bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemical and Electrochemical Synthesis of Some Substituted N,N′‐Diacyl‐p‐phenylenediamines
Authors: Šuprina Mihela , Vorkapić‐Furač Jasna
Published: October 2006

Some N,N′‐diacyl‐p‐phenylenediamines substituted with halogens (2a‐c) were prepared. Their polarographic reduction in N,N‐dimethylformamide with Et4NClO4 was performed and discussed. The mechanism of the electrochemical reduction is stated. Large‐scale electrolytic reductions of 2a‐b to 3a‐b were performed.
Synthese von potentiellen Naftopidil‐Metaboliten
Authors: Kutscher Bernhard , Engel Jürgen , Fleischhauer Ilona , Niebch Georg
Published: October 2006

Es wird über die Synthese von vier potentiellen Metaboliten [Desmethyl‐Naftopidil (1), 4‐(Phenyl)‐hydroxy‐Naftopidil (2), 4‐(Naphthyl)‐hydroxy‐Naftopidil (3), Desanaphthyl‐Naftopidil (4)] des selektiven α1‐Antagonisten Naftopidil berichtet.
Synthese von basisch substituierten 5H‐Pyrimido[4,5‐c]‐2‐benzazepinen
Authors: Troschütz Reinhard , Grün Lothar
Published: October 2006

Die potentiell ZNS‐wirksamen Titelverbindungen 19a‐c lassen sich durch eine neunstufige Synthese ausgehend von Phthalaldehydsäure herstellen. Durch Knoevenagel‐Kondensation von 5 mit den Acetonitrilen 2a‐g und folgender Reduktion mit NaBH4 erhält man die Dihydrozimtsäurenitrile 3. Nur 3a läßt sich zu den 2‐Benzazepinnitrilen 9a,b cyclisieren. Ammonolyse von 9a führt zum Enaminonitril 10, das mit den Orthoestern 11a‐c die Imidsäureester 12a‐c gibt. Nachfolgende Ammonolyse liefert die Tricyclen 16a,b. Nach Umwandlung der Lactamfunktion von 16 in das Imidoylchlorid 17 folgt Aminolyse mit den Aminen 18a‐c zu den Titelverbindungen 19a‐c.
Nitrosierungen an Hydrazinderivaten, 10. Mitt.: Oxidationen an Thiourethanen, 11. Mitt.: Reaktionen von 3‐Aminorhodaninen unter nitrosierenden Bedingungen
Authors: Hanefeld Wolfgang , Helfrich Volker , Hunz Ingrid , Jalili Mohamed A. , Schlitzer Martin
Published: October 2006

C‐5‐unsubstituierte 3‐Aminorhodanine 1 werden durch NaNO2/HCl, Nitrosyl‐ und Nitroniumtetrafluoroborat in 5‐Hydroximinorhodanine 2 überführt, durch HNO3 in 5‐Hydroximinothiazolidin‐2,4‐dione 3. 5‐Aralkyliden‐3‐aminorhodanine 7 werden durch HNO2 unter drastischen Bedingungen in 2‐Stellung oxidativ desulfuriert.
Regioselektive Kondensationen sowie N‐Acylierungen an 3‐Aminorhodaninen
Authors: Hanefeld Wolfgang , Schlitzer Martin
Published: October 2006

3‐Aminorhodanin wurde regioselektiv an der 3‐Amino‐ oder der 5‐Methylengruppe mit Aldehyden kondensiert. Mit Carbonsäurechloriden oder ‐anhydriden gelingt die Acylierung der 3‐Aminofunktion.
New NO‐Donors with Antithrombotic Activities and Vasodilating Activities, III: 3,4‐Disubstituted N‐Nitroso‐5‐sydnone Imines
Authors: Rehse Klaus , Schleifer Klaus‐Jürgen
Published: October 2006

38 title compounds have been synthesized. They bear a wide variety in substituents including alkyl‐, aryl‐, arylalkyl‐, and styryl groups. The antiplatelet activities elucidated in the Born‐test with collagen cover more than two orders of magnitude (IC50 = 0.3‐45 μmol/L). These effects depend on the presence of the N‐NO‐group. This is shown by comparison with the corresponding sydnone imines, sydnone cyanimines, and sydnones. The most suitable substituents were phenylethyl, styryl, and hexyl at either position of the molecule. Seven compounds, most of them styryl derivatives, have IC50 values below 1 μmol/L. It is suggested that the differences in activity are connected with the ability of the compounds to bind to the platelet membrane.
Reactions with Thiaxanthen‐9‐ol: New Thiaxanthene Derivatives with Molluscicidal and Nematocidal Activity
Authors: El‐Sakka Ibrahim A. , Zeid Ibrahim F. , Abdel‐Bary Hamed M. , Abdel‐Mageed Ahmed E. S.
Published: October 2006

Thiaxanthen‐9‐ol (1) was condensed with nitriles 2a‐e to yield the thiaxanthen‐9‐yl‐acetonitriles 3a‐e. With the thiols 7a‐d, 1 yielded the thioethers 8a‐d.
Facile Synthesis of Tetrazolylchromonoids and Related Compounds
Authors: Patonay Tamás , Lévai Albert
Published: October 2006

The reaction between the appropriate nitriles and tributyltin azide (TBTA) provides an easy and efficient method for the synthesis of the title compounds. Treatment of thiocyanate 9b with TBTA affords the alkylthio‐substituted tetrazole 10b.
Simultaneous Determination of (R)‐ and (S)‐Brefanolol in Human Plasma: High‐Performance Liquid Chromatographic Assay on a Chiral Stationary Phase
Authors: Neubeckm Monika , Henke Dorit , Spahn‐Langguth Hildegard , Mutschler Ernst
Published: October 2006

A new method for the quantitative enantiospecific determination of rac‐brefanolol, a vasodilating β‐adrenoceptor blocking agent, in human plasma is described. After an alkaline liquid‐liquid extraction from biological material and a preseparation on a silica gel column with fractional collection of the eluate, the separation of the underivatized enantiomers is performed by high‐performance liquid chromatography on cellulose tris‐4‐methylbenzoic acid polymer coated on silica gel. The UV‐absorbance of the eluate was monitored at 254 nm. Determination limits are 10 ng enantiomer per ml plasma and allow the performance of pharmacokinetic studies after the aimed therapeutic dosages.
Salicylamides Containing Amino Acid or Pyran Moieties with Molluscicidal Activity
Authors: Nawwar Galal A. M.
Published: October 2006

Salicylamide amino acid conjugates were prepared utilizing 5‐formyl‐, 5‐dicyanoethenyl‐, and 5‐nitroethenylsalicylic acid. 5‐Substituted salicylanilides were treated with glycine and formaldehyde in a Mannich type reaction affording the corresponding 3‐(N‐glycino)salicylanilides. The reactions of anilines with pyrans containing the salicylyl moiety yielded the corresponding salicylanilides. The obtained compounds were tested for molluscicidal activity.
Synthese von 5H‐Pyrido[2,3‐c]‐2‐benzazepinen
Authors: Troschütz Reinhard , Grün Lothar
Published: October 2006

