Showing papers in "Archiv Der Pharmazie in 2003"

1-N-substituted thiocarbamoyl-3-phenyl-5-thienyl-2-pyrazolines: synthesis and evaluation as MAO inhibitors.

Abstract: Twelve new 1-N-substituted thiocarbomoyl-3-phenyl-5-thienyl-2-pyrazoline derivatives were synthesized and evaluated their for antidepressant, anxiogenic and mammalian monoamine oxidase (MAO)-A and Binhibitory activities by in vivo and in vitro tests. MAO was isolated and purified from the mitochondrial pellet of bovine liver homogenates and human platelets. All of the new compounds inhibited the total MAO activity of liver homogenates and the inhibition was found to be time-dependent. Four compounds (3 i-3 l) inhibited MAO-B selectively and irreversibly in a classical non-competitive manner with IC(50) values in the range of 22.00-91.50 microM. The rest of the compounds appeared to be non-selective reversible inhibitors. It was suggested that the p-methoxy group on the phenyl ring in the compounds increased the inhibitory effect and selectivity toward MAO-B. The reversible and unselective inhibition of MAO by the remaining compounds was suggested to be related to their properties of acting ability to act as both as substrate and inhibitor at the same time. However, none of the novel compounds showed antidepressant activity as expected suggesting formation of inactive metabolites. We conclude that the compounds appeared as which functioned as selective MAO-B inhibitors might have promising features as therapeutic properties in the treatment of Parkinson disease. In vivo studies are needed to verify this hypothesis.

Novel 3,3a,4,5,6,7-hexahydroindazole and arylthiazolylpyrazoline derivatives as anti-inflammatory agents.

Abstract: A novel series of 7-benzylidene-3, 3a, 4, 5, 6, 7-hexahydro-3-phenyl-2H-indazole substituted at the 2-position were synthesized. The reaction of 2, 6-bis-benzylidenecyclohexanone (1) with thiosemicarbazide in the presence of NaOH afforded a mixture of the 3-H, 3a-H trans 2 and cis 2a diastereoisomers which have been separated by fractional recrystallization. Interaction of the first intermediate 2 with substituted phenacyl bromides, aromatic aldehydes and chloroacetic acid in presence of a mixture of acetic acid and acetic anhydride, and 2, 3-dichloroquinoxaline yielded the corresponding 7-benzylidene-3, 3a, 4, 5, 6, 7-hexahydro-3-phenyl-2H-indazole derivatives substituted at the 2-position with 4-aryl-2-thiazolyl 3a, b, 5-arylidene-4, 5-dihydro-4-oxo-2-thiazolyl 4a, b and thiazolo[4, 5-b]quinoxalin-2-yl 5, respectively. Moreover, the other intermediates 3, 5-diaryl-1-thiocarbamoyl-2-pyrazolines 7a-d were reacted with the previously-mentioned reagents and gave the corresponding 3, 5-diaryl-1-(4-aryl-2-thiazolyl)-2-pyrazolines 8a-h, 3, 5-diaryl-1-(5-arylidene-4, 5-dihydro-4-oxo-2-thiazolyl)-2-pyrazolines 9a-d and 3, 5-diaryl-1-(thiazolo[4, 5-b]quinoxalin-2-yl)-2-pyrazoline derivatives 10a, b, respectively. Some of the newly prepared compounds were subjected to evaluation for their anti-inflammatory activity. The structures of the new compounds were confirmed by elemental analyses as well as (1)H-NMR, IR, and MS data.

Design and synthesis of some substituted 1H-pyrazolyl-oxazolidines or 1H-pyrazolyl-thiazolidines as anti-inflammatory-antimicrobial agents.

