Showing papers in "Archiv Der Pharmazie in 1997"
TL;DR: Analysis of the inhibitory effect exerted by several derivatives on microsomal aromatase in vitro activity indicates that azolyl‐substituted indoles containing an imidazole moiety are more potent inhibitors than triazole derivatives.
Abstract: In the challenge to develop potent inhibitors of aromatase for reducing the levels of estrogens, we found that azolyl-substituted indoles inhibit aromatase activity, 3-(1-Azolylmethyl)-1H-indoles 9-15 and 3-(1-azolyl-1-phenylmethyl)-1H-indoles 22-25 were prepared, and tested on their ability to inhibit P450 arom. Analysis of the inhibitory effect exerted by several derivatives (11, 12, 22, and 23) on microsomal aromatase in vitro activity indicates that azolyl-substituted indoles containing an imidazole moiety are more potent inhibitors than triazole derivatives. In the first series, the introduction of the N-benzyl moiety has been found to enhance the inhibitory profile of these 3-(1-azolylmethyl)-1H-indole derivatives. The corresponding 4-fluoro derivative 12 displays the highest inhibitory activity (IC50 = 0.0718 microM) of all investigated compounds; thus, 12 is 258 times as potent as aminoglutethimide (AG). The presence of a chloro grouping in para position of the phenyl ring in compounds 22 and 24 exerts a positive effect only in the triazol-l-yl sub-series: compound 25 is 4-fold more potent than 24.
54 citations
TL;DR: A significant difference in potency towards the lung carcinoma cell line was observed among the cobalt complexes, indicating that the complexed ligand may influence cytotoxic activity.
Abstract: The interaction of organometallic compounds with biological systems, generally called bioorganometallic chemistry, is receiving increasing interest. We present the first part of our studies concerning the biological activity of organometallic compounds. Several alkyne-cobalt carbonyl complexes inhibited the growth of human melanoma and lung carcinoma cell lines. They are more active than uncomplexed dicobalt octacarbonyl, cobalt chloride, or the free ligand. A significant difference in potency towards the lung carcinoma cell line was observed among the cobalt complexes, indicating that the complexed ligand may influence cytotoxic activity. These results suggest that further exploratory work with such cobalt-alkyne complexes is warranted.
53 citations
TL;DR: A series of 2‐(anilino or 2,6‐dichloroanilino)‐1,5(6)‐disubstituted‐1H‐benzimidazoles (1–43) were prepared by reaction of several 2‐ chloro‐ or 2‐chloromethyl‐1h‐benZimidzoles with aniline derivatives with the best activity.
Abstract: A series of 2-( anilino or 2,6-dichloroanilino)- 1,5(6)-disubstituted-1H-benzimidazoles (1-13) were prepared by reaction of several 2-chloro- or 2-chloromethyl- lH-benzimidazoles.with aniline derivatives. The prepared compounds were screened for their in vitro antibacterial and antifungal activities. Compounds 2, 8, and 9 exhibited the best activity.
52 citations
TL;DR: Surprisingly, in contrast to the phenol series, in the imidazole series the compounds with a side chain amino group turned out to be considerably more potent than the corresponding strongly basic guanidines, appearing to be different for the diphenylalkylamide NPY antagonists with one or two basic groups.
Abstract: Potent arpromidine-type histamine H2 receptor agonists such as BU-E-76 (He 90481) were among the first non-peptides reported to display weak neuropeptide Y (NPY) Y1 receptor antagonist activity. In search of new chemical leads for the development of more potent NPY antagonists, a series of N,N-disubstituted omega-guanidino and omega-aminoalkanoic acid amides were synthesized on the basis of structure-activity relationships and molecular modeling studies of arpromidine and related imidazolylpropylguanidines. In one group of compounds the imidazole ring was retained whereas in the second group it was replaced with a phenol group representing a putative mimic of Tyr36 in NPY. Although the substitution patterns have not yet been optimized, the title compounds are NPY Y1 antagonists in human erythroleukemia (HEL) cells (Ca2+ assay) achieving pKB values in the range of 6.3-6.6. For representative new substances tested in the isolated guinea pig right atrium histamine H2 receptor agonism could not be found. In the N-(diphenylalkyl)amide series, compounds with a trimethylene chain were more active Y1 antagonists than the ethylene homologs. Concerning the spacer in the omega-amino or omega-guanidinoalkanoyl portion, the best activity was found in compounds with a four- or five-membered alkyl chain or a 1,4-cyclohexylene group. Surprisingly, in contrast to the phenol series, in the imidazole series the compounds with a side chain amino group turned out to be considerably more potent than the correspondence strongly basic guanidines. Thus, the structure-activity relationships appear to be different for the diphenylalkylamide NPY antagonists with one or two basic groups.
