Showing papers in "Archiv Der Pharmazie in 1998"
TL;DR: A novel series of homologous O and S isosteric tertiary amines was synthesised and structure‐activity studies furnished N‐(5‐phenoxypentyl)pyrrolidine which was active in vivo and remarkably has a Ki = 1.3 μM as an H3 antagonist.
Abstract: Histamine has been converted into a non-imidazole H3-receptor histamine antagonist by addition of a 4-phenylbutyl group at the N alpha-position followed by removal of the imidazole ring. The resulting compound, N-ethyl-N-(4-phenylbutyl)amine, remarkably has a Ki = 1.3 microM as an H3 antagonist. Using this as a lead compound, a novel series of homologous O and S isosteric tertiary amines was synthesised and structure-activity studies furnished N-(5-phenoxypentyl)pyrrolidine (Ki = 0.18 +/- 0.10 microM, for [3H]histamine release from rat cerebral cortex synaptosomes) which, more importantly, was active in vivo. Substitution of NO2 into the para position of the phenoxy group gave N-(5-p-nitrophenoxypentyl)pyrrolidine, UCL 1972 (Ki = 39 +/- 11 nM), ED50 = 1.1 +/- 0.6 mg/kg per os in mice on brain tele-methylhistamine levels.
118 citations
TL;DR: Some sulfonamide and sulfonylurea derivatives of unsubstituted and 5‐methylsubstituting 1,2‐benzisothiazole were studied in vitro for their antimicrobial properties against bacteria and fungi and structure‐activity relations are discussed.
Abstract: Some sulfonamide and sulfonylurea derivatives of unsubstituted and 5-methylsubstituted 1,2-benzisothiazole were studied in vitro for their antimicrobial properties against bacteria and fungi. Compounds 7 and 8 exhibited good antibacterial activity against Gram positive bacteria. A strong synergism was observed when their growth-inhibitory effect was assayed in combination with trimethoprim by using Bacillus subtilis and Staphylococcus aureus as test microorganisms. The antimycotic action of benzenesulfonylurea derivative 9 was very marked for Madurella mycetomatis and dermatophytes Epidermophyton floccosum, Microsporum gypseum and Trichophyton spp.. Structure-activity relations are discussed.
68 citations
TL;DR: Evaluation of the cytotoxicity of free chlorambucil and the respective albumin conjugates in the MCF7 mamma carcinoma and MOLT4 leukemia cell line employing a propidium iodide fluorescence assay demonstrated that the conjugate in which chlor Ambucil was bound to albumin through an ester bond was not as active as chlorambuccil.
Abstract: In our efforts to improve the selectivity and toxicity profile of antitumor agents, four maleimide derivatives of chlorambucil (1-4) were bound to thiolated human serum albumin which differ in the stability of the chemical link between drug and spacer. 1 is an aliphatic maleimide ester derivative of chlorambucil, whereas 2-4 are acetaldehyde, acetophenone, and benzaldehyde carboxylic hydrazone derivatives. HPLC stability studies at pH 5.0 with the related model compounds 5, 7, 8, and 9, in which chlorambucil was substituted by 4-phenylbutyric acid, demonstrated that the carboxylic hydrazone derivatives have acid-sensitive properties: the acid lability of 7 was particular prominent with a half-life of only a few hours. The aikylating activity of albumin-bound chlorambucil was determined with the aid of 4-(4-nitrobenzyl)pyridine (NBP), demonstrating that on average three equivalents were protein-bound. Evaluation of the cytotoxicity of free chlorambucil and the respective albumin conjugates in the MCF7 mamma carcinoma and MOLT4 leukemia cell line employing a propidium iodide fluorescence assay demonstrated that the conjugate in which chlorambucil was bound to albumin through an ester bond was not as active as chlorambucil. In contrast, the conjugates in which chlorambucil was bound to albumin through carboxylic hydrazone bonds were as or more active than chlorambucil in both cell lines. In particular. the conjugate in which chlorambucil was bound to albumin through an acetaldehyde carboxylic hydrazone bond exhibited IC 50 values which were approximately 4-fold (MCF7) to 13-fold (MOLT4) lower than those of chlorambucil. Preliminary toxicity studies in mice showed that this conjugate can be administered at higher doses in comparison to unbound chlorambucil.