Abstract: Four series of 1 H-pyrazole derivatives have been synthesized. The first series was synthesized starting with the reaction of 3-(5-bromo-2-thienyl)-1-phenyl-1 H-pyrazole-4-carboxaldehyde 1 with L-serine, L-cysteine, or L-penicillamine, followed by N-protection using (Boc)(2)O to provide compounds 2. The latter compounds could be N-deprotected by 4N HCl/dioxane to afford the second series 3 or reacted with NH(4)OH in the presence of DCC/HOBt to give the corresponding amides 4 followed by N-deprotection giving rise to compounds 5. The newly synthesized compounds were evaluated for their anti-inflammatory-antimicrobial activities. In addition, the ulcerogenic and acute toxicity profiles were determined. Compound 5b (2RS, 4R)-2-[3-(5-bromo-2-thienyl)-1-phenyl-1H-pyrazol-4-yl]-5-methylthiazolidine-4-carboxamide, proved to be the most active anti-inflammatory-antimicrobial agent in the present study with a good safety margin and no ulcerogenic effect.

Antimycobacterial activity of 1-substituted indolizines.

Abstract: Indolizine derivatives were tested as antimycobacterials against Mycobacterium tuberculosis H(37)Rv (ATCC 27294)in BACTEC 12B medium using the Microplate Alamar Blue Assay. The most active compounds examined carry an alpha-hydroxybenzyl substituent in the indolizine 1-position. MICs against Mycobacterium tuberculosis for these compounds were 6.25 microg/mL

Relationship between the structure and antimycobacterial activity of substituted salicylanilides.

Abstract: A series of 143 salicylanilides substituted in positions 4 and 5 and in positions 3' and 4' was synthesized. The compounds were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii, and Mycobacterium avium. To describe the structure-antimycobacterial activity relationships (QSARs), an approach based on the combination of the Free-Wilson and Hansch methods was employed (the substituent constants were used in the case of the substituents on the phenyl ring; indicator parameters were used for the substituents on the acyl moiety). The relationships between the antimycobacterial activity and physico-chemical parameters of all substituents were also explored. The quadratic representation of lipophilicity parameters did not lead to significant correlations.

Synthesis and in vitro evaluation of the anticancer activity of novel fluorinated thiazolo[4, 5-d]pyrimidines.

Abstract: The synthesis of several thiazolo[4, 5-d]pyrimidines containing a fluorophenyl moiety substituted at different positions and through different bridges is described. Twenty new compounds were prepared and evaluated for their anticancer activity using the USA-NCI in-vitro screening program. Three compounds were found active and their anticancer activity against 60 human tumor cell lines are described in detail.

Activities of Prenylphenol Derivatives from Fruitbodies of Albatrellus spp. on the Human and Rat Vanilloid Receptor 1 (VR1) and Characterisation of the Novel Natural Product, Confluentin

Abstract: Several prenylphenols from basidiocarps of European and Chinese Albatrellus spp., namely grifolin (1), neogrifolin (2), confluentin (3), scutigeral (4), and albaconol (5) were investigated concerning their activities in test models for vanilloid receptor modulation. The isolation of these compounds from A. confluens and structure elucidation of the novel natural product confluentin (3) are described. The effects of scutigeral and neogrifolin on vanilloid receptors were studied by means of electrophysiological methodology on rat dorsal root ganglion neurons as well as on recombinant cell lines expressing the rat VR1 receptor. Concurrently, the effects of compounds 1-5 on a reporter cell line expressing the human vanilloid receptor VR1 were measured. In contrast to previous studies reported in the literature, the results of these investigations suggest that fungal prenylphenols act as weak antagonists (activity in the muM range), rather than exhibiting agonistic activities.

Substituted Quinazolines, Part 2. Synthesis and In‐Vitro Anticancer Evaluation of New 2‐Substituted Mercapto‐3H‐quinazoline Analogs

Abstract: A new series of 2-substituted mercapto-3H-quinozolines bearing 6-iodo and 2-heteroarylthio functions was synthesized and screened for their in vitro antitumor activity. Eighteen compounds were identified as active anticancer agents. N'-[(3-Benzyl-4-oxo-6-iodo-3H-quinazoline-2-yl)thioacetyl]-N(3)-ethylthiosemicarbazide (10), N-benzoyl-N'-[2-(3-benzyl-4-oxo-6-iodo-3H-quinozolin-2-yl)thioacetyl]hydrazine (12), and 2-[(3, 6-dioxo-pyridazin-4-yl)thio]-3-benzyl-4-oxo-6-iodo-3H-quinazoline (20) proved to be the most active members in this study. They showed MG-MID, GI(50) values of 12.8, 11.3, and 13.8 microM, respectively. The detailed synthesis and biological screening data are reported.