39 citations
TL;DR: The moderate binding activity of 1–5,7,9–10, 13 is attributable to the lack of the optional proton acceptor at position‐1, while the inactivity of the 1,4‐dione derivatives 15–17 is due to the absence of the essential proton acceptance at position•3.
Abstract: Some pyrazolo[3,4-c]quinoline-4-ones 1-14 and pyrazolo[3,4-c]-quinoline-1,4-diones 15-17 were prepared and biologically evaluated for their binding at the benzodiazepine receptor (BZR) in rat cortical membranes. The moderate binding activity of 1-5, 7, 9-10, 13 is attributable to the lack of the optional proton acceptor at position-1, while the inactivity of the 1,4-dione derivatives 15-17 is due to the lack of the essential proton acceptor at position-3. These conclusions confirm the validity of our proposed pharmacophoric model.
35 citations
TL;DR: The synthesis and biological evaluation as potential CCK‐B receptor ligands of a number of 1‐isopentyl‐3‐aryloxycarbamoyl‐5‐aryl‐1,5‐benzodiazepines substituted with halogen atoms on the benzo‐fused ring is here briefly discussed.
Abstract: The synthesis and biological evaluation as potential CCK-B receptor ligands of a number of 1-isopentyl-3-aryloxycarbamoyl-5-aryl-1,5-benzodiazepines substituted with halogen atoms on the benzo-fused ring is here briefly discussed.
34 citations
TL;DR: A three‐point pharmacophore explaining interactions of buspirone‐like molecules with the receptor binding site is proposed, and structure‐activity relationship is discussed for the affinity to 5‐HT1A receptor.
Abstract: Preparation and affinity to 5-HT1A and 5-HT2A receptors of new buspirone analogues 7-17 are reported. The compounds possess high to low affinity to 5-HT1A and moderate to low to 5-HT2A receptors. The crystal structures have been determined for compounds 11, 12, 13, and 14. For low affinity ligand (15) of 5-HT1A receptor conformational analysis was performed and compared with similar analyses performed for know high (buspirone 1) and very high (WY-48,723 2) affinity ligands of the receptor. Structure-activity relationship is discussed for the affinity to 5-HT1A receptor. A three-point pharmacophore explaining interactions of buspirone-like molecules with the receptor binding site is proposed.
32 citations
TL;DR: Preparation 4d is comparable in its effectiveness to CsA, so it may be potentially used as an agent for prolongation of the function of transplanted organs and two other compounds may potentially be used in cases where only one type the immune response is required for combating pathogen invasion.
Abstract: A series of 5-aminomethinimino-3-methyl-4-isoxazolecarboxylic acid phenylamides 4 has been prepared by condensation of 5-amino-3-methyl-4-isoxazolecarboxylic acid phenylamides 1 with trichloroacetic aldehyde. Alcoholysis of trichloro derivatives 2 gave 5-alkoxymethine derivatives 3 which, on reaction with an appropriate amine, formed the corresponding compounds 4. The compounds obtained were evaluated for their immunological activity. The properties of three compounds, described in this report, permitted inhibition of the immune response in all possible ways: diminishing both types of immune response (4d), humoral immune response (4a), or cellular immune response (4c). Preparation 4d is comparable in its effectiveness to CsA, so it may be potentially used as an agent for prolongation of the function of transplanted organs. Two other compounds may potentially be used in cases where only one type the immune response is required for combating pathogen invasion.