52 citations
TL;DR: It was found that compound 6a having a 2‐methoxyphenyl group at position 5 and a benzylidene group at positions 2 was the most potent compound in this series.
Abstract: In this study, thirty six new 2-benzylidene-7-methyl-3-oxo-5- phenyl-2,3-dihydro-5H-thiazolo[3,2-alpha]pyrimidine-6-carboxylic acid methyl esters were synthesized and characterized by spectral, crystallographic, and elemental analysis. The antiinflammatory activity of the compounds was tested by the carrageenan hind paw edema test. It was found that compound 6a having a 2-meth-oxyphenyl group at position 5 and a benzylidene group at position 2 was the most potent compound in this series. All the compounds that were tested for ulcer activity gave positive results.
44 citations
TL;DR: The replacement of ascorbylPalmitate by dehydroascorbyl palmitate provided microparticles incompletely releasing the incorporated drug and characterized by a non‐constant release rate over time due to the higher lipophilicity of dehydration which hinders its disposition at the water/oil interface and thus decreases the crosslinking efficiency and increases the lipophilsicity of the microparticle surface.
Abstract: This study deals with the production of chitosan microparticles containing insulin by interfacial crosslinkage of chitosan solubilized in the aqueous phase of a water/oil dispersion in the presence of ascorbyl palmitate. The use of ascorbyl palmitate as interfacial crosslinker is based on its amphiphilic properties allowing its disposition at the water/oil interface of the preparative dispersion, thus permitting covalent bond formation with the amino groups of chitosan when its oxidation to dehydroascorbyl palmitate takes place during microparticle preparation. This preparation method produced microparticles characterized by high loading levels of insulin, completely releasing the drug in about 80 h at an almost constant release rate as determined by spectrophotometric and spectrofluorimetric methods. In contrast, the replacement of ascorbyl palmitate by dehydroascorbyl palmitate provided microparticles incompletely releasing the incorporated drug and characterized by a non-constant release rate over time due to the higher lipophilicity of dehydroascorbyl palmitate which hinders its disposition at the water/oil interface and thus decreases the crosslinking efficiency and increases the lipophilicity of the microparticle surface. The efficiency of the spectrofluorimetric and spectrophotometric methods used for determination of the stability and release of the insulin from the chitosan microparticles is also discussed.
42 citations
TL;DR: A series of 48 propafenone‐type modulators of multidrug resistance was synthesized and their P‐glycoprotein inhibitory activity was measured using the daunomycin efflux assay, showing that modifications on the central aromatic ring generally influence pharmacological activity.
Abstract: A series of 48 propafenone-type modulators of multidrug resistance was synthesized and their P-glycoprotein inhibitory activity was measured using the daunomycin efflux assay. Both a Free-Wilson and a combined Hansch/Free-Wilson analysis were performed using log P, partial log P and molar refraction values as Hansch descriptors. The results of the Free-Wilson analysis show that modifications on the central aromatic ring generally influence pharmacological activity, whereby in almost all cases a decrease in MDR-modulating potency is observed (Q2cv = 0.66). The combined approach results in equations with remarkably higher predictive power (Q2cv = 0.83), specifically molar refractivity shows high significance in all equations derived. This indicates that polar interactions also contribute to protein binding.
42 citations
TL;DR: 2‐Acetyl‐(6‐picolyl)‐4N‐substituted thiosemicarbazones and their copper(II) complexes were shown to be potent antineoplastic and cytotoxic agents against murine and human cultured cells and were as active against solid tumor growth as clinically useful agents.
Abstract: 1-Acetyl-(6-picolyl)- 4 N-substituted thiosemicarbazones and their copper(II) complexes were shown to be potent antineoplastic and cytotoxic agents against murine and human cultured cells. Numerous derivatives were as active against solid tumor growth as clinically useful agents.The agents inhibited L 1210 DNA and RNA syntheses with inhibition of key regulatory enzyme activities of the purine pathway as well as nucleoside kinase activities. d[NTP] pools were reduced and DNA strand scission occurred. These agents were DNA topoisomerase II inhibitors with lower IC 50 values than that of VP-16. However, they did not cause L 1210 DNA protein linked breaks and actually protected against those breaks afforded by VP-16. The agents were not synergistic with VP-16 in reducing cell growth or DNA synthesis although they did reduce growth of L 1210 cells in agar suspended media.