Investigations of new pyridazinone derivatives for the synthesis of potent analgesic and anti-inflammatory compounds with cyclooxygenase inhibitory activity.

Abstract: In this study we describe the synthesis of two novel 4-phenyl-and 4-(2-chlorophenyl)-6-(5-chloro-2-oxo-3H-benzoxazol-7-yl)-3(2H)-pyridazinone derivatives (compounds 8a and b) and their testing as inhibitors of cyclooxygenases (COX-1 and COX-2). Both compounds inhibited COX-1 (by 59 % and 61 % for compounds 8a and 8b respectively and COX-2 (by 37 % and 28 % for compounds 8a and 8b respectively) at a concentration of 10 microM. Furthermore, we tested the analgesic and anti-inflammatory activities of the synthesized compounds in vivo by using the p-benzoquinone-induced writhing test and the carrageenan-induced hind paw edema model, respectively. Compounds 8a and 8b showed potent analgesic and anti-inflammatory activities without causing gastric lesions in the tested animals.

Studies on novel 7-acyl-5-chloro-2-oxo-3H-benzoxazole derivatives as potential analgesic and anti-inflammatory agents.

Abstract: In this study, a series of (7-acyl-5-chloro-2-oxo-3H-benzoxazol-3-yl)alkanoic acid derivatives were synthesized and evaluated for their analgesic and anti-inflammatory activities by using the p-benzoquinone-induced writhing test and the carrageenan hind paw edema model, respectively. Acetic acid-induced peritoneal capillary permeability test and serotonin-induced hind paw edema test were also employed for the most active compounds. The test results indicated that (7-acyl-2-oxo-3H-benzoxazol-3-yl)alkanoic acids (Compounds 6 a-c, 8 a-c, 10 a-c) were equally or more potent analgesic and anti-inflammatory agents than aspirin and indomethacin respectively. The compounds 8 a and 8 c, but not 8 b which have the longest carbon chain on alkanoic acid moiety did not induce gastric lesion in mice.

Synthesis, biological activity, and docking studies of new acetylcholinesterase inhibitors of the bispyridinium type.

Abstract: A novel series of acetylcholinesterase (AChE) inhibitors of the bispyridinium type was synthesized and the inhibitory activity against AChE and butyrylcholinesterase (BChE) measured. In essence, the substitution pattern influenced the inhibitory potency against AChE, where the most active bispyridiniumoxime (TMB-4) was bisbenzyl substituted followed by monobenzyl substituted, bismethyl substituted, and unsubstituted derivatives of TMB-4. Hence, the bisbenzyl ether of TMB-4 was further investigated. In order to obtain diverse lipophilic and electronic properties for these bisbenzyl bispyridinium derivatives (so-called DUO series), the lateral ring substitution was systematically varied. The lowest IC(50) value against AChE found thus far in the DUO series was 0.34 microM. Docking studies were carried out to elucidate the differences in biological activity. A general binding mode for nearly all compounds could be identified by these investigations. In this binding mode, the docked ligands span the narrow, deeply buried active-site gorge, interacting with Trp84 at the bottom of the gorge, Tyr334 or Phe331 halfway down the gorge, and Trp279 at the peripheral anionic site at the mouth of the gorge. For specific ligands, additional interactions were found which helped to explain their deviating activity. Based on the promising characteristics of the novel acetylcholinesterase inhibitors presented, a series of structurally related, optimized candidates will be developed.

Synthesis and analgesic and anti-inflammatory activity of some new (6-acyl-2-benzoxazolinone and 6-acyl-2-benzothiazolinone derivatives with acetic acid and propanoic acid residues.