32 citations
TL;DR: A new, efficient, and highly sensitive test method for the screening of dual cyclooxygenase‐1 (COX‐1) and 5‐lipoxygenases (5‐LOX) inhibitors and PGE2 and LTB4 respectively were determined by highly selective and sensitive ELISA kits, using monoclonal antibodies.
Abstract: The aim of our study was to investigate structure activity relationship following the replacement of the 6-phenyl substituent at the 6,7-diaryl-2,3-dihydropyrrolizine template by various heteroaromatic residues. In this context we developed a new, efficient, and highly sensitive test method for the screening of dual cyclooxygenase-1 (COX-1) and 5-lipoxygenase (5-LOX) inhibitors. We used human platelets as a source of COX-1 and human PMNLs as a source of 5-LOX. Both cell types were isolated from the same volume of blood. PGE2 and LTB4 respectively were determined by highly selective and sensitive ELISA kits, using monoclonal antibodies. For a single determination at most 0.5 mL whole blood is needed.
31 citations
TL;DR: The binding results show that only three of the title compounds displayed micromolar receptor affinity, demonstrating how disappointing the synthesis of receptor ligands based only on interaction models can be.
Abstract: The synthesis and glycine-NMDA binding activity of a series of quinazoline-2-carboxylic acids 1 and quinazoline-2,4-diones 2, containing all the essential and optional pharmacophoric descriptors required by a putative glycine antagonist model, are reported. The binding results show that only three of the title compounds displayed micromolar receptor affinity, demonstrating how disappointing the synthesis of receptor ligands based only on interaction models can be.
29 citations
TL;DR: Starting from amino(di)azines and 2‐chloro‐6‐methyliso(thio)cyanate a series of aryl‐substituted urea and thiourea derivatives was prepared and screened as potential antiepileptics, but only 2b and 3c exhibited adequate anticonvulsant effects, whereas 3d and 4d were found to be convulsants per se.
Abstract: Starting from amino(di)azines and 2-chloro-6-methyliso(thio)cyanate a series of aryl-substituted urea and thiourea derivatives was prepared and screened as potential antiepileptics. Among the new derivatives tested, only 2b and 3c exhibited adequate anticonvulsant effects, whereas 3d and 4d were found to be convulsants per se.
TL;DR: From these series of compounds, 2‐(1H‐benzimidazol‐2‐ylamino)‐6‐hydroxy‐5‐phenylpyrimidin‐4(3H)‐ones was confirmed to have a moderate in vitro anti‐HIV activity.
Abstract: In an ongoing effort to develop novel non-nucleoside human immunodeficiency virus inhibitors, a series of substituted 2-(1H-benzimidazol-2-ylamino)pyrimidin-4(3H)-ones and related derivatives were synthesized via cyclocondensation of 2-ganidino-1H-benzimidazole with diethyl ethoxymethylenemalonate, substituted diethyl malonates, some beta-keto esters and 2-acetylbutyrolactone. From these series of compounds, 2-(1H-benzimidazol-2-ylamino)-6-hydroxy-5-phenylpyrimidin -4(3H)-ones (5f, NSC 666286) was confirmed to have a moderate in vitro anti-HIV activity.
TL;DR: The results of the in vitro and in vivo effect of guaiazulene, a natural azulene derivative, on rat hepatic cytochrome P450 (CYP) indicate potential useful applications of gu aiazulenes.
Abstract: The in vitro and in vivo effect of guaiazulene, a natural azulene derivative, on rat hepatic cytochrome P450 (CYP) is investigated. Furthermore, paracetamol hepatotoxicity is induced in rats and the activity of specific cytochrome P450 forms, involved in the metabolic activation of paracetamol to the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI) is examined, after the administration of guaiazulene, using diagnostic cytochrome P450 substrates. It is found that guaiazulene inhibited considerably CYP1A2 and CYP2B1 and had a weak effect on CYP1A1 in rat hepatic microsomal fractions. Guaiazulene administered to rats did not produce any macroscopic toxic effect and caused no change of liver weight, microsomal protein and total cytochrome P450 content. Guaiazulene inhibited CYP1A2 activity in rats with or without paracetamol intoxication. Considering that CYP1A2 participates in the formation of NAPQI, as well as in the metabolic activation of several toxic and carcinogenic compounds, these results, in combination with the antioxidant activity of guaiazulene that we have found in previous investigations, indicate potential useful applications of guaiazulene.
