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Alkylated phenol and methoxytoluene derivatives were catalytically and selectively oxidized to the corresponding 1,4-benzoquinones in good conversions and yields. Reactions were performed with hydrogen peroxide (H2O2)/methyltrioxorhenium (CH3ReO3) in 1-butyl-3-methylimidazolium tetrafluoroborate [bmim]BF4, a neutral ionic liquid. Compounds were tested in vitro for their antifungal activity against the growth of several widespread soil fungi. Some of them were proved to be potent inhibitors of Fusarium sp. than ketoconazole, a commercially available and expensive antifungal agent.

The unique electronic and structural characteristics of 1,4-beilzoquinones with possibilities for numerous interactions such as coordination, hydrogen bonding accompanied by proton and/or electron transfer, pi-interactions, and redox activity, are used by nature to perform important biological reactions. In spite of their wide use in supramolecular chemistry for construction of functional materials, the intercorrelation of their versatile interactions has not been completely evaluated. The impacts of hydrogen bonding and cations on interactions of quinoid skeleton are studied on the prepared series of alkali (Li(+), Na(+), K(+), NH(4)(+), and Rb(+)) chloranilate hydrates, and anhydrous caesium homologue. The pi center dot center dot center dot pi stacking interactions of chloranilate dianions observed in the structures of sodium chloranilate dihydrate and caesium sodium chloranilate monohydrate [with centroid separation distances of 3.662(1) and 3.740(2) angstrom and shifts of 1.698 and 1.358 angstrom. respectively] are tuned by hydrogen bonding involving water Molecules. The crystal structures of potassium and rubidium chloranilate monohydrates are isostructural whereas their ammonium homologue, due to the presence of cation with pronounced proton-donor activity, exhibits completely different hydrogen bonding network. In the six of seven structures studied chloranilate dianion reveals the crystallographic symmetry C(i).

Department of Chemistry, Govt. College, Ajmer-305 001, Rajasthan, India Department of Pure & Applied Chemistry, M. D. S. University, Ajmer-305 009, Rajasthan, India E-mail : kgojha_mdsu@rediffmail.com Fax : 91-145-2670484 Manuscript received 6 August 2008, accepted 1 October 2008 An environmentally benign solvent-free microwave-assisted synthesis of biologically active 2,5-diarylamino- 3,6-dihalo-1,4-benzoquinones by the condensation of substituted anilines and chloranil has been reported on the inorganic solid support of silica gel.

Reactions of N,N`-disubstituted hydrazinecarbothioamides 8a-c and substituted thioureidoethylthioureas 9a-c with 2,3,5,6-tetrachloro-1,4-benzoquinone (chloranil, 10a) and 2,3,5,6-tetrabromo-1,4-benzoquinone (bromanil, 10b) to form N,N`-disubstituted [1,3,4]thiadiazole-2,5-diamines 11a-c, 6,7-dichloro-3-substituted amino-1H-benzo[1,3,4]- thiadiazine-5,8-diones 12a-c, 2,3,7,8-tetrahalothianthrene-1,4,6,9-tetraones 13a,b, 5,6,8- trihalo-7-oxo-3,7-dihydro-2H-quinoxaline-1-carbothioic acid substituted amides 14a-c, 15a-c and 7-substituted imino-[1,3,6]thiadiazepane-3-thiones 16a-c are reported. Rationales for the observed conversions are presented.

0\. Titelblatt und Inhaltsverzeichnis 1\. Einleitung 1 2\. Zielsetzung 39 3\. Synthese der Zielverbindungen 43 4\. Untersuchung der Zielverbindungen 83 5\. Ergebnisse und Diskussion 95 6\. Zusammenfassung 119 7\. Chemisch-experimenteller Teil 129 8\. Biochemisch-experimenteller Teil 179 9\. Photochemoluminometrische Bestimmung der antioxidativen Eigenschaften 193 10\. Bestimmung der Lipophilie 197 11\. Literaturverzeichnis 201 12\. Abbildungsverzeichnis 213, Ziel der vorliegenden Dissertation war die Weiterentwicklung der Modellverbindung 1 [2-(3,5-Di-tert- butyl-4-hydroxyphenyl)-3-hydroxy-1,4-naphthochinon] durch Strukturvariationen in den Segmenten A, B und C. Durch diese Variationen sollte eine Verbesserung der 5-Lipoxygenase (5-LO)-Aktivität in den submikromolekularen Bereich erreicht werden sowie die Beeinflussung der weiteren für die Eicosanoidsynthese relevanten Enzyme (12-LO und COX-1) studiert werden. Am Ende sollte dann die Aufstellung eines Struktur-Wirkungs-Modells stehen. Segment A: Durch Integration von Heteroatomen in diesem Segment wurden Arylchinolin-5,8-dione, Arylisochinolin-5,8-dione und Arylbenzo[b]thiophen-4,7-dione gewonnen. Segment B: Durch die Variationen in Segment B wurde hauptsächlich eine Selektivitätsverschiebung zugunsten der 12 -LO-Aktivität angestrebt. Es wurden Salicyl- und Zimtsäure-Strukturen sowie Propionsäure- und Cumarin-Strukturen eingeführt. Segment C: Bei den Variationen in Segment C handelt es sich ausschließlich um Variationen an der vinylogen Carbonsäure-Struktur. Neben den Halogenen (F, Cl, Br, I, CN) wurden Malonsäure-Derivate und Thiole in dieser Position eingeführt. Des weiteren wurden bereits bestehende 5-LO-Inhibitoren weiterentwickelt: Das Cystein- Derivat konnte zu den trizyklischen Benzothiazinen, die 1,2-Naphthochinone zu den Benzo[a]phenazinen und das Benzo[b]naphtho[2,1-d]furan konnte durch Spaltung zum dihydroxylierten Aryl-1,4-naphthochinon weiterentwickelt werden. Die Substanzen wurden in zellbasierten in vitro-