Abstract: In this study for developing potent analgesic and anti-inflammatory compounds, we synthesized 6-acyl-2-benzoxazolinone and 6-acyl-2-benzothiazolinone derivatives with acetic acid and propanoic acid side chain, and performed preliminary screening of their in vivo analgesic and anti-inflammatory activities at a single dose of 100 mg/kg inmice by a p-benzoquinone-induced writhing test and a Carrageenaninduced hind paw edema model, respectively. We also determined their gastric ulceration effects in the tested animals. Propanoic acid derivatives were generally found to have higher analgesic and anti-inflammatory activities, and among them, 3-(6-benzoyl-2-benzothiazolinon-3-yl)propanoic acid (Compound 4 a) exhibited the highest analgesic and anti-inflammatory activity. However, all compounds showed lower anti-inflammatory effects than we observed for indomethacin at 10 mg/kg dose. Consequently, 6-acyl-2-benzoxazolinone/2-benzothiazolinones having propanoic acid side chain might lead to further studies for developing better candidates with potent analgesic and anti-inflammatory effects while acetic acid derivatives do not exhibit comparable satisfactory features.

Synthesis of Novel Isoxazolidine Derivatives and Their Antifungal and Antibacterial Properties

Abstract: The synthesis of some biologically interesting isoxazolidine derivatives has been accomplished by the cycloaddition reaction of C-(4-biphenyl)-N-(3-methylphenyl) nitrone and C-(4-biphenyl)-N-(3-chlorophenyl) nitrone to monosubstituted alkenes. The compounds were screened for their antibacterial and antifungal activities. Among the tested compounds 3a (ii), 3a (vii), 3a (viii), 3b (iv), 3b (vii), and 3b (viii) showed significant antifungal activity comparable with that of the standard drug Nystatin against Botrydiplodia theobromae.

Antimycobacterial and antifungal isosters of salicylamides.

Abstract: A set of 40 derivatives of 3-hydroxypicolinic acid and 2-sulfanylbenzoic acid, isosteric to salicylanilides was synthesized. The compounds were evaluated for in vitro activity against Mycobacterium tuberculosis, Mycobacterium kansasii and Mycobacterium avium, Candida albicans, Candida tropicalis, Candida krusei, Candida glabrata, Trichosporon beigelii, Aspergillus fumigatus, Absidia corymbifera, Trichophyton mentagrophytes and Microsporum gypseum. Structure-activity relationships of antimycobacterial activity and antifungal activity against T. mentagrophytes and M. gypseum were analyzed by the Free-Wilson method. An increase in antimycobacterial activity was observed only for the sulfanylbenzoic acid derivatives, especially those with the benzyl moiety. The antifungal activity was not significant.

Synthesis and in vitro antibacterial evaluation of novel imidazo[2',1':5,1]-1,2,4-triazolo[4,3-c]-quinazoline derivatives of 5-thioxo-1, 2, 4-triazole, 4-oxothiazolidine, and their open-chain counterparts.

Abstract: Two novel series of imidazo[2′, 1′:5, 1]-1, 2, 4-triazolo[4, 3-c]quinazolines bearing 5-thioxo-1, 2, 4-triazoles, 6a—f, and 4-oxothiazolidines, 7a—f, were synthesized from corresponding thiosemicarbazide derivatives, 5a—f The stepwise methodology applied to the preparation of compounds 5a—f was initiated with reaction of the parent 3-amino-1, 2, 4-triazolo[4, 3-c]quinazolines, 2, with ethyl 2-chloroacetoacetate resulting in annelation of the imidazole ring to give esters, 3a—c However, hydrazinolysis of these ester derivatives gave the corresponding acid hydrazides, 4a—c, which on reaction with the appropriate alkyl isothiocyanate yielded compounds 5a—f In turn, compounds 5, were cyclized with potassium hydroxide or with ethyl bromoacetate to give the corresponding thioxotriazoles 6 and oxothiazolidines 7, respectively All synthesized compounds were screened for their in vitro antibacterial activity against various Gram-positive and Gram-negative bacteria Some test compounds were found to possess potent antibacterial activities Compound, 7f, exhibited much higher potency than the reference standard ciprofloxacin, against both types of bacteria, particularly, Gram-positive organisms

4‐(5‐Chloro‐2(3H)‐benzoxazolon‐3‐yl) Butanoic Acid Derivatives: Synthesis, Antinociceptive and Anti‐inflammatory Properties

Abstract: In this study, 4-(5-chloro-2(3H)-benzoxazolone-3-yl)butanoic acid and its ethyl ester as well as its ten new amide derivatives have been synthesized. Their structures have been elucidated by IR, 1H-NMR spectra and elemental analysis. The compounds were screened for antinociceptive and anti-inflammatory activities. The highest antinociceptive and anti-inflammatory activities were exhibited by Compound 11 which has carboxylic acid structure. A various decrease in antinociceptive and anti-inflammatory activity was observed by amidation of the carboxylic acid moiety of this compound.