TL;DR: The α1‐adrenergic and 5‐HT1A serotonergic receptor affinities of a series of 1‐arylpiperazines are presented and the influence of the terminal substituents on the α1-adrenoreceptor affinity and the 5‐ HT1A/α1 receptor selectivity is discussed.
Abstract: The alpha(1)-adrenergic and 5-HT1A serotonergic receptor affinities of a series of 1-arylpiperazines are presented. The role of the spacer and the influence of the terminal substituents on the alpha(1)-adrenoreceptor affinity and the 5-HT1A/alpha(1) receptor selectivity are discussed.
TL;DR: Two series of derivatives containing the quinazolinone‐4 moiety are synthesised, exhibiting a strong stimulatory activity with regard to cellular immune response and a strong inhibitory action in both types of the immune response.
Abstract: The synthesis of two series of derivatives containing the quinazolinone-4 moiety is described. 3-Amino-2(1H)-thioxo-4(3H)-quinazolinone (1) was subjected to reactions with halogenoketones and halogenoaldehydes, leading to the production of the corresponding ketones, aldehydes, Schiff bases, and 6-oxo-1,4,5-thiadiazin[2,3-b]quinazoline derivatives. Subsequently, 1 was condensed with selected alpha, beta-unsaturated carbonyl compounds, aldehydes, ketones, acid chlorides, and esters. The compounds were tested for their potential activity in a model of humoral and cellular immune response. The tests showed that the compounds exhibited differential immunotropic activities. Of particular interest is compound 19, exhibiting a strong stimulatory activity with regard to cellular immune response and compound 16 exerting a strong inhibitory action in both types of the immune response.
TL;DR: It is suggested that the physical properties as well as the chemical reactivity are to be considered in relation to the antitumor action of 2‐substituted naphthazarin compounds.
Abstract: A series of 2-substituted naphthazarin derivatives, 5,8-dihydroxy-1,4-naphthoquinone (DHNQ) derivatives and 5,8-dimethoxy-1,4-naphthoquinone (DMNQ) derivatives, were synthesized, and their cytotoxic activity against some cancer cell lines and antitumor action against S-180 tumor were evaluated. In general, 2-(1-hydroxyalkyl)-DHNQ derivatives showed a higher cytotoxicity than 2-(1-hydroxyalkyl)-DMNQ derivatives, implying a predominant role of redox cycling rather than electrophilicity in cytotoxicity. 2-(1-Alkoxy-4-methylpentyl) or 2-(1-acyloxy-4-methylpentyl) derivatives were produced by alkylation or acylation at the C-1' position of 2-(1-hydroxy-4-methylpentyl)-DHNQ or DMNQ derivatives. Although the cytotoxicity differed according to the size of the alkyl or acyl chain, alkylation or acylation at the C-1' position did not improve the cytotoxicity remarkably, and DHNQ derivatives were still more cytotoxic than DMNQ derivatives. Separately, in vivo testing showed that 2-(1-acyloxyalkyl)-DHNQ derivatives or 2-(1-alkoxyalkyl)-DHNQ derivatives expressed a higher antitumor action than 2-(1-hydroxyalkyl)-DMNQ or -DHNQ derivatives in contrast to the cytotoxicity observations. The total size of two side chains at C-1' seemed to govern the antitumor activity, with 9 to 11 carbon atoms being optimal. Thus, it is suggested that the physical properties as well as the chemical reactivity are to be considered in relation to the antitumor action of 2-substituted naphthazarin compounds.
TL;DR: 14b may be an interesting new lead compound for the development of more potent and selective A2A‐antagonists with azo structure due to the facile synthetic access to 8‐(phenylazo)xanthine derivatives, which are obtained by coupling of 8‐unsubstituted xanthines with phenyldiazonium salts.