Die Titelverbindungen lassen sich auf zwei verschiedenen Wegen herstellen: Durch Ringschlußreaktionen des 2‐Benzazepin‐enaminonitrils 1 mit den C2‐Bausteinen 2, 7 und 8 sind die Tricyclen 6, 9 und 10 zugänglich. ‐Beim zweiten Weg werden die 2‐Amino‐3‐benzoylpyridine 16a,b zu den 2‐Amino‐3‐benzylpyridinen 18a,b reduziert. Benzoylierung von 18a,b führt zu den Dibenzoylverbindungen 20 und 21, die sich in die Monobenzoylverbindungen 22 und 23 überführen lassen. Ringschluß nach Art der Bischler‐Napieralski‐Reaktion führt mit 22a,b und 23a,b zu den 5H‐Pyrido[2,3‐c]‐2‐benzazepinen 24a,b, und 25a,b. ‐ Mittels 1H‐, 13C‐ und 15NNMR‐Daten wird bewiesen, daß Benzoylacetimidsäureethylester (12a) als Benzoylketen‐O,N‐acetal 12a AE vorliegt.
A Khellin‐like 7,7′‐Glycerol‐bridged Bischromone with Anti‐anaphylactic Activity
Authors: Löwe Werner , Maske Peggy V. , Müller Wolfgang
Published: October 2006

The synthesis of the title compound 3 is described. Its performance in Passive Cutaneous Anaphylaxis (PCA) testing was evaluated.
Zur Pharmakokinetik von Lipidsenkern, 10. Mitt.: Zweiter Beitrag zur Frage der Dehalogenierung des Lipidsenkers Ciprofibrat
Authors: Oelschläger Herbert , Hellwich Karl‐Heinz , Rothley Dietrich
Published: October 2006

Das in der Lit. als Metabolit von rac‐1 postulierte Monochlorderivat rac‐2 wurde ausgehend von rac‐3 in vier Stufen dargestellt. Die partielle Dehalogenierung erfolgte mit LiAlH4, eine neue Zuordnung der entstehenden Stereoisomere NMR‐spektroskopisch. Bei oraler Gabe von rac‐1 an Probanden in multiple dose‐Studien konnte mit rac‐2 als Referenzsubstanz dieses im Rahmen der Nachweismöglichkeiten (HPLC, UV‐Detektor) weder im Plasma noch im Harn nachgewiesen werden.
7‐Fluor‐4‐chromon‐3‐Schwefel‐Verbindungen
Authors: Löwe Werner , Elz Sigurd , Reiser Harald , Schott Susan
Published: October 2006

Ausgehend von der Sulfinsäure 4, die aus dem Enaminon 3 und Thionylchlorid herstellbar ist, werden eine Reihe neuer 7‐Fluor‐4‐chromon‐3‐Schwefelverbindungen 5‐12 hergestellt. Insbesondere wird das Flosequinan‐analoge Sulfoxid 12 synthetisiert und auf vasodilatierende Wirkung an der isolierten Rattenaorta geprüft.
Approach to Detect Substrates Suitable to Measure the Coumarin 7‐Hydroxylase (Cyp 2a‐5) ‐ Structure‐Activity Relationships
Authors: Tegtmeier Martin , Legrum Wolfgang
Published: October 2006

Besides coumarin, which up to now has remained the most selective substrate for the coumarin 7‐hydroxylase (Coh), 7‐ethoxycoumarin, quinoline, 4‐methylcoumarin, 7‐ethoxy‐4‐methylcoumarin, 7‐ethoxy‐4‐ethylcoumarin, and psoralen are suitable for this enzyme. ‐ The quantification of the suitability of a substrate to selectively measure the coumarin 7‐hydroxylase is achieved by a graphic method. ‐ Requirements for serving as a substrate of the Coh are bicyclic ring systems with an electron rich moiety.
4‐(β‐D‐Ribofuranosyl)pyridazine: Neue C‐Nukleoside durch [4+2]‐Cycloaddition mit inversem Elektronenbedarf
Authors: Richter Marianne , Seitz Gunther
Published: October 2006

Es wird ein Syntheseweg zu neuen C‐Nukleosiden beschrieben mit in 3,6‐bzw. in 3,5,6‐Stellung substituierten Pyridazinen als heterocyclischem Aglykon. [4+2]‐Cycloaddition der Alkin‐substituierten Precursoren 1 bzw. 10a‐d mit den 1,2,4,5‐Tetrazinen 2a,b, deren Diazadiensystem durch elektronenziehende Substituenten aktiviert ist, führen zu den O‐geschützten 4‐(β‐D‐Ribofuranosyl)pyridazinen 4a,b bzw. 12a‐d. Nachfolgende hydrierende Abspaltung der Schutzgruppen liefert die neuen C‐Nukleosiden 5a bzw. 13a‐d in mittleren bis guten Ausb.
Polycyclische aromatische Alkaloide, 10. Mitt.: Annonaceen‐Alkaloide mit antimykotischer Aktivität
Authors: Bracher Franz
Published: October 2006

Es werden zwei Strategien zur Synthese isomerenreiner Azafluorenone beschrieben. Cyclisierung der Arylnicotinsäure 7 mit Polyphosphorsäure und anschließende hydrogenolytische Abspaltung des Bromsubstituenten führt zu 8‐Methoxyonychin (3) (“Methode A”). Parham‐Cyclisierung der Carbonsäure 7 oder des Esters 6 liefert das Annonaceen‐Alkaloid 6‐Methoxyonychin (2) (“Methode B”).

In einem Agar‐Diffusionstest zeigen 2, 3 und Onychin (9a) eine mäßige, 9e eine starke Hemmwirkung gegen Candida albicans. Andere Azafluorenone sind praktisch unwirksam. Das strukturverwandte Azaoxoaporphin‐Alkaloid Sampangin (12) hingegen besitzt eine sehr starke antimykotische Aktivität.
Friedel‐Crafts‐Reaktion einiger N‐Acylaziridine: Oxazoline als Zwischenstufen
Authors: Mall Thomas , Buchholz Berthold , Stamm Helmut
Published: October 2006

3‐Substituierte 1‐Acyl‐2‐phenylaziridine 1a,b und 2b lieferten mil AlCl3 in Benzol ohne Wärmezufuhr überraschend die entspr. Friedel‐Crafts‐Produkte 3a,b und 4b (acylierte 1‐substituierte 2,2‐Diphenylethylamine), die teilweise zu 1,1,2,2‐Tetraphenyläthan (5) weiterreagierten. Daneben wurden die Oxazoline 6a,b und 7b gefunden. Anhand des 2,4,5‐Triphenyloxazolins 6b wird gezeigt, daß die Oxazoline Zwischenstufen für 3, 4 und 5 sind. Die ungewöhnliche heterolytische Ringöffnung dieser speziellen Oxazoline wird diskutiert.
Chinoid substituierte 1,2,4‐Dithiazole als Bausteine für Heterocyclensynthesen
Authors: Briel Detlef , Leistner Siegfried
Published: October 2006