37 citations
TL;DR: A novel class of HIV protease inhibitors containing allophenylnorstatine with a hydroxymethylcarbonyl (HMC) isostere is designed and synthesized, which exhibited potent in vitro and in vivo antiviral activities with low cytotoxicity.
Abstract: The development of an effective therapeutic agent for the treatment of AIDS continues to be a challenging problem. Since the discovery that the virally encoded HIV protease is vital for propagation, inhibition of this enzyme has become a major target for AIDS chemotherapy. Consequently, numerous efforts aimed at the development of potent and selective inhibitors have been undertaken[2]. Based on the substrate transition state, we designed and synthesized a novel class of HIV protease inhibitors containing allophenylnorstatine [Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid] with a hydroxymethylcarbonyl (HMC) isostere. Among them, the tripeptide KNI-272 was a highly selective and superpotent HIV protease inhibitor (Ki=5.5 pM)[3]. KNI-272 exhibited potent in vitro and in vivo antiviral activities with low cytotoxicity[4]. The NMR, X-ray crystallography, and molecular modeling studies showed that the HMC group in KNI-272 interacted excellently with the aspartic acid carboxyl groups of the HIV protease active site[5].
32 citations
TL;DR: All final compounds were tested in vitro for their inhibitory activity on the release of TNF‐α, using stimulated peripheral mononuclear blood cells (PBMCs).
Abstract: The synthesis of 5'-substituted thalidomide analogs is described. The amino acids 2 necessary to synthesize the target compounds were prepared by Michael reaction. Condensation of 2 with phthalic anhydrides followed by reaction with urea yielded 4 as diastereomeric mixtures. Furthermore glutethimide (5) was brominated by an improved method and the resulting compound 6 was reacted in several steps with sodium azide, hydrogen, and phthalic anhydride to give 8. In a similar manner, 6 was reacted with sodium azide and various phthalic anhydrides to give 9, 10, and 11. All final compounds were tested in vitro for their inhibitory activity on the release of TNF-alpha, using stimulated peripheral mononuclear blood cells (PBMCs). Compounds with an additional aromatic substituent in position 5' of the thalidomide molecule were more active than thalidomide. Compound 11 was able to reduce increased levels of IL-2 in vitro.
32 citations
TL;DR: The synthesis of nine original morpholine derivatives, i.e. 2‐aryl‐4‐(3‐arylpropyl)morpholines, is described and the structure of all synthesised derivatives was proved by IR and 1H‐N MR, and some of them by 13C‐NMR.
Abstract: The synthesis of nine original morpholine derivatives, i.e. 2-aryl-4-(3-arylpropyl)morpholines, is described. The structure of all synthesised derivatives was proved by IR and 1H-NMR, and some of them by 13C-NMR. Acute toxicity studies of the compounds were performed on mice. A comparative pharmacological study of the in vivo effects on the central nervous system was undertaken using the screening tests: hexobarbital induced sleeping time: locomotor activity; and behaviour despair (for antidepressive activity). The most active compound 4-(2-benzoylethyl)-2-phenyl-3-methyl) morpholine 4e was studied for MAO-A and MAO-B inhibition in vitro in rat brain mitochondria preparations.
27 citations
TL;DR: A lack of endothelial metabolism is suggested to be the reason for this therapeutically favorable behaviour of spontaneously hypertensive rats.
Abstract: Twenty eight organic azides were synthesized and tested for their antithrombotic and blood pressure lowering activities in rats (60 mg/kg, p.o.). In fifteen compounds significant antithrombotic effects were observed. In thirteen cases a significant lowering of the blood pressure of spontaneously hypertensive rats (SHR) was seen. The peak activities in both systems were found for hexyl azide (4), 2-phenylethyl azide (14), and 4-pyridinecarboxylic acid azide (23). In these compounds the inhibition of thrombus formation in mesenteric arterioles was > 20%. The lowering of blood pressure was > 10% and long lasting (> 6 h) in 4 and 14 while 23 had a shorter duration of action (approximately 4 h). In two classes of azides, namely branched aliphatic azides (e.g. 2-azidopentane 9) and aliphatic carbonyl derivatives (e.g. benzoyl-azido-methane 17), only antithrombotic properties were observed. A lack of endothelial metabolism is suggested to be the reason for this therapeutically favorable behaviour.