1, 2-dihydroisoquinoline-N-acetic acid derivatives as new carriers for specific brain delivery I: synthesis and estimation of oxidation kinetics using multivariate calibration method.

Abstract: In order to overcome the slow oxidation of 1, 2-dihydro-N-alkylisoquinoline, 1, 2-dihydroisoquinoline-N-acetic acid derivatives (3b—d) were designed and synthesized as new chemical delivery systems (CDS) for the brain. Molecular orbital calculations for the suggested derivatives revealed that these carriers are stable against oxidation. However, hydrolysis to their corresponding anions will accelerate the rate of oxidation, and accordingly increase the efficiency of brain specific delivery. A multivariate calibration method for in vitro determination of the oxidation rate for the suggested brain specific chemical delivery system is described. The method is based on measurement of individual rates of oxidation of prepared 1, 2-dihydroisoquinolines, using silver ions to provide the corresponding quaternary forms. Components of binary mixtures formed through the oxidation step (composed of the dihydro-compound and its quaternary form), showed a considerable degree of spectral overlapping — more than 90% in all cases. Resolution of these binary mixtures under investigation has been accomplished mainly using classical least squares analysis. Kinetic oxidation data of the tested compounds revealed that these new CDSs have a reasonable oxidation rate for efficient brain delivery.

Synthesis and Pharmacological Investigations of Some 4-Hydroxycoumarin Derivatives

Abstract: The synthesis of ten coumarin derivatives of 4-hydroxycoumarin and various unsaturated ketones and aldehydes is described. The structures of the synthesized compounds were confirmed by IR, (1)H-NMR, and mass-spectral data. Acute toxicity studies of the compounds were performed on mice by oral and intraperitoneal administration. A comparative pharmacological study of the in vivo anticoagulant effects of the derivatives with respect to warfarin, showed that the compounds have anticoagulant activity. Compounds 4-hydroxy-3-[1-phenyl-2-(4'-chlorobenzoyl)ethyl]-2H-1-benzopyran-2-one 2b, 4-hydroxy-3-[1-(4-fluorophenyl)-3-oxobutyl]-2H-1-benzopyran-2-one 3a, and 3, 3'-p-bromobenzylidene-bis-(4-hydroxy-2H-1-benzopyran-2-one) 4b showed slight acute toxicity and a greater anticoagulant effect than warfarin.

New Cyanopeptide‐Derived Low MolecularWeight Thrombin Inhibitors

Abstract: Thrombosis is the result of defective regulation of the hemostasis system. This cardiovascular disorder may lead to deep vein thrombosis, myocardial infarction, and stroke. The majority of current drug research is focused on finding inhibitors of thrombin - the global player in hemostasis. In our work, we emphasize investigation of the marine environment to yield new lead structures from marine organisms like blue-green algae (cyanobacteria). This article deals with the design, syntheses, and inhibition tests of new low molecular weight thrombin inhibitors utilizing cyanopeptides, the secondary metabolites of cyanobacteria with interesting biological activities, as new lead structures. Starting with aeruginosin 98-B (2) as a lead structure, we have developed and synthesized new, selective acting inhibitors of thrombin (RA-1001 and RA-1002), which are suitable targets for further structure-activity studies.

Synthesis, in vitro and in vivo evaluation of a delivery system for targeting anticancer drugs to the brain.