1,2,4‐Dithiazole 1 sind als Bausteine zur Synthese von mono‐ und bicyclischen Heterocyklen geeignet. So können substituierte Triazole 2, Oxadiazole 3, 4, Pyrimidine 6, Triazine 9, 10 und Benzoxazine 11 dargestellt werden. Hierbei fungiert das 1,2,4‐Dithiazolsystem als CNC‐ oder OC3NC‐Synthon.
Cycloadditionen von Cyclopropenon an 1,2,4‐Triazine, eine neue Synthese von Pyrazolo[1,2‐a]1,2,4‐triazin‐6‐onen
Authors: Massa Werner , Kang Hak‐Chul , Rischke Monika , Seitz Gunther
Published: October 2006

Im Gegensatz zu Cyclopropen, 3,3‐Dimethoxycyclopropen oder 1,2‐Diphenylcyclopropenon reagiert unsubstituiertes Cyclopropenon mit verschieden substituierten Triazinen regioselektiv an der NN‐Bindung zu neuen Pyrazolo[1,2‐a]1,2,4‐triazin‐6‐onen in mittleren Ausbeuten. Die Struktur des Pyrazolo[1,2‐a]1,2,4‐triazins 11 konnte mittels Röntgenstrukturanalyse gesichert werden.
Cer(IV) Oxidationen, 10. Mitt.: Oxidation von ω‐Phenylalkyldicarbonyl‐ und dicarbonyl‐analogen Verbindungen
Authors: Holzgrabe Ulrike , Reinhardt Jürgen , Zlotos Gabriele
Published: October 2006

Die Oxidation der ω‐Phenylalkylmalonsäurederivate 1a‐f führt nicht nur zu Cyclisierungsprodukten 2, sondern auch zu offenkettigen Nitro‐, Alkohol‐ und Acetoxyderivaten 3–7. Es wird eine empfindliche Abhängigkeit der Produktverteilung von Reaktionstemp. und Wassergehalt des Reaktionsmediums sowie der Natur der Carbonylgruppen beobachtet. Das während der Reaktion entstehende Ce3+‐Ion ist für die Entstehung offenkettiger Nebenprodukte verantwortlich.
Structure‐Activity Relationship Studies of CNS Agents, XV: N‐[ω‐(4‐Aryl‐1‐piperazinyl)alkyl]‐2‐oxo‐1,2,3,4‐tetrahydroquinolines and ‐4‐oxo‐1,2,3,4‐tetrahydropyrazino[1,2‐a]indoles: New, Highly Potent 5‐HT1A Ligands ωN‐[ω‐(4‐Aryl‐1‐piperazinyl)alkyl]‐2‐oxo‐1,2,3,4‐tetrahydrochinoline und ‐4‐oxo‐1,2,3,4‐tetrahydropyrazino‐[1,2‐a]indole: Neue starke 5‐HT1A Liganden
Authors: Mokrosz Jerzy L. , Duszyńska Beata , Paluchowska Maria H.
Published: October 2006

1‐Arylpiperazines and their 4‐alkyl derivatives, which contain a terminal amide fragment, produce a variety of pharmacological effects and behavioral responses which result directly from activation of different central receptor systems. Previously we showed that derivative 1 had a higher 5‐HT1A affinity than its isomeric isoquinolinone counterparts. We also concluded that the specific arrangement of the amide bond for compound 1 was definitely favorable at 5‐HT1A receptors. Our recent studies have shown that compound 5 is a potent antagonist of 5‐HT1A, 5‐HT2 and D2 receptors, and may be considered a novel atypical antipsychotic agent. Furthermore, derivative 5 may be classified as a highly active and non‐selective 5‐HT1A, 5‐HT2 (Table) and D2 (Ki = 40 nM) ligand with very high affinity for α1 receptors (Ki = 0.34 nM) and fairly moderate for D1 ones (Ki = 335 nM).
Antimycobakteriell wirksame Carbazolderivate
Authors: Mahboobi Siavosh , Kuhr Sabine , Meindl Wolfgang
Published: October 2006

Beschrieben wird die Synthese von Carbazolderivaten und deren Prüfung auf antimycobakterielle Eigenschaften (M. tuberculosis H 37 Ra, Middle‐brook‐7H9‐Nährlösung). ‐ Die unterschiedliche Hemmwirkung von Diastereomeren wird an 32 und 33 untersucht. ‐ Die unterschiedliche Hemmwirkung eines Racemates und des jeweiligen rechtsdrehenden Enantiomers wird an (±)‐12 und (+)‐12 bzw. (±)‐5 und (+)‐5 geprüft. ‐ (+)‐12 wird durch enantioselektive Synthese dargestellt.
Hypoxic Radiosensitizers: Substituted Styryl Derivatives
Authors: Nudelman Abraham , Falb Eliezer , Odesa Yael , Shmueli‐Broide Naomi
Published: October 2006

A number of novel styryl epoxides, N‐substituted‐styryl‐ethanolamines, N‐mono and N,N′‐bis‐(2‐hydroxyethyl)‐cinnamamides ‐ analogues to the known radiosensitizers RSU‐ 1069, pimonidazole and etanidazole ‐ display selective hypoxic radiosensitizing activity. The styryl group, especially when substituted by electron withdrawing groups, was found to be bioisosteric to the nitroimidazolyl functionality. The most active derivative 2‐(2′‐nitrophenyl)ethen‐1‐yl‐oxirane 8a displayed a sensitizer enhancement ratio (SER) of 5 relative to misonidazole.
Inhaltsstoffe von Fagaceae (Cupuliferae), 19. Mitt.: Triterpensaponine und Acylflavonoide aus Quercus robur var. stenocarpa Beck.
Authors: Romussi Giovanni , Parodi Brunella , Pizza Cosimo , De Tommasi Nunziatina
Published: October 2006

Aus den Blättern von Quercus robur L. var. stenocarpa Beck. wurde neben vier bekannten Glycosiden ein neues Triterpensaponin isoliert und als 28‐β‐D‐Glucopyranosylester der 2α,3β,19α‐Trihydroxy‐12‐oleanen‐24,28‐dicarbonsäure (1) identifiziert.
Ester des Naproxens als potentielle Prodrugs zur Hautpenetration 2. Mitt.: Penetrationseigenschaften an exzidierter Mäusehaut
Authors: Weber Horst , Meyer‐Trümpener Klaudia , Lippold Bernhard C.
Published: October 2006

In einem in vitro Modell an exzidierter Haut von Nacktmäusen wurden die Penetrationseigenschaften ausgewählter Naproxenester untersucht. Die Werte für den jeweiligen Permeabilitätskoeffizienten und den maximalen Flux wurden ermittelt und mit den physikochemischen Eigenschaften der Substanzen korreliert. Dabei erweist sich neben der Octanollöslichkeit die Wasserlöslichkeit als besonders wichtig. Ein Modell für die Vorhersage des Penetrationsverhaltens wird vorgeschlagen.
Investigation of the Conformational Influences on the Estrogenic Activity of 1,2‐Bis(2,6‐dichloro‐4‐hydroxyphenyl)‐ethylenediamines and of their Platinum(II) Complexes, II: Synthesis and Studies on the Estrogenic Activity of cis‐ and trans[Bis(2,6‐dichloro‐4‐hydroxybenzylamine)]dihaloplatinum(II)‐Complexes
Authors: Gust Ronald , Schönenberger Helmut
Published: October 2006

