic chalcones in the writhing test, a visceral pain model in mice. The majority of these compounds proved more active than some analgesic drugs, such as aspirin and acetaminophen, two reference drugs used here for comparison. Four chalcones, 9, 10, 16, and 17, were selected for more detailed studies, since they exhibited significant antinociceptive activities and chemical structures of interest. They caused dose-related inhibitions, proving about 15-, 10-, 9-, and 8-fold more active than the standard drugs. When administrated orally, only chalcone 9 proved to be effective. These chalcones might be further used as a model to obtain new and more potent analgesic drugs.

Synthesis of new thiazolylthiazolidinylbenzothiazoles and thiazolylazetidinylbenzothiazoles as potential insecticidal, antifungal, and antibacterial agents.

Abstract: A series of 2-{[2'-(3''-chloro-2''-oxo-4''-substitutedaryl-1''-azetidinyl)-1',3'-thiazol-4'-yl] thio}benzothiazoles (4a-4e) and 2-{[(2'-(2''-substitutedaryl-4''-thiazolidinon-3''-yl)-1',3'-thiazol-4'-yl]thio}benzothiazoles (5a-5e) have been synthesized from 2-[(2'-substitutedarylidenylimino-1',3'-thiazol-4'-yl)thio]benzothiazoles (3a-3e). The structure of these compounds has been elucidated by elemental (C, H, N) and spectral (IR, (1)H-NMR, Mass) analysis. Furthermore, compounds 3a-3e, 4a-4e, and 5a-5e were screened for insecticidal activity against Periplaneta americana and antifungal, antibacterial activities in vitro against different strains of fungi and bacteria. Out of the fifteen compounds tested, compound 5b, 2-{[2'-(2''-p-hydroxy-m-methoxyphenyl)-4''-thiazolidinon-3''-yl)-1',3'-thiazol-4'-yl]thio}benzothiazole, was found to possess most prominent insecticidal activity.

Synthesis and biological evaluation of some pyrrolo[2,3-d]pyrimidines.

Abstract: Pyrrolo[2,3-d]pyrimidine and tetrazolopyrimidine derivatives 2a, b-5a, b were prepared. Also, acyclic and cyclic C-nucleosides 7a, b-12a, b were prepared by treating compound 6 with some aldoses. All prepared products were tested for antiviral activity against hepatitis-A virus (HAV, MBB-cell culture adapted strain) and herpes simplex virus type-1 (HSV-1). Plaque reduction infectivity assay was used to determine virus count reduction as a result of treatment with tested compounds. Compound 2a showed the highest effect on HAV, while compound 11b showed the highest effect on the HSV-1 virus.