Abstract: In the present study we synthesized aza-analogs of 8-styrylxanthines, in which the ethenyl bridge is replaced by an imine, amide, or azo function, in order to investigate structure-activity relation-ships of the 8-substituent of A 2A -selective xanthine derivatives. Thus, various 8-substituents were combined with theophylline or caffeine, respectively, and affinities of the novel compounds for adenosine A 1 - and A 2A -receptors were determined and compared with those of analogous 8-stytylxanthine derivatives. 8-(Benzylideneamino)caffeine derivatives exhibited high affinity and selectivity for A 2A -adenosine receptors, but were unstable in aqueous buffer solution at physiological pH values. 8-(Phenylazo)caffeine derivatives were less potent than corresponding 8-styrylcaffeine derivatives at adenosine receptors. The most potent azo compound of the present series was 8-(m-chlorophenylazo)caffeine (14b) exhibiting a K i value of 400 nM a A 2A -adenosine receptors and 20-fold selectivity versus A 1 -receptors. Due to the facile synthetic access to 8-(phenylazo)xanthine derivatives, which are obtained by coupling of 8-unsubstituted xanthines, with phenyldiazonium salts, 14b may be an interesting new lead compound for the development of more potent and selective A 2A -antagonists with azo structure.
TL;DR: The results suggest that the antiarrhythmic and hypotensive effect of compound 7 and MG‐1 is related to their adrenolytic properties, and that those properties depend on the presence of a phenylpiperazine moiety.
Abstract: A series of the derivatives of 1-[2-hydroxy-3-(4-phenyl-1-piperazinyl])propyl]-pyrrolidin-2- one (MG-1) was synthesized and tested for electrocardiographic, antiarrhythmic, and antihypertensive activity as well as for alpha 1- and alpha 2-adrenoceptors binding affinities. Some of the compounds of this series slightly decreased the heart rate, prolonged P-Q, Q-T intervals and QRS complex. Only compound 7 (1-[2-hydroxy-3-(4-phenyl-1-piperazinyl)propyl]-pyrrolidine) possesses potent antiarrhythmic and a slight hypotensive properties, and affinity for alpha 1- and alpha 2-adrenoceptor. The results suggest that the antiarrhythmic and hypotensive effect of compound 7 and MG-1 is related to their adrenolytic properties, and that those properties depend on the presence of a phenylpiperazine moiety.
TL;DR: In this article, a series of 6,11-dialkylated pyridazino- [3,4-b][1,5]benzodiazepin-5-ones with a 3-chloro-8-nitro, 8amino, 8-acetylamino, or 8-chloros substitution pattern was prepared via N-alkyl-3-alkylamino-6-chloroencinnyl-N-(2-chlorono-5)-nitrophenyl) -pyridazine-4-carbox
Abstract: Starting from 3,6-dichloro-N-(2-chloro-5-nitrophenyl)-pyridazine-4-carboxamide (7) a series of 6,11-dialkylated pyridazino- [3,4-b][1,5]benzodiazepin-5-ones with a 3-chloro-8-nitro, 8-amino, 8-acetylamino, or 8-chloro substitution pattern was prepared via N-alkyl-3-alkylamino-6-chloro-N-(2-chloro-5-nitrophenyl) -pyridazine-4-carboxamides. The new compounds were screened as non-nucleoside reverse transcriptase inhibitors. The influence of the substitution pattern in compounds 10-13 on inhibitory potency is discussed.
TL;DR: A group of racemic isopropyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(thienyl)‐5‐pyridinecarboxylates 7a–f were prepared using a modified Hantzsch reaction that involved the condensation of a thienylcarboxaldehyde 4a-f with isoproyl 3‐aminocrotonate 5 and nitroacetone 6.