2,6‐Dichloro‐4‐hydroxybenzylamine (1) and its N‐methyl (2) and N‐ethyl (3) derivatives were synthesized and tested for estrogen receptor affinity as well as for estrogenic activity. In contrast to their related highly active 1,2‐bis(2,6‐dichloro‐4‐hydroxyphenyl)ethylenediamines (meso‐4 ‐ meso‐6) none of the benzylamines showed hormonal activity. The coordination of the benzylamine 1 to platinum did not lead to an estrogenic compound. The reasons for the different activity of [meso‐1,2(bis‐2,6‐dichloro‐4‐hydroxyphenyl)ethylenediamine]dichloroplatium(II) (meso‐4‐PtCl2) and cis[bis(2,6‐dichloro‐4‐hydroxybenzylamine)]dichloroplatinum(II) (cis‐1‐PtCl2), the latter of which can be considered as a ring‐opened counterpart of the highly active meso‐4‐PtCl2, are thoroughly discussed under inclusion of conformational facts. The results of this and the preceding work show, that the pharmacophore meso‐1,2‐bis(2,6‐dichloro‐4‐hydroxyphenyl)ethylenediamine (meso‐4) which is exclusively responsible for the estrogenic activity of meso‐4‐PtCl2 causes comparable hormonal effects in two different conformations with O‐O distances of about 8 Å (complex) and of about 12 Å (diamine). Therefore, we discuss two binding sites for estrogens in their receptor.
Synthesis of Related Substances of Cefadroxil
Authors: Hendrix Christel , Roets Eugène , Roesems Siegfried , Busson Roger , Rozenski Jef , Janssen Gerard , Hoogmartens Jos
Published: October 2006

The chemical synthesis of some related substances of the cephalosporin antibiotic cefadroxil is described. These compounds which may be present in commercial samples originate from the semisynthetic preparation of the antibiotic or from degradation. The preparation of these products enables the validation of selective quantitative analytical methods, such as liquid chromatography and tlc.
Synthesen von Chromon‐3‐sulfonylharnstoffen
Authors: Löwe Werner , Matzanke Norbert , Rütjes Thomas
Published: October 2006

Eine neue Methode zur Herstellung der Chromon‐3‐sulfonylharnstoff‐Derivate 20 und 22, ausgehend von den Enamionen 18 und 21, Chlorsulfonylisocyanat und 4‐Chloranilin, wird beschrieben. Darüber hinaus erhält man durch Reaktion des Sulfonamids 8 mit Phenylisocyanat den Chromon‐3‐sulfonylharnstoff 17. Versuche, Sulfonylharnstoffe aus den Carbamaten 9‐12 herzustellen, die sich vom Sulfonamid 8 ableiten, waren erfolglos.
Structure Activity Relationships of 4‐Substituted 1‐Acyl and 1,2‐Diacyl‐1,2,4‐triazolidine‐3,5‐diones as Anti‐inflammatory Agents in Rodents
Authors: Hall Iris H. , Simlot Rupendra , Izydore Robert A.
Published: October 2006

1‐Acyl and 1,2‐diacyl 1,2,4‐triazolidine‐3,5‐diones proved to be potent anti‐inflammatory agents in rodents at 8 or 20 mg/kg. They were effective against induced edema, pleurisy, and septic shock. Furthermore, these agents were potent in blocking the writhing reflex suggesting that they should be effective against local pain generated by inflammatory processes. These compounds were not lysosomal hydrolytic enzyme or proteolytic enzyme inhibitors in mouse liver, macrophages or human leukocytes. However, the agents were potent inhibitors of prostaglandin and leukotriene de novo synthesis and have potential in acting as free radical scavengers.
Platelet Aggregation Inhibiting and Anticoagulant Effects of Oligoamines, XXV: Interactions of the Oligoamine RE 1492 with Biomembranes
Authors: Kesselhut Annette , Ebel Hans , Bruchhausen Franz V. , Rehse Klaus
Published: October 2006

The absorption of D‐glucose by rat thymocytes is reduced to half of control by 30 μmol/L and decreased to 10 % by 100 μmol/L of RE 1492. This is backed by the fact that the absorption of 2‐deoxy‐D‐glucose is inhibited in the same extent. The more hydrophilic oligoamine RE 1888 had an analogous but smaller effect while spermine was ineffective. In a lipid peroxidation model RE 1492 or spermine in a concentration of 100 μmol/L nearly completely inhibited for formation of Fe3+ ions when the phospholipid was mimicked by adenosine monophosphate. This suggests an interaction with negatively charged membrane phospholipids. RE 1888 had an equal but smaller effect. The effect of RE 1492 on lipid order and lipid motility was checked on ovine lymphocyte membranes by fluorescence polarization measurements. The steady state as well as the limiting anisotropy as an expression for lipid order is decreased by rising concentrations of RE 1492. The use of several anthroyloxy stearic acids as fluorescent probes also shows an increased lipid motility in several areas of the membrane bilayer. The use of fluorescent parinaric acids suggests that areas of high regularity, i.e. liquid crystal formation are involved, too.
Synthese von Carbazolderivaten, 1. Mitt.: Über die Reaktion von 3‐(2‐Nitroethenyl)indol‐2‐malonestern mit Michael‐Akzeptoren
Authors: Mahboobi Siavosh , Burgemeister Thomas , Kastner Fritz
Published: October 2006

Michael‐analoge Reaktionen der Verbindungen vom Typ 9 wurden untersucht: Additionreaktionen mit Acrolein und Methylvinylketon führen in Abhängigkeit von den Reaktionsbedingungen zu den Pyridoindolin 16 oder 14 und/oder zu Tetrahydrocarbazolen vom Typ 17 oder 15. Unter Triton B‐Katalyse zeigen die Verbindungen 15 retro‐Michael‐Eliminierung der Nitromethyl‐Gruppe, gefolgt von Hydrolyse/Decarboxylierung und Dehydrierung zu den zweifach substituierten Carbazolen 20. Im Fall von 17a konnte das primäre Eliminierungsprodukt 18 isoliert werden. Das Synthesepotential dieser Reaktionen wird diskutiert. Einige der beschriebenen Verbindungen und ihrer Derivate sind antimykobakteriell aktiv.
New NO‐Donors with Antithrombotic and Vasodilating Activities, XI: 2‐Nitrosiminobenzimidazoles
Authors: Rehse Klaus , Birkhofer Gerhard
Published: October 2006

Thirteen 1,3‐disubstituted title compounds were synthesized and tested for their antiplatelet activity (Born test, collagen). Three derivatives inhibited the platelet aggregation halfmaximally in concentrations < 20 μmol/L.
Pentafluorophenyl Esters of Dicarboxylic Acids
Authors: Imming Peter , Jung Myung‐Hee
Published: October 2006

Di‐ and half‐esters of various dicarboxylic acids and dicarboxylic monoamides with pentafluorophenol were prepared. Their syntheses, properties, and spectroscopic data are reported.
Binding of Chloroquine and of Some Derivatives to Human Serum Albumin
Authors: Kinawi Abdelwahab , Dietz Martin , Schmidt Roland , Löwe Werner
Published: October 2006

Ein Hindernis bei der Durchführung einer erfolgreichen Chemotherapie gegen Malaria ist die Resistenzentwicklung der Plasmodien gegenüber herkömmlichen Wirkstoffen, insbesondere gegen Chloroquin. ‐ Bei der Entwicklung von neuen Antimalariamitteln bieten die befallenen Erythrozyten wegen ihrer erhöhten Empfindlichkeit gegenüber Oxidationsmitteln einen geeigneten Angriffspunkt, für eine Reihe von Stoffklassen (z.B. Nitroverbindungen, Peroxide und Chinone)1,2).