TL;DR: Time‐course investigations of FUB 181 in mice showed a rapid mode of action with the highest value 3 h after p.o. application, and it appears to block histamine H3 receptors potently and selectively.
Abstract: A series of 4-(ω-taryialkyloxy)alkyl)-1H-imidazoles, and related sulphur-containing compounds have been prepared and evaluated for their histamine H 3 -autoreceptor antagonist in vuro potency in an assay on synaptosomes of rat cerebral cortex. in addition, the in vivo potency has been determined from the changes in N τ -methylhistamine levels in brain after p.o. administration to mice. Compounds with different alkyl chains and various aryl moities nave been synthesized and tested to explore structure-activity relationships. Within this series of novei antagonists, (1H-imidazol-4-yl)methyl and 2-(1H-imidazol-4-yl)ethyl ether derivatives showed low to moderate H 3 -receptor antagonist potency, whereas the corresponding allyl and propyl derivatives were compounds with high antagonist in vivo potency. Corresponding thioether or sulphoxide derivatives also showed antagonist activity. Additionally, some ether derivatives possessed high in vivo potency as well. The most active ether derivatives under in vivo conditions were 4- 3-(3-(4-fluorophenyl)propyloxy)propyl)-1H-imidazole (11b) and the corresponding chloro compound 11c (FUB 181) with ED 50 values of 0.76 and 0.80 mg/kg, respectively. On the other hand, all compounds tested showed weak activity at histamine H 1 or H 2 receptors. Furthermore, the most promising ether FUB 181 exhibited low activity at adrenergic μ 1 , β 1/2 , serotonergic 5-HT 2A , 5-HT; and muscarinic M 3 receptors. Time-course investigations of FUB 181 in mice showed a rapid mode of action with the highest value 3 h after p.o. application. Thus, FUB 181 appears to block histamine H 3 receptors potently and selectively.
TL;DR: Two alkyl‐3,4‐bis(4‐methoxyphenyl)pyrrole‐2‐carboxylates proved to be potent cytotoxic agents in the murine L1210 lymphoid leukemia screen and caused L 1210 DNA fragmentation after 24 h incubation at 100 μM.
Abstract: Two alkyl-3,4-bis(4-methoxyphenyl)pyrrole-2-carboxylates proved to be potent cytotoxic agents in the murine L1210 lymphoid leukemia screen. DNA synthesis was preferentially inhibited with the major target of the agents being de novo purine biosynthesis at the regulatory enzyme sites of PRPP-amido transferase and IMP dehydrogenase. Other enzymatic activities which were suppressed by the drugs were DNA polymerase alpha, RNA polymerases, ribonucleoside reductase and dihydrofolate reductase. The d[NTP] pools, nucleoside kinase and the pyrimidine pathway were not affected by the presence of drugs. The DNA molecule itself was not the target of the agents, i.e. no alkylation of nucleotide bases, intercalation between bases or cross-linking of DNA strands occurred. The agents did cause L1210 DNA fragmentation after 24 h incubation at 100 microM.
TL;DR: After oral administration to rats, fourteen compounds significantly inhibited the formation of thrombi in arterioles and venules and the strongest effect was observed with ethene‐bis‐carboxamidoxime (2q), which had been synthesized as prodrugs and showed smaller antithrombotic effects.
Abstract: Seventeen amidoximes (2a-q) comprising aliphatic (2a-d), aromatic (2e-n), and bis compounds (2o-q) have been synthesized. In the Born test 4-chlorophenylethenecarboxamidoxime (21) was most active and inhibited the blood platelet aggregation induced by collagen with an IC50 = 3 microM. After oral administration to rats (60 mg/kg) fourteen compounds significantly inhibited the formation of thrombi in arterioles and venules. The strongest effect was observed with ethene-bis-carboxamidoxime (2q) (31% in arterioles and 18% in venules). The O-ethoxycarbonylderivatives 3 and the corresponding 1,2,4-oxadiazol-5-ones 4, which had been synthesized as prodrugs, showed smaller antithrombotic effects.