Abstract: A group of racemic isopropyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(thienyl)-5-pyridinecarboxylates++ + 7a-f were prepared using a modified Hantzsch reaction that involved the condensation of a thienylcarboxaldehyde 4a-f with isopropyl 3-aminocrotonate 5 and nitroacetone 6. In vitro calcium channel antagonist activities were determined using a guinea pig ileum longitudinal smooth muscle (GPILSM) assay. Compounds 7a-f exhibited weaker calcium channel antagonist activity (IC50 = 10(-5) to 10(-7) M range) than the reference drug nifedipine (IC50 = 1.43 x 10(-8) M). The point of attachment of the C-4 thienyl ring system was a determinant of antagonist activity [3-thienyl (7b) > 2-thienyl (7a)]. A 5-substituent in the 2-thienyl moiety influenced antagonist activity where the potency order was 5-bromo-2-thienyl 7f > or = 5-methyl-2-thienyl 7c > 2-thienyl 7a. Although the 5-methyl-2-thienyl 7c and 3-methyl-2-thienyl 7d isomers are equipotent antagonists, the 5-bromo-2-thienyl compound 7f appears to be marginally more active than the 4-bromo-2-thienyl isomer 7e. The 2-thienyl compound 7a, unlike the 3-thienyl isomer 7b, exhibited an agonist effect on GPILSM in the absence of the muscarinic agonist carbachol. Effects of the 2-thienyl 7a and 3-thienyl 7b isomers on the magnitude of calcium current were determined in guinea pig ventricular myocytes with voltage clamp techniques. Results showed that 2-thienyl 7a inhibited calcium current (antagonist) when voltage steps were made from a potential of -40 mV. However, when voltage steps were made from -60 mV, 7a enhanced calcium current (agonist). The 3-thienyl isomer 7b had little, if any, effect on calcium current.
TL;DR: The pyrrolidino enaminones, with the carboxylic acid chain fixed at the nitrogen, inhibit cyclooxygen enzyme more potently or selectively than 5‐lipoxygenase.
Abstract: The pyrrolidino enaminones, with the carboxylic acid chain fixed at the nitrogen, inhibit cyclooxygenase more potently or selectively than 5-lipoxygenase. According to the structure-activity relationships discussed the potency depends significantly on the chain length of the carboxylic acid, the substitution pattern of the heterocyclic moiety and of the phenyl group. Compound 4c is the most efficient inhibitor of cyclooxygenase. For the binding profile the unfolded conformation of arachidonic acid and the energy-minimized conformations of flurbiprofen, diclofenac, ML 3000, and lead compound 4a were compared. In addition to known structural features, similar distances of the carboxylic acid function and the phenyl residue were found as hypothesized to explain the interaction with the active sites of the enzyme. The inhibition of cyclooxygenase was determined in a bovine thrombocyte intact cell assay and that of 5-lipoxygenase using intact bovine PMNLs.
TL;DR: Structural activity relationship studies showed, that the 5‐hydroxy derivates 6a–d fit the log P/log potency correlation line previously established for a series of propafenone analogs.
Abstract: A series of 5-hydroxy and 5-benzyloxy analogs of the antiarrhythmic and multidrug resistance (MDR) modulating drug propafenone was synthesized and the MDR-modulating activity of the compounds was evaluated using a daunomycin efflux assay system. The key step of the synthesis is the selective reduction of the double bond in 1-without cleavage of the benzyl group thus leading to the phenol 3. Alkylation with epichlorohydrine followed by nucleophilic epoxide ring opening gave the benzylated target compounds 5a-d. Subsequent cleavage of the benzyl group gave the 5-hydroxy analogs 6a-d. Structure activity relationship studies showed, that the 5-hydroxy derivates 6a-d fit the log P/log potency correlation line previously established for a series of propafenone analogs. In contrast, all four 5-benzyloxy analogs 5a-d showed almost identical EC 50 values, independent of their log P value.
TL;DR: The BZR inactivity of the 1,2,5‐trione derivatives 11–12 shows that the right collocation of the essential L2 lipophilic substituent is of paramount importance for receptor‐ligand interaction.
Abstract: Some 1,2,4-triazolo[4,3-a)quinoxalines 1-10, and 1,2,4-triazino[4,3-a(quinoxalines 11-12 were prepared and biologically evaluated for their binding at the benzodiazepine receptor (BZR) in rat cortical membranes. We BZR affinity of 1-10 demonstrates that the presence of a proton acceptor at position-1 is important for the potency of a BZR ligand. On the other hand, the BZR inactivity of the 1,2,5-trione derivatives 11-12 shows that the right collocation of the essential L. 2 lipophilic substituent is of paramount importance for receptor-ligand interaction.