Abstract: A 1, 4-dihydropyridine pyridinium salt type redox system is described as a general and flexible method for site-specific and sustained delivery of drugs to the brain. This concept was used in the present investigation as a model to deliver an alkylating antitumor agent into the brain. A bis-(chloroethyl)amine drug was hooked to 1, 4-dihydropyridine chemical delivery system (CDS) through an amide linkage. Five new-target compounds (23-27) of the 1, 4-dihydropyridine CDS type were synthesized through the reduction of five new pyridinium quaternary intermediates (18-22). The synthesized 1, 4-dihydropyridines were subjected to various chemical and biological investigations to evaluate their ability to cross the blood-brain barrier (BBB), and to be oxidized biologically into their corresponding quaternary compounds. The in vitro oxidation studies showed that 1-benzyl-3-[N-[2-bis(2-chloroethyl)aminoethyl]-carbamoyl]-1, 4-dihydropyridine (23) and 1-(4-nitrobenzyl)-3-[N-[2-bis(2-chloroethyl)aminoethyl ]carbamoyl]-1, 4-dihydropyridine (27) could be oxidized into their corresponding quaternary compounds 18 and 22 respectively, at an adequate rate, which ensure the release of the carried anticancer drug. The in vivo studies showed that compound 23 was able to cross the BBB at detectable concentrations. On the other hand, the in vitro alkylation activity studies revealed that 1-(4-nitrobenzyl)-3-[N-[2-bis(2-chloroethyl)aminoethyl]carbamoyl]pyridinium bromide (22) is an alkylating agent with activity comparable to the known drug chlorambucil.

Synthesis of 5-substituted 2-methylbenzimidazoles with anticancer activity.

Abstract: A series of compounds comprising the thiocarboximidopyrazolyl 5, the phenylpyrazolyl 6, the dimethylpyrazolyl 7, the nitrophenylpyrazolyl 8, the dimethyloxazolyl 9, the benzoxazepinyl 10, and pyrimidyl 11 a-c derivatives of 3-(2-methyl-1H-benzimidazol-5-ylazo)pentane-2, 4-dione was synthesized. Moreover, 5-amino-2-methylbenzimidazole (3) was reacted with phthalic anhydride or maleic anhydride in acetic acid or in toluene to produce 12-15. Treating 5, 6-diamino-2-methylbenzimidazole (16) with ethyl cyanoacetate or diethyl malonate or acetyl acetone leads to the formation of the benzodiazepine derivatives 17-20. The cytotoxic activity of the compounds 2, 7, 9, 10, and 11 was tested against 60 types of human cancer cell lines. Compounds 7 and 9 were found to be the most potent.

Invesgations on the Influence of Halide Substituents on the Estrogen Receptor Interaction of 2, 4, 5‐Tris(4‐hydroxyphenyl)imidazoles

Abstract: Previously, we reported on the synthesis and estrogen receptor (ER) interaction of imidazoles, which had to be 1-alkyl-4, 5-bis(2-halo-4-hydroxyphenyl) substituted for a high relative binding affinity (RBA >1 %). This led to the assumption that a shielding of the polar heterocyclic system is a prerequisite for ER binding. In continuation of this study we synthesized 2, 4, 5-tris(4-hydroxyphenyl)imidazoles with Cl-or F-atoms in the ortho-positions of the aromatic rings and evaluated whether they mediate sufficient hydrophobicity for ER interaction. 2-(2, 6-Dichloro-3/4-hydroxyphenyl)-4, 5-bis(2-halo-4-hydroxyphenyl)imidazoles were synthesized by reaction of the respective methoxy-substituted benzil with either the 2, 6-dichloro-4-methoxy-or the 2, 6-dichloro-3-methoxybenzaldehyde in ammonium acetate solution. The required ether cleavage was performed subsequently with BBr(3). In the competition experiment with [(3)H]estradiol the imidazoles with the a C2-standing (2, 6-dichloro-4-hydroxyphenyl) ring showed an RBA >0.02 %, but did not activate the luciferase gene in estrogen receptor positive MCF-7-2a breast cancer cells stably transfected with the plasmid ERE(wtc)luc. In the test for antagonistic potency only the 2-(2, 6-dichloro-4-hydroxyphenyl)-4, 5-bis(4-hydroxyphenyl)imidazole 3 antagonized the effects of 1 nM estradiol slightly. From these data, it can be concluded that a C2-standing 2, 6-dichloro-4-hydroxyphenyl ring is not appropriate to optimize the ER interaction of 4, 5-(4-hydroxyphenyl)imidazoles.