TL;DR: A series of 2‐phenylimidazo[1,2‐a]pyridine‐3‐carboxylic esters, acids, and amides were synthesized and pharmacologically tested in order to evaluate their antiinflammatory and analgesic activity and their ulcerogenic action on the gastro‐intestinal tract.
Abstract: A series of 2-phenylimidazo[1,2-a]pyridine-3-carboxylic esters, acids, and amides were synthesized and pharmacologically tested in order to evaluate their antiinflammatory and analgesic activity and their ulcerogenic action on the gastro-intestinal tract. The most active member of this series of compounds was found to be 6-methyl-2-phenylimidazo[1,2-a]pyridine-3-carboxylic acid (5c).
TL;DR: A series of substituted xanthones was synthesized in order to prove the hypothesis that electron-withdrawing substituents enhance the antimycobacterial activity of these compounds, which was described by means of a QSAR equation with 13 C NMR chemical shifts as independent parameters.
Abstract: A series or substituted xanthones was synthesized in order to prove the hypothesis that electron-withdrawing substituents enhance the antimycobacterial activity of these compounds, which is described by means of a QSAR equation with 13 C NMR chemical shifts as independent parameters. The key step of the synthesis is the formation of substituted 2-phenoxybenzoic acids by Ullmann reaction followed by intramolecular Friedel-Crafts acylation, leading to methyl-, carboxy-, nitro-, cyano-, and aminoxanthones as a test set for QSAR investigations. Spectroscopic data ( 1 H and 13 C chemical shifts, IR, UV) of these xanthones are presented and analyzed. Specific shift increments for xanthones depending on the substituent position and on the position of the respective proton/carbon atom as well as additivity rules were developed.
TL;DR: Twenty‐two nitroso compounds with cyano, acyloxy, or carbonyl groups in geminal position were prepared and considerable antiplatelet activity was observed in each class of compounds, suggesting that the above pharmacological effects are mediated by a NO dependent mechanism.
Abstract: Twenty-two nitroso compounds with cyano, acyloxy, or carbonyl groups in geminal position were prepared, eight of them for the first time. In the solid state these compounds dimerize to colorless azodioxides. Exceptions are the 4-nitrobenzoyloxynitroso compounds 7b, f, and g which form bright blue crystals. In vitro (Born test, collagen) considerable antiplatelet activity was observed in each class of compounds. Azodioxides with cyano groups in geminal position (3a, b) were most active (IC50 approximately 10 microM) suggesting the importance of strong electron withdrawing groups in geminal position to the azodioxide partial structure. When administered orally to rats (60 mg/kg) all compounds inhibited the thrombus formation in mesenteric arterioles and venules. The acetyloxy derivatives 5d and 5e were most active (18-21% inhibition in arterioles and 11-15% inhibition in venules). In aqueous media at 37 degrees C the cyanonitroso compound 3b and the benzoyloxynitroso compound 7a decomposed to nitric oxide and its reduced form nitrosohydrogen. This suggests that the above pharmacological effects are mediated by a NO dependent mechanism.
TL;DR: Compound 1, at a dose of 100 μg/mouse, significantly inhibited the humoral immune response and, at the same time, stimulated the cellular type of that response and that of the proliferative response of mouse splenocytes to concanavalin A was inhibited only at a higher dose (2 μg/ml).