TL;DR: In this paper, two series of anticonvulsants, viz. derivatives of N-benzylamides of alpha-(4-phenylpiperazine)-gamma-hydroxybutyric acid (A) and derivatives of n-benzenylpicianamines of alpha(4-benzylpiderazine)-Gamma-hedric acid(B), were investigated.
Abstract: In a search for new anticonvulsants, two series of compounds, viz. derivatives of N-benzylamides of alpha-(4-phenylpiperazine)-gamma-hydroxybutyric acid (A) and derivatives of N-benzylamides of alpha-(4-benzylpiperazine)-gamma-hydroxybutyric acid (B), were investigated. These amides were obtained by aminolysis of 3-(4-phenyl-, or 4-benzylpiperazine)-tetrahydrofuran-2-one with primary arylalkylamines (i.e. 2-phenylethylamine and 2,3,4-substituted derivatives of benzylamine). Preliminary pharmacological tests, a maximal electroshock (MES) and a subcutaneous metrazole (scMet), and a rotorod toxicity assay were employed. All compounds displayed anticonvulsant activity at range of doses 100-300 mg/kg in the MES screens. In order to point to some structural features correlating with the MES anticonvulsant activity crystal structure analysis followed by conformational analysis was carried out on two representative compounds of series A and B.
TL;DR: A number of novel pyridazinomorphinans have been synthesized by the inverse electron demand Diels‐Alder reaction of various 3,6‐disubstituted 1,2,4,5‐tetrazines with enamines derived from dihydrocodeinone and with codeinone, with lower affinity at μ and κ opioid receptors in radioligand binding assays.
Abstract: A number of novel pyridazinomorphinans have been synthesized by the inverse electron demand Diels-Alder reaction of various 3,6-disubstituted 1,2,4,5-tetrazines with enamines derived from dihydrocodeinone and with codeinone. Reduction of some of the pyridazinomorphinans did not furnish the expected pyrroloepoxymorphinans; in all cases investigated reductive cleavage of the epoxybridge was observed to yield dihydropyridazino- or pyrrolomorphinans. The structures of all new compounds were assigned by the spectral data, that of the cycloadduct of codeinone was additionally verified by X-ray crystallography. Compounds 5a, 8, 11a and 16 have been evaluated for their affinity at mu and kappa opioid receptors in radioligand binding assays. Their ability to inhibit [3H]DAMGO binding at mu and [3H]U 69.593 binding at kappa receptors, respectively as compared to codeine has been found to be lower.
TL;DR: The most active compounds, 3 and 9, did not show in vivo antimalarial activity in mice and the activity could not be increased significantly, compared with 3.
Abstract: 1,4-Epidioxy-bisabola-2,12-diene (3) and aromatic hydroperoxides (4, 5) were prepared by photoxidation of gamma-curcumene (1). Reduction and esterification of 6 and 7 afforded compounds 9 to 10. All compounds were tested in vitro for antimalarial activity. The activity could not be increased significantly, compared with 3. The most active compounds, 3 and 9, did not show in vivo antimalarial activity in mice.
TL;DR: There is a relationship between the electrophilic OH radical scavenging properties (RSC) of the tested molecules and the value of their HOMO energy derived from semiempirical MO calculations.
Abstract: A series of fused 5,5-diphenyl and 5-arylidene-2-thiohydantoin derivatives were examined for their oxygen free radical inhibitory and radical scavenging properties (RSC) using both an enzymic and non-enzymic biological generators of free radicals. Non-enzymic lipid peroxidation (OH. radicals) was assayed as the amount of malondialdehyde (MDA) that had been formed during incubation of boiled rat liver microsomes in the presence of ascorbic acid and ferric ions. Superoxide anions (.O2- anion radicals) were generated enzymatically in the xanthine-xanthine oxidase system. Among the 20 investigated compounds only four fused arylidene 2-thiohydantoin derivatives showed weak antioxidant activity scavenging OH. radicals. There is a relationship between the electrophilic OH. radical scavenging properties (RSC) of the tested molecules and the value of their HOMO energy derived from semiempirical MO calculations.