New antithrombotic 1-phthalazinamines with serotonin antagonistic properties.

Abstract: We report nineteen 4-aryl- and 4-arylalkyl-1-phthalazinamines (5-8) which we prepared and tested for antithrombotic properties. All compounds were assayed for their antiplatelet activity in the "Born test" with collagen as inducer of the aggregation. N-[4-(1H-1, 2, 4-triazol-1-yl)butyl]-4-phenyl-1-phthalazin-amine (7 c) was the most potent compound, having an IC(50) of 8 microM. When 5-HT (Serotonin) was used to start aggregation the N-(furan-2-yl-methyl)-4-phenyl-1-pthtalazinamine (8 a) had an IC(50) of 2 microM. In vivo potencies were highly significant. N-[5-(1H-1, 2, 4-triazol-1-yl)pentyl]-4-phenyl-1-phthalazinamine (7 d) inhibited thrombus formation by 12% (P < 0.002) in arterioles and 7% (P < 0.01) in venoles as tested with our laser thrombosis model. For compound 8 a we surprisingly found an antagonism to the 5HT(2A) receptor, which is most likely the mechanism of the inhibition of aggregation by this compound.

Dopamine receptor ligands. Part VII [1]: novel 3-substituted 5-phenyl-1, 2, 3, 4, 5, 6-hexahydro-azepino-[4, 5-b]indoles as ligands for the dopamine receptors.

Abstract: A number of 5-phenyl-1, 2, 3, 4, 5, 6-hexahydro-azepino-[4, 5-b]indoles 3 were synthesized with different substituents at the azepine-N position (methyl-, allyl-, 2-phenyl-ethyl-, cyclopropylmethyl- and unsubstituted). Furthermore, the indole-N-methylated compound was generated and by using norephedrines and norpseudoephedrines as a chiral pool, 4-methyl-5-phenyl-1, 2, 3, 4, 5, 6-hexahydro-azepino-[4, 5-b]indoles were prepared which contained racemisation at the reacting C-atom. These compounds, as well as the ring-open amino-alcohols, were screened for their affinity to the hD(1)-, hD(5)-, hD(2L)-, and hD(4)-receptors (c please check sentence). They had micromolar affinities for the receptors and showed the highest affinity to the D(1)-subtype family. The cyclic compounds possessed the highest affinity, with the cyclopropylmethyl-(3c) and methyl-substituents (3 e) being the most active of the tested compounds. Based on an intracellular cAMP-assay, the unsubstituted compound (at the azepine-N position) turned out to be an agonist for the D(1)-and D(5)-subtype family, whereas the substituted compounds showed (partial) agonistic, or even inverse agonistic activity.

Synthesis of novel MKC-442 analogues with potent activities against HIV-1

Abstract: Bis(alken-1-yloxy)methanes 2 were synthesized by reacting 2-cyclohexenol, 3-cyclohexenylmethanol, cinnamyl alcohol and its alpha-methyl analogue with dibromomethane. Condensation of 2 with 5, 6-disubstituted uracil derivatives 1 resulted in the desired MKC-442 analogues 3-6. The most active compounds, N-1 cinnamyloxymethyl- and N-1 2-methyl-3-phenylallyloxymethyl substituted 5-ethyl-6-(3, 5-dimethylbenzyl)uracils (5b and 6b), showed activity against wild-type HIV-1 in the nanomolar range, and against Y181C andY181C+K103N, mutant strains known to be resistant to MKC-442, in the micromolar range.

Brain delivery of HIV protease inhibitors.

Abstract: To overcome the problems of peptidomimetic drug delivery to the specific organs, the use of dihydropyridine pyridinium chemical delivery systems to deliver peptides to the brain is considered in this work. An HIV protease inhibitor lead compound; KNI 279 was selected for the study. The N-alkylated dihydroisoquinoline derivatives of KNI-279 were synthesized and tested for their ability to be oxidized by brain homogenate and showed good results with reasonable half-life times specially for the N-alkoxycarbonyl-methyl derivative 8. The in-vivo distribution of compound 8 proved the brain delivery and locked in property of HIV PR inhibitors in the brain. All the prepared compounds (both quaternary and dihydro derivatives) showed between 51 and 86 % HIV PR inhibitory activity compared to the parent compound.