Abstract: 2-Aminobenzimidazole reacted with selected esters of alpha, beta-unsaturated acids and alpha, beta-unsaturated ketones to form derivatives of 1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-2-ones, 1,4-dihydropyrimido[1,2-a]benzimidazoles, and 2-acetylaminobenzimidazole. 2-Cinnamoylaminobenzimidazole, 4-phenyl-1,2,3,4-tetrahydropyrimido[1,2,-a]benzimidazol-2-on e, 4-(benzimidazol-2-ylamino)-4-phenylbutan-2-one, and 4-methyl-2-phenyl-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole were tested for their potential activity in immunological assays in the mouse model. Compound 1, at a dose of 100 micrograms/mouse, significantly inhibited the humoral immune response and, at the same time, stimulated the cellular type of that response. The proliferative response of mouse splenocytes to concanavalin A was inhibited only at a higher dose (2 micrograms/ml). The immunotropic activity of 4, on the other hand, was uniformly strongly inhibitory in all applied tests. The suppressive activity of 4 was lower in the cellular immune response and proliferation tests than that of cyclosporin A.
TL;DR: In this paper, the pyrrolobenzothiazine structure was deduced on the basis of 2D 1H NMR-NOESY experiments and fully determined by X-ray data.
Abstract: Acid catalyzed cyclization reactions of both 3-alkyl- and 3-aryl-substituted N-(2,2-dialkoxyethyl)-3,4-dihydro-2H-1,4-benzothiazines (2) lead to 2,3-dihydro-pyrrolo[1,2,3-de]-1,4-benzothiazines (3). The pyrrolobenzothiazine structure was deduced on the basis of 2D 1H NMR-NOESY experiments and fully determined by X-ray data. Compounds 3a-c showed poor antibacterial activity. However, the 3-phenyl-N-(2,2-dimethoxyethyl)-3,4-dihydro-2H-1,4-benzothiazine (2b') showed antifungal activity against Aspergillus niger 16-fold greater than miconazole.
TL;DR: Compound 19 represents a model for compounds with potential antitumor activity and cdc25 phosphatase inhibitory properties and is compared to 5‐substituted‐2‐bromoindolo[3,2‐ b]quinoxaline, which was synthesized and characterized.
Abstract: Several derivatives of 5-substituted 2-bromoindolo[3,2-b]quinoxaline were synthesized and characterized. The synthesized compounds were evaluated for their antitumor activity using the National Cancer Institute-in vitro-disease oriented antitumor screen and two biochemical mechanism-based screens (cdc2 kinase and cdc25 phosphatase). Compound 19 showed broad spectrum antitumor activity with full panel (MG-MID) GI50. TGI, and LC50 of 14.2, 31.6- and 66.2 microM, respectively. In addition it inhibited cdc2 kinase and cdc25 phosphatase with IC50's of 70 and 25 microM, respectively. Thus, compound 19 represents a model for compounds with potential antitumor activity and cdc25 phosphatase inhibitory properties.
TL;DR: The deacylated compound 10 was found to be the most active of the series, inhibiting inflammation due to Baker’s yeast, a property which is absent from most selective cyclooxygenase only inhibiting non‐steroidal anti‐inflammatory drugs (NSAIDs).
Abstract: A series of adamantane-containing molecules consisting of two lipophilic centers which are linked by different bridges (oxime esters, oxime ethers, amides, and symmetric alcohols), were designed and synthesized as anti-inflammatory agents. Their anti-inflammatory activity was evaluated as their ability to inhibit phlogistic-induced mouse paw edema. Some of the tested compounds exhibited activity comparable to that of diclofenac, others had a weaker activity, while some oxime esters proved to enhance the inflammatory response. In all cases, activity was dose-dependent. The deacylated compound 10 was found to be the most active of the series, inhibiting inflammation due to Baker's yeast, the mechanism of which involves mainly the activation of lipoxygenase and/or complement systems, a property which is absent from most selective cyclooxygenase only inhibiting non-steroidal anti-inflammatory drugs (NSAIDs).
TL;DR: The larvicidal activity of some of these products against Culex pipiens was evaluated in this paper, where the ring closure of some products produces the heterocyclic systems pyrimidone (3), oxadiazine (6), Oxadiazole (8), benzimidazole (10), benzothiazole(12), and benzoxazinone (14).
Abstract: Decomposition of 2-propenoyl azide (1c) with nitrogen, oxygens and sulfur nucleophiles affords the azido displacement products. Ring closure of some of these products produces the heterocyclic systems pyrimidone (3), oxadiazine (6), oxadiazole (8), benzimidazole (10), benzothiazole (12), and benzoxazinone (14). The larvicidal activity of some of these products against Culex pipiens was evaluated.