TL;DR: Synthesis of several new 9‐anilino, phenylhydrazino, and sulphonamido analogs of 2‐ or 4‐methoxy‐6‐nitroacridine derivatives is described, showing a potential anticancer activity and their inhibitory effect on major cell cycle control proteins cdc2 kinase and cdc25 phosphatase as possible molecular targets that may account for antimitotic potency.
Abstract: Synthesis of several new 9-anilino, phenylhydrazino, and sulphonamido analogs of 2- or 4-methoxy-6-nitroacridine derivatives is described. The prepared compounds were tested for their in vitro antitumor activity against 60 human tumor cell lines by the National Cancer Institute (NCI) and showed a potential anticancer activity. Compounds 9-(phenylhydrazino)-2-methoxy-6-nitroacridine (8a) and 9-(4-chlorophenylhydrazino)-4-methoxy-6-nitroacridine (9b) exhibited a broad spectrum antitumor activity with full panel (MG-MID) median growth inhibition (GI50), of 16.1 and 10.9 microM and total growth inhibition (TGI) of 66.7 and 37.9 microM, respectively. Meanwhile, compounds 15a and 15b showed moderate selectivity toward leukemia cell lines. As a trial to explore the mode of action of their antitumor activity, the 6-nitroacridine analogs were evaluated for their inhibitory effect on major cell cycle control proteins cdc2 kinase and cdc25 phosphatase as possible molecular targets that may account for antimitotic potency. None of the tested compounds proved to exert their activity via this antimitotic mode of action.
TL;DR: The 3,5‐isoxazolidinedione and 2‐ isoxazoline‐5‐one derivatives as cytotoxic agents demonstrated potent cytotoxicity against the growth of human Tmolt3 T cell leukemia, murine P388 and L1210 leukemias, as well as human HeLa‐S3 uterine carcinoma and glioma tumor cell growth.
Abstract: The 3,5-isoxazolidinediones and 2-isoxazolin-5-ones demonstrated potent cytotoxicity against the growth of human Tmolt3 T cell leukemia, murine P388 and L1210 leukemias, as well as human HeLa-S3 uterine carcinoma and glioma tumor cell growth The specificity of the 3,5-isoxazolidinedione and 2-isoxazoline-5-one derivatives as cytotoxic agents varied with the histological type of tumor cell Selected compounds were active against solid HeLa uterine KB nasopharynx, skin A431, SW-480 adenocarcinoma, osteosarcoma and glioma growth Selected compounds demonstrated in vivo antineoplastic activity against Ehrlich ascites carcinoma growth In L-1210 leukemia cells, the agents blocked DNA and protein synthesis at 25, 50 and 100 microM over 60 min The agents were effective in reducing rate limiting enzymes in the de novo purine and pyrimidine pathways In addition they suppressed dihydrofolate reductase and ribonucleoside reductase activities with moderate inhibition of DNA and RNA polymerase activities DNA itself was not a target of the agents
TL;DR: In this paper, capillary gas chromatography (GC) and ion-selective electrode potentiometry (ISE) were used to quantify the amount of fluoride impurities in pharmaceutical grade calcium ascorbate.
Abstract: Fluoride impurities in pharmaceutical grade calcium ascorbate were determined analytically by capillary gas chromatography (GC) and ion-selective electrode potentiometry (ISE). In the GC method, the amount of fluoride impurities was quantitatively analyzed following the conversion of fluoride to its corresponding trimethylsilane derivative using trimethylchlorsilane. The derivatization procedure was performed under acidic conditions and the generated trimethylfluorsilane was subsequently extracted with n-hexane prior to GC analysis using isopentane as an internal standard.
In the potentiometric method, the fluoride content was determined by relating the potential of the sample solution at different concentrations to a calibration curve. A comparative evaluation between the two methods was validated according to their linearity, precision, and accuracy. The fluoride concentrations found by means of GC and ISE were (0.94 ± 0.04) ppm and (0.85 ± 0.12) ppm, respectively. The student's t-test (error of the first kind α = 0.1) indicated that there was no significant difference between the results obtained by the two methods.