Die Bindung von Chloroquin sowie von anderen Antimalariamitteln an Serumproteine verdient besondere Beachtung, da hier das Blut zusätzlich zu seiner gewöhnlichen Funktion als Speicher‐ und Transportmittel das “Zielorgan” (befallene Erythrozyten) darstellt1).

Basische Stoffe zeigen im allgemeinen eine schwache Affinität zum HSA. Sie werden aber relativ häufig an saurem α1‐Glucoprotein und zum Teil an γ‐Globulin gebunden3,4). Unter der Voraussetzung, daß diese Stoffe sich passiv zwischen dem Hämoglobin und den Serumproteinen verteilen, ist anzunehmen, daß die Konzentration in den Erythrozyten von den Affinitäten der Stoffe zu den beteiligten Proteinen abhängt.
Transdermal Absorption of Dimethindene in Man
Authors: Radler Susanne , Blaschke Gottfried
Published: October 2006

Dimethindene and its metabolite N‐demethyldimethindene were determined in human urine after dermal administration of dimethindene. The HPLC‐method used was previously described. Data of 8 volunteers are presented. After 32 h an average of 0.023% of the administered dose of dimethindene and 0.022% of N‐demethyldimethindene were excreted into urine. Since also after oral administration of dimethindene only about 1% of unmetabolised dimethindene is found in urine it can be concluded that a certain amount of dimethindene is absorbed through the skin after dermal administration.
Darstellung und Reaktionen von 2‐Methylen‐canrenon
Authors: Görlitzer Klaus , Moormann Peter , Pollow Kunhard , Schaffrath Michael
Published: October 2006

Ausgehend vom Mannich‐Salz 1 des Aldosteronantagonisten Canrenon oder von 2‐Methylen‐canrenon (2) wurden die am A‐Ring anellierten Hetero‐ und Carbocyclen 5, 6, 8–13 dargestellt. Mit den Verbindungen 2, 3, 4b, 5, 6b, 8 und 12 wurden Bindungsstudien am Estradiol‐, Progesteron‐, Androgen‐, Glucocorticoid‐ und Mineralocorticoid‐Rezeptor sowie an den Serumproteinen Sexualhormonbindendes Globulin (SHBG) und Corticosteroidbindendes Globulin (CBG) durchgeführt. Die relativen Bindungsaffinitäten lagen bei CBG unter 1%, in allen anderen Fällen niedriger als 0.01%.
Some Analogues of 1,4‐Disubstituted Piperazines as Hypnotic and Sedative Agents
Authors: Chilmonczyk Zdzisław , Bogdal Maria , Zaworska Alicja , Cybulski Jacek , Szelejewski Wiesław
Published: October 2006

Preparation, analytical data, and biological properties such as acute toxicity, influence on spontaneous and amphetamine induced locomotor activity, hypnotic activity, influence on hexobarbital narcosis and anticonvulsant activity of new analogues of pyrimidyl piperazines ‐ ethyl 3‐[4‐(2‐pyrimidyl)‐1‐piperazinyl]‐3‐oxopropanoate (4), 1‐[4‐(2‐pyrimidyl)‐1‐piperazinyl]‐1,3‐butandione (5), ethyl 3‐[4‐(2‐pyrimidyl)‐1‐piperazinyl]butanoate (6) and 1‐[4‐(2‐pyrimidyl)‐1‐piperazinyl]‐2‐acetyl‐1‐hexanone (7) ‐ are reported.
Synthesis of Pyrryl Aryl Sulfones Targeted at the HIV‐1 Reverse Transcriptase
Authors: Artico Marino , Silvestri Romano , Stefancich Giorgio , Massa Silvio , Pagnozzi Eugenia , Musu Daniela , Scintu Franca , Pinna Elisabetta , Tinti Enrico , La Colla Paolo
Published: October 2006

Various aryl 1‐pyrryl sulfones were synthesized and tested as inhibitors of HIV‐1, 2‐Nitrophenyl‐2‐ethoxycarbonyl‐1‐pyrryl sulfone, the most active among test derivatives, was selected as lead compound of the aryl pyrryl sulfone series. The in vitro anti‐HIV‐1 activity and cytotoxicity of 41 compounds is reported. Some structure‐activity relationships are discussed also in comparison with the known NPPS (2‐nitrophenyl phenyl sulfone).
Synthesis and Biochemical Evaluation of (Carbamoylalkenyl)phenyloxy Carboxylic Acid Derivatives as Non‐steroidal 5α‐Reductase Inhibitors
Authors: Kattner Lars , Göhring Sigrid , Hartmann Rolf W.
Published: October 2006

Several (carbamoylalkenyl)‐ and (carbamoylalkenyl)phenyloxy carboxylic acids (Table 1) and some of their ethyl esters (Table 2) were synthesized and evaluated in vitro as inhibitors of steroid 5α‐reductase. Inhibitors of this enzyme may be useful in treating dihydrotestosterone‐related diseases such as prostate cancer and benign prostatic hyperplasia. Using an enzyme preparation obtained from human prostate carcinoma tissue, the inhibition values ranged from 0 to 57 % at the given dose of 100 μM. In the series of free acids, surprisingly, the compounds showed only modest inhibitory potency (0–26 %). By contrast, the ethyl esters displayed inhibition values up to 57 %. Structure‐activity relationships are discussed.
Synthesis of (S)‐3,4‐Diaminobutanenitriles as Precursors for 3‐Amino‐GABA Derivatives
Authors: Gmeiner Peter , Hummel Evi , Haubmann Christian , Höfner Georg
Published: October 2006

Starting from natural asparagine (1) a synthesis of the protected (S)‐3,4‐diaminobutanenitriles 5 and 8a–c via the β‐homoserine derivative 2 is described. The amino function in position 4 was introduced by Mitsunobu‐coupling or by reductive amination when a strange deformylation of the amino aldehyde 7 was observed as a side reaction. The Mitsunobu‐product 5 was converted into the dibenzylamine substituted GABA 6b which was investigated for its affinity at the GABA‐A receptor.
Synthese und Pharmakodynamische Aktivität von 2‐(3‐(2‐Phenylethyl)benzofuran‐2‐yl)‐N‐propyl‐ethanamin
Authors: Ecker G. , Helml T. , Fleischhacker W. , Noe C. R. , Studenik Christian , Schade Bettina , Heistracher Peter
Published: October 2006