TL;DR: The semiquantitative evaluation of activity against the different strains of mycobacteria resulted in a classification into three activity classes, which will be used as dependent parameter in QSAR investigations, to be published in Part 3 of this series.
Abstract: A series of substituted xanthones was tested for their activity against four mycobacterial strains (Mycobacterium tuberculosis, M. avium, M. lufu, M. smegmatis) by determination of the minimum inhibitory concentrations (MIC values). For the most active compounds, supplementary characterisation was performed by bacterial growth kinetics, which allows a more precise interpretation of their antimycobacterial effects. From the test set, 1-methyl-2,4,7-trinitroxanthone (8a) showed the highest antimycobacterial activity with a MIC value of 3 micrograms/mL against M. tuberculosis, which is comparable to the effect of well known drugs used in the treatment of tuberculosis. For all other compounds, the MIC values could not be determined, due to the comparatively low activity and to the poor solubility of the compounds, respectively. The semiquantitative evaluation of activity against the different strains of mycobacteria resulted in a classification into three activity classes, which will be used as dependent parameter in QSAR investigations, to be published in Part 3 of this series.
TL;DR: Derivatives with larger substituents in the 1‐position showed reduced binding to benzodiazepine and A2A‐AR, but increased A1‐AR affinity, the 2‐thienylmethyl derivative 3f being the most potent and selective A1-AR ligand of the present series.
Abstract: Starting from 3-(3-chloro-1H-pyrazol-5-yl)-1H-quinoxalin-2-one (2) a series of substituted [1,2,4]triazolo[4,3-a]quinoxalines (3a-f) was prepared via a multistep reaction sequence. Affinities of the novel derivatives 3a-f for benzodiazepine as well as for adenosine A1- and A2A-receptors of rat brain were determined by radioligand binding assays. 1-Methyl-4-(3-chloro-1H-pyrazol-5-yl) derivative 3a exhibited submicromolar affinity for the benzodiazepine binding site of GABAA receptors (Ki = 340 nM) and was less potent at A1-(Ki = 7.85 microM) and A2A-(Ki = 1.43 microM) adenosine receptors (AR). Derivatives with larger substituents in the 1-position showed reduced binding to benzodiazepine and A2A-AR, but increased A1-AR affinity, the 2-thienylmethyl derivative 3f being the most potent and selective A1-AR ligand of the present series (Ki = 200 nM).
TL;DR: A set of eight derivatives of 6,8‐dichloro‐3‐phenyl‐2H‐1,3‐benzoxazine‐2,4(3H)‐dione and nine derivatives, substituted on the phenyl ring, was prepared by the reaction of the corresponding salicylanilides with ethyl chloroformate.
Abstract: 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.
TL;DR: A series of (+) 3‐[(3‐substituted‐5‐methyl‐4‐thiazolidinon‐2‐ylidene)hydrazono]‐1H‐ 2‐indolinones (2a–h) and 3‐ [(2‐thioxo‐3‐ substituting‐4,5‐imidazolidinedion‐1‐yl)imino]‐3a–g were synthesized by the
Abstract: A series of (+/-) 3-[(3-substituted-5-methyl-4-thiazolidinon-2- ylidene)hydrazono]-1H-2-indolinones (2a-h) and 3-[(2-thioxo-3-substituted-4,5-imidazolidinedion-1-yl)imino] -1H-2-indolinones (3a-g) were synthesized by the cyclization of 3-(4-substituted-thiosemicarbazono)-1H-2-indolinones (1a-h) with ethyl 2-bromopropionate in anydrous ethanolic medium and oxalyl chloride in anhydrous diethyl ether, respectively. The structures of 2 and 3 were confirmed by analytical and spectral data (IR, 1H NMR, 13C NMR, and EIMS). The configuration of 3 was assigned on the basis of 1H NMR and 13C NMR data. 2c, 2d, 2g, 2h, and 3a-g were evaluated for anticonvulsant activity against maximal electroshock (MES) and subcutaneous pentylenetetrazol (ScMet) induced seizures. Among the compounds tested, only 2d exhibited some activity in anticonvulsant identification (Phase I) trials in mice. 2a, 2b, 2d, 2g, 2h, and 3a-g were additionally tested for potentiating effects on pentobarbital induced hypnosis in mice. All of the test compounds increased the sleeping time of pentobarbital significantly (p < 0.05) and the most potent compound was found to be 3a.