A triterpene ozonide from Senecio selloi.

Abstract: From the dried and fresh aerial parts of Senecio selloi Spreng, De Candolle (Asteraceae), the new triterpene ozonide 1 was isolated. Its structure was elucidated by NMR experiments, including inverse techniques HMQC and HMBC and by synthesis from the precursor 2 In contrast to natural peroxides, no antiplasmodial activity was detected for the ozonide 1.

Synthesis and Cytotoxicity of Substituted Ethyl 2-Phenacyl-3-phenylpyrrole-4-carboxylates

Abstract: The substituted ethyl-2-phenacyl-3-phenylpyrrole-4-carboxylates were synthesized by a condensation of a beta-chloroenal and an alpha-aminoketone under neutral conditions. They proved to be potent cytotoxic agents against the growth of murine L1210 and P388 leukemias and human HL-60 promyelocytic leukemia, HuT-78 lymphoma, and HeLa-S(3) uterine carcinoma. Selective compounds were active against the growth of Tmolt(3) and Tmolt(4) leukemias and THP-1 acute monocytic leukemia, liver Hepe-2, ovary 1-A9, ileum HCT-8 adenocarcinoma, and osteosarcoma HSO. A mode of action study in HL-60 cells demonstrated that DNA and protein syntheses were inhibited after 60 min at 100 microM. DNA and RNA polymerases, PRPP-amido transferase, dihydrofolate reductase, thymidylate synthase, and TMP kinase activities were interfered with by the agent with reduction of d[NTP] pools. Nonspecific interaction with the bases of DNA and cross-linking of the DNA may play a role in the mode of action of these carboxylates.

Synthesis and Effects on the COX‐1 and COX‐2 Activity in Human Whole Blood ex vivo of Derivatives Containing the [1]Benzothienol‐[3, 2‐d]pyrimidin‐4‐one Heterocyclic System

Abstract: Methyl and phenyl derivatives containing the [1]Benzothieno [3, 2-d]pyrimidin-4-one system have been synthesized and tested as inhibitors of COX-1 and COX-2 activities in human whole blood (HWB) ex vivo; all compounds turned out to be weak inhibitors of COX-1 activity, as deduced from the TXB(2) (thromboxane B) generation; the acid phenyl derivative 11 b was an interesting inhibitor of COX-2 activity, as deduced from the PGE(2) (prostaglandine E) generation.

Structure-activity studies of novel amidine analogues of chlorambucil: correlation of cytotoxic activity with DNA-binding affinity and topoisomerase II inhibition.

Abstract: A series of amidine analogues of chlorambucil (9-12), where 5-[4-(N-alkylamidino)phenyl]-2-furancarboxamide and the chlorambucil moiety are linked by a NH(CH(2))(2)NH chain, was synthesized and their cytotoxicity has been tested against the growth of human breast cancer MCF-7 cells. Evaluation of the cytotoxicity of compounds 9-12 employing a MTT assay and inhibition of [(3)H]thymidine incorporation into DNA demonstrated that these conjugates were more active than chlorambucil. Data from the ethidium displacement assay indicated that these compounds bind in the minor groove of DNA and show moderate specificity for AT base pairs. Compounds 9-12 were potent topoisomerase II inhibitors, with 50% inhibitory concentrations (IC(50))ranging from 10 to 40 microM. The cytotoxicity of the compounds 9-12 correlates with their DNA-binding affinities and their relative potency as topoisomerase II inhibitors. Altogether, these data suggest (i) that the cytotoxic activity of compounds 9-12 may be due to the combined effects of alkylation, DNA-minor groove binding, and (ii) that N-(2-aminoethyl)-5-(4-N-alkylamidinophenyl)-2-furancarboxamides (5-8) ligands are suitable linkers that favors DNA targeting by chlorambucil derivatives.