Im Rahmen von Struktur‐Wirkungs‐Untersuchungen an Klasse I‐Antiarrhythmika wurden die Benzofuranethanamine 3a und 3b synthetisiert, und 3a wurde pharmakologisch geprüft. Schlüsselschritt der Synthese war die chemoselektive Reduktion des Chloracetyl‐Dihydrobenzofurans 5 zum Chlorethylbenzofuran 9 mit Triethylsilan/BF3 · Et2O. Die Ergebnisse einer Reihe weiterer Reduktionsversuche von 5 werden ebenfalls beschrieben. Pharmakologische Untersuchungen an isolierten Präparaten von Meerschweinchenherzen zeigten, daß 3a eine ähnliche negativ inotrope und chronotrope Wirkung wie Propafenon und das entsprechend rigidisierte Benzofuran 1a besitzt. Im Unterschied zu diesen Substanzen zeigte 3a jedoch keine β1‐Adrenozeptoren‐blockierende Aktivität.
Acidity and Stability of 10‐Substituted 1,8‐Dihydroxy‐9(10H)‐anthracenones
Authors: Müller Klaus , Gawlik Ingo , Wiegrebe Wolfgang
Published: October 2006

The decomposition of 10‐substituted anthralin derivatives in dimethyl sulfoxide and ethanol was determined. While 10‐ω‐phenylalkylidene derivatives were thoroughly stable, 10‐ω‐phenylacyl‐substituted compounds were slowly degraded to danthron and the corresponding carboxylic acids. However, the stability of these derivatives was markedly improved as compared to that of anthralin. Determination of the pKa values showed that the ω‐phenylacyl derivatives were somewhat stronger acids than anthralin, while ω‐phenylalkylidene‐substitution generally leaves the acidity of the anthralin part unchanged.
Structure‐Activity Relationship Studies of CNS Agents, XXI: Two Derivatives of 1‐(o‐Methoxyphenyl)piperazine with an Opposite Function at 5‐HT1A Receptors
Authors: Mokrosz Jerzy L. , Klodzinska Aleksandra , Boksa Jan , Bojarski Andrzej J. , Duszynska Beata , Chojnacka‐Wójcik Ewa
Published: October 2006

It is intriguing that all postsynaptic 5‐HT1A receptor antagonists which belong to the 1‐arylpiperazine class of ligands have a 1‐(o‐methoxyphenyl)‐piperazine fragment or its structural equivalent (e.g. benzodioxane moiety) in their structure2–5). One of them, NAN‐190 (1) may be regarded as a classic postsynaptic 5‐HT1A antagonist whose pharmacological and biochemical profiles have been well recognized2,6,7). Moreover, regarding all the known 5‐HT1A antagonists, systematic structure‐activity studies have been conducted for NAN‐190 only, as yet2,5,8,9).

Recently we showed that the simplification of the amide portion in NAN‐190 (1) did not change its in vivo profile; moreover, MM‐77 (2) also appeared to be a potent postsynaptic antagonist of 5‐HT1A receptors5). Even more dramatic structure simplification (of. 3 vs. 1) did not abolish the antagonistic properties of 3. According to Glennon and coworkers, compound 3 behaved like a weak postsynaptic 5‐HT1A antagonist in some biochemical tests8.9). By contrast, replacement of the 1‐(o‐methoxyphenyl)piperazine fragment in NAN‐190 by a bridged 1‐phenylpiperazine ring system resulted in analog 5, which was completely inactive in the in vivo models used5).
Biomimetic Aromatic Hydroxylation of Selected Diphenylmethane Derivatives
Authors: Fröhlich Luela , Pietzyk Birgit , Göber B.
Published: October 2006

Many oxidation systems using iron or manganese porphyrins as catalysts and various oxygen atom donors have been reported to mimic cytochrome P‐450‐dependent monooxygenases1–3). Such systems are very efficient for epoxidation of alkenes and reasonably for alkane hydroxylation. Few authors also reported about the activity to hydroxylate aromatic rings. In these cases low yields were found for hydroxylation of anisole, benzene, naphthalene, and toluene4–7). Biomimetic systems based on metalloporphyrin catalysts can be used for preparative oxidation of some substrates and appear particularly useful for the preparation of oxidized metabolites of drugs or other xenobiotics.
The N‐(9‐Xanthenyl) Derivative of 2‐Carbamoylphenoxyacetic Acid
Authors: Benicke Stephan , Grigat Hartmut
Published: October 2006

Derivatisierungen sind neben Farbreaktionen geeignete Methoden zur Identifizierung und Charakterisierung organischer Verbindungen. Daher werden in zunehmendem Maße auch in der pharmazeutischen Analytik bestimmte Arzneistoffe, z.B. solche mit aciden NH‐Funktionen, durch Derivatisierung mit Xanthydrol (9‐Xanthenol, 1) identifiziert und charakterisiert1,2). Xanthydrol ist auch ein Reagenz des Arzneibuches, wobei das dort angewandte Verfahren der Xanthenylierung von Harnstoff umgekehrt zur quantitativen Bestimmung des Xanthydrols dient3,4).

Auf Grund ihres NH‐aciden Charakters liefern insbesondere unsubstituierte Säureamide in glatter Kondensation zumeist gut kristallisierende Xanthydrol‐Derivate5).
Regioisomeric 5(3)‐Aminomethyl‐3(5)‐phenylisoxazoles: Synthesis, Spectroscopic Discrimination, and Muscarinic Activity
Authors: Dannhardt Gerd , Lambrecht Günter , Laufer Stefan , Mutschler Ernst , Schweiger Johannes
Published: October 2006

The regioselective synthesis of isomeric 5(3)‐aminomethyl‐3(5)‐phenyl isoxazoles using different methods is described. Spectroscopic data, especially mass spectrometric fragmentation, were used to identify and characterize the regioisomers. The muscarinic activity of these isoxazoles was assayed on isolated guinea‐pig ileum and atria as well as on isolated rabbit vas deferens.
Polarographische Untersuchung von Nedocromil, 2. Mitt: Polarographie von Nedocromil‐Natrium
Authors: Hermening Petra , Hoffmann Hermann
Published: October 2006

Nedocromil‐Natrium 1 zeigt ein stark pH‐abhängiges Reduktionsverhalten. Während im Bereich pH 2–5 zwei Stufen zu beobachten sind, wobei Stufe 1 in zwei Teilprozesse (1a und 1b) aufgespalten ist, tritt bei pH 6 erstmalig eine 3. Stufe auf. Bei pH‐Werten > 7 sind im Gleichspannungspolarogramm nur noch die Stufen 1a, 2 und 3 vorhanden. Zur kompletten Reduktion von 1 werden insgesamt acht Elektronen pro Molekül transferiert, es werden beide α,β‐ungesättigten Ketofunktionen zu den entsprechenden gesättigten Carbinolen reduziert.

Die Aufklärung des Reduktionsmechanismus wurde durch vergleichende Untersuchungen an Chromon‐2‐carbonsäure 2 und N‐Ethylchinoloncarbonsäure 31) unterstützt.
Synthesis and Antibiotic Activity of 1‐Cycloalkoxymethyl‐4‐dimethylaminopyridinium and 1‐[(1‐Alkoxy)ethyl]‐4‐dimethylaminopyridinium Chlorides
Authors: Pernak Juliusz , Michalak Lucyna , Krysinski Jerzy , Kuncewicz Zbigniew
Published: October 2006

DMAP reacts readily with chloromethylcycloalkyl ethers and α‐chloroethyl alkyl ethers to give stable (1a–1e) and unstable (2a–2h) pyridinium chlorides. Reaction of these chlorides with NaOH produces the corresponding 4‐pyridones. All the chlorides synthesized showed antibiotic activity. Particularly high activity against microbes representing cocci, rods, fungi, and bacilli was shown by 1‐cyclododecyloxymethyl‐4‐dimethylaminopyridinium chloride 1d and 1‐[(1‐dodecyloxy)ethyl]‐4‐dimethylaminopyridinium chloride 2f.
Structure‐Activity Relationship Studies of CNS Agents, Part 23[1]): N‐(3‐Phenylpropyl)‐ and N‐[3(E)‐Cinnamyl]‐1,2,3,4‐tetrahydroisoquinoline Mimic 1‐Phenylpiperazine at 5‐HT1A Receptors
Authors: Mokrosz Jerzy L. , Bojarski Andrzej J. , Charakchieva‐Minol Sijka , Duszynska Beata , Mokrosz Maria J. , Paluchowska Maria H.
Published: October 2006

The 5‐HT1A receptor affinities and ionization constants of a set of 1‐arylpiperazine (4) 1,2,3,4‐tetrahydroisoquinoline (6), and ‐quinoline (7) containing N‐(ω‐arylalkyl) or N‐(E)‐cinnamyl substituents as well as two morpholine derivatives (8a, 8b) were determined. It was shown that some tetrahydroisoquinoline (6c, 6d) and morpholine (8a) derivatives were 5‐HT1A ligands equipotentto 1‐phenylpiperazine (4a) and 1,2,3,4,4a5‐hexahydropyrazino[1,2‐a]indole (5). On the basis of molecular modelling studies it was also demonstrated that 6c, 6d and 8a mimicked very well the reference structures of 4a and its rigid analog 5. Another, more complex 1,2,3,4‐tetrahydroisoquinoline derivative 3, which served as a model compound to confirm the previously reported 5‐HT1A binding mode of derivatives 1a–d and 2, had the highest 5‐HT1A affinity (Ki = 6.7 ± 0.5 nM) of all the investigated compounds.
Synthesis, Toxicological, Pharmacological, and Bronchodilating Activity in vitro of some Xanthineacetic Acid Derivatives
Authors: Peikov Plamen , Danchev Nikolai , Zlatkov Alexander , Ivanov Dimiter , Belcheva Nadya
Published: October 2006

The possibility of the preparation of some ester derivatives of dimethylxanthines from 1‐theobromine‐ and 7‐theophylline acetic acids and 7‐(2‐hydroxyethyl)‐theophylline by DCC/DMAP‐mediated esterification under mild conditions was studied. The structures of the compounds synthesized and by products isolated were demonstrated by microanalyses, UV‐, IR‐, and 1H NMR data. Acute toxicity assessment of the compounds on mice showed that compounds 4, 5, 6, and 7 are less toxic than aminophylline. A pharmacological study of the in vitro broncholytic effect (IC50 and pD2 values) of the derivatives and aminophylline showed that the new compound 4 (1,2,3,6‐tetrahydro‐1,3‐dimethyl‐2,6‐dioxo‐7H‐purine‐7‐acetic acid 2‐(1,2,3,6‐tetrahydro‐1,3‐dimethyl‐2,6‐dioxo‐7H‐purine‐7‐yl)ethyl ester) has a strong bronchodilating effect on serotonine‐ and acetylcholine‐induced spasm in guinea pig trachea. The same compound does not influence barbiturate — induced hypnosis and locomotor activity, unlike to the effect of the aminophylline, used as a reference substance.
Proof of the Bis(oxazolidine)methane Structure for the Norephedrine—Formaldehyde Condensation Product
Authors: Aitken David J. , Chiaroni Angèle , Riche Claude , Husson Henri‐Philippe
Published: October 2006

The norephedrine—formaldehyde condensation product, a potential prodrug, was shown to have a bis(oxazolidine)methane structure by an X‐ray crystallography study.
Synthesis, Antitumoral and Antiviral Evaluation of Halo‐ and Demethyl‐Yatein Derivatives
Authors: Medarde Manuel , de Clairac Rafael Peláez‐Lamamié , López Jose Luis , Grávalos Dolores Ga , Feliciano Arturo San
Published: October 2006

Several chloro‐ and iodo‐lignanolides have been obtained by direct halogenation of aromatic rings from yatein and 4′‐O‐demethylyatein. They were assayed as antineoplastics, in order to check the influence in the activity of substitution in both aromatic rings. Although these compounds show a modest antineoplastic activity, it is far from that displayed by yatein and podophyllotoxin. These results confirm that demethylation and the introduction of halo substituents diminish the activity of lignans of the dibenzylbutyrolactone type.
Structure‐Activity Relationships in a Series of 8‐Substituted Xanthines as Bronchodilator and A1‐Adenosine Receptor Antagonists
Authors: Corsano Stefano , Strappaghetti Giovannella , Scapicchi Rossana , Lucacchini Antonio , Senatore Generoso
Published: October 2006

Four new derivatives of 8‐piperazine ethyl xanthine were synthesized and their bronchospasmolytic activity and A1‐adenosine affinity were studied. Their relaxant action in the tracheal muscle was lower than that of theophylline and that of theophylline derivatives substituted at the 7‐position. Only compound 9, where the methyl group in the 1‐position of the theophylline was substituted by an isobutyl group, shows a good affinity towards the A1‐adenosine receptor.
Structure‐Activity Relationship Studies of CNS Agents, Part 25: 4,6‐Di(heteroaryl)‐2‐(N‐methylpiperazino)pyrimidines as New, Potent 5‐HT2A Receptor Ligands: A Verification of the Topographic Model
Authors: Mokrosz Maria J. , Strekowski Lucjan , Kozak Wei Xing , Duszyńska Beata , Bojarski Andrzej J. , Kłodzinska Aleksandra , Czarny Agnieszka , Cegła Marek T. , Dereń‐Wesołek Anna , Chojnacka‐Wójcik Ewa , Dove Stefan , Mokrosz Jerzy L.
Published: October 2006

A series of new 4,6‐di(heteroaryl)pyrimidines containing an N‐methylpiperazino group (6–13) or an ethylenediamine chain (15–20) in position 2 were synthesized and their 5‐HT1A and 5‐HT2A receptor affinities were determined. It was shown that the substituent effects on the 5‐HT2A affinity are additive and could be described quantitatively. In a behavioral model it was also demonstrated that 6–11 are 5‐HT2A receptor antagonists. The molecular modelling results suggested that the distances between the basic nitrogen atom and the two aromatic centers (d1 = 5.2−8.4 Å, d2 = 5.7−8.5 Å, and d3 = 4.6−7.3 Å) define the molecular topography of the 5‐HT2A receptor antagonists under study.
Facile Syntheses of C2‐Symmetrical HIV‐1 Protease Inhibitors
Authors: König Stephan , Ugi Ivar , Schramm Hans J.
Published: October 2006

With the goal of obtaining inexpensive yet potent anti‐AIDS drugs, simple inhibitors of HIV‐1 protease were synthesised. The C2‐symmetrical pseudopeptidic substrate analogues can be prepared as inhibitors for HIV‐1 protease starting from symmetrical ketones 3a–d by a facile four‐step synthesis. After bromination of 3a–d to α,α′‐dibromoketones 4a–d, we synthesised the diamino compounds 6a–c by Gabriel synthesis, which were then coupled with Z‐valine to yield inhibitors with a central keto group 2a–c. We also synthesised inhibitors including a central hydroxy group 8a‐d a‐i by azidation, reduction with LiAlH4 and coupling of the β,β′‐diaminohydroxy compounds with appropriate peptides. The first set of compounds showed only weak inhibition whereas the latter reach Ki values of up to 3.0 μM.
On the Fluorescence Reaction of Pharmaceutically Important 1,3‐Diamines and o‐Aminobenzenesulfonamides with Homophthalaldehyde
Authors: Troschütz Reinhard , Heinemann Oliver
Published: October 2006

On treatment with pharmaceutically important primary 1,3‐diamines 2 and 8 as well as o‐aminobenzenesulfonamides 13–15, homophthalaldehyde (1) yields the intensely blue fluorescent, heteroanellated isoquinolines 5 and 9, as well as moderately fluorescent isoquinobenzothiadiazines 16–18.
Nucleosides and Nucleotides, Part 144 Synthesis and Antiviral Activity of 5‐Substituted (2′S)‐2′‐Deoxy‐2′‐C‐Methylcytidines and ‐uridines[1]
Authors: Awano Hirokazu , Shuto Satoshi , Miyashita Takanori , Ashida Noriyuki , Machida Haruhiko , Kira Toshihiko , Shigeta Shiro , Matsuda Akira
Published: October 2006

Synthesis of several 5‐substituted (2′S)‐2′‐deoxy‐2′‐C‐methylcytidines (8) and ‐uridines (6, 11) has been accomplished using radical deoxygenation of the 2′‐tert‐alcohols via their methyl oxalyl esters as a key reaction. Anti‐herpes simplex virus type‐1 and ‐2, and anti‐varicella‐zoster virus activities of the newly synthesized nucleosides were evaluated. Among them, the 5‐iodouracil derivative 6e showed the most potent activity against herpes simplex virus type‐1, with an EC50 of 0.14 μg/mL without showing cytotoxicity up to 100 μg/mL, but had a weak activity against herpes simplex virus type‐2 and no activity against varicella‐zoster virus up to 50 μg/mL in vitro. Although the 5‐fluorocytosine derivative 8b had a potent anti‐herpes simplex virus type‐1 activity (EC50 = 0.22 μg/mL), it was rather cytotoxic to the CCRF‐HSB‐2 human T‐cell line (IC50 ≥ 1.0 μg/mL).
Syntheses and Selective Inhibitory Activities of Terphenyl‐Bisamidines for Serine Proteases
Authors: von der Saal Wolfgang , Engh Richard A. , Eichinger Andreas , Gabriel Bernhard , Kucznierz Ralf , Sauer Jürgen
Published: October 2006

Biphenyl nitriles 5a—c, terphenyl dinitriles 11a—d, and naphthalene‐bis(benzonitrile) 11e were prepared by palladium‐catalyzed cross coupling reactions and subsequently converted to biphenyl amidines 8a—c and bis(benzamidines) 4a—e. Among the biphenyl amidines 8 only the meta‐derivative 8b inhibits factor Xa and trypsin (Ki = 10 μM). The terphenyl bisamidine 4c does not inhibit factor Xa, trypsin, thrombin, and plasmin, while 4a and 4d are almost equipotent inhibitors of theses enzymes (Ki 1–6 μM), and 4b and 4e are selective for trypsin (Ki = 0.2 and 0.3 μM; but Ki > 1 μM for factor Xa, thrombin, and plasmin). X‐ray analysis of crystals of 4b complexed with bovine trypsin revealed a unique binding mode: one benzamidino group binds in the S1 site to the side chain carboxylate of Arg189. The central phenyl group is twisted away from the S2/S3 sites and the second amidino group contacts the Asn143 side chain.
Platelet Aggregation Inhibiting and Anticoagulant Effects of Oligoamines, Part 32 Antimicrobial Effects of Oligoamines
Authors: Rehse Klaus , Woyke Christian , Rodloff Arne , Hahn Helmut
Published: October 2006

Twenty‐four oligoamines belonging to six (1–6) structurally different types were tested in vitro for their antibacterial activity against 14 different bacterial species comprising a total of 187 strains. Ten compounds were able to inhibit growth of at least one strain at concentrations ⩽10 μmol/L. For three compounds, minimum inhibitory concentrations for some strains were even below 1 μmol/L. Clear structure‐activity relationships showed that the inhibitory effect depended on the bridge connecting the nitrogen atoms, the substitution of the nitrogens, and the number of nitrogen atoms present in one molecule. Substitutions like N‐4‐phenylbutyl, N‐octyl, and N‐nonyl were most active, while short (butyl) and long (dodecyl) substituents diminished or abolished the activity. The antimicrobial spectrum of the oligoamines tested here covered gram‐positive (e.g. Staphylococcus aureus, Listeria monocytogenes, Bacillus subtilis) and gram‐negative (e.g. Escherichia coli, Citrobacter spp., Acinetobacter spp.) microorganisms. The type of action was classified as bactericidal. As the inhibition of growth is complete immediately after the addition of the oligoamines, an interaction with the bacterial cell‐membrane is probable.
Tolperisone: Evaluation of the Lidocaine‐Like Activity by Molecular Modeling
Authors: Fels Gregor
Published: October 2006

Tolperisone (1), a muscle relaxant with lidocaine‐like activity, was compared to lidocaine (2) by molecular modeling methods. Conformational search analysis has been employed to find the global minima of these compounds along with numerous low energy conformations from which specific conformers were extracted that show good superimposition of the structural features important for protein binding. Two additional compounds, mepi‐ (3) and bupivacaine (4), were included in the analysis to validate the method as these ligands show very close structural and pharmacological relationship to lidocaine (2) and are assumed to bind to an identical site. As a result we find conformers of all four ligands that have exactly the same position and orientation of the potential sites for hydrogen bonding with the rest of the molecule showing close comparison of the three‐dimensional geometry. Semiempirical calculations furthermore reveal good agreement of the electrostatic potentials of these conformations indicating similar interactions with a receptor. We conclude that tolperisone (1) and lidocaine (2) despite their chemical divergence can still attach to identical protein binding sites.