TL;DR: A range of 14 derivatives of flavone‐8‐acetic acid with a heterocyclic substituent in place of the 2‐phenyl group have been prepared and their anti‐tumour activity evaluated in vitro against a panel of human and murine tumour cell lines and in vivo against MAC 15A.
Abstract: A range of 17 derivatives of flavone-8-acetic acid (FAA) with a 6-methyl substituent have been prepared and their anti-tumour activity evaluated in vitro against a panel of human and murine tumour cell lines and in vivo against MAC 15A While many of the compounds show activity comparable to FAA in vitro, this essentially disappears in vivo, possibly due to degradation before the compounds can reach the tumour site
TL;DR: All pyrazole derivatives proved ineffective in protecting cell cultures against the HIV‐1‐induced cytopathogenicity, and none of the compounds was active against the bacteria and fungi tested.
Abstract: In view of the biological relevance of triazole-based heterocyclic structures as antifungal, antiviral, and antitumor agents, we have synthesized a series of substituted pyrazolo[3,4-d]-1,2,3-triazoles (2e-h, 2j, 4b) which we evaluated for their cytostatic and antiviral (HIV-1 included) activity and for their capability to inhibit the multiplication of various human pathogenic fungi and bacteria. Moreover, the biological activities of a few compounds, namely pyrazolo[3,4-d]oxazoles (3a-e) and pyrazolo[3,4-d]-1,2,3-triazoles (2a-d, 4a, 5), previously obtained by us but not investigated for their biological activity, were also studied. Only compounds 3a-e were endowed with a significative antiproliferative activity on the human lymphoblastoid cell line MT-4 cells. All pyrazole derivatives proved ineffective in protecting cell cultures against the HIV-1-induced cytopathogenicity, and none of the compounds was active against the bacteria and fungi tested.
TL;DR: Two series of 3-cyano-2(1H)-oxopyridine derivatives carrying various aryl substituents at position 4 and (4-((7-chloro or trifluoromethylquinol-4-yl)amino)phenyl) substituent at position 6 were synthesized and evaluated for their antitumor activity as discussed by the authors.
Abstract: Two series of 3-cyano-2(1H)-oxopyridine and 3-cyano-2(1H)-iminopyridine derivatives carrying various aryl substituents at position 4 and (4-((7-chloro or trifluoromethylquinol-4-yl)amino)phenyl) substituent at position 6 were synthesized and evaluated for their antitumor activity. Compounds 3f and 6d showed high selectivity towards leukemia cell lines with full panel median growth inhibition GI50 average sensitivity towards all cell lines (MG-MID) at 7.9 and 19.7 microM and leukemia subpanel GI50 average sensitivity towards leukemia cell lines (MG-MID) at 1.74 and 2.9 microM, respectively, also they exhibited full panel total growth inhibition TGI (MG-MID) at 34.8 and 59.0 microM and leukemia subpanel TGI (MG-MID) at 5.3 and 13.5 microM, respectively.
TL;DR: The synthesis of suramin analogues bearing a 2‐phenyl‐benzimidazole moiety and results of the anti‐HIV, cytostatic, and antiangiogenic screening are presented.
Abstract: The synthesis of suramin analogues bearing a 2-phenyl-benzimidazole moiety is described. Aminoarene sulfonic acids 2a-e are acylated with 3,4-dinitrobenzoyl chloride 3 yielding the amides 4a-e which are hydrogenated to the corresponding diamines 5a-e. These are treated with 3-nitrobenzaldehyde, yielding the azomethines 7a-e and their isomers 8a-e and 9a-e. Key step in the synthesis of the target compounds 12a-e is the oxidation of the azomethines with oxygen to the benzimidazoles 10a-e. These are hydrogenated to the amines 11a-e reacting with phosgene to yield the symmetric ureas 12a-e. Results of the anti-HIV, cytostatic, and antiangiogenic screening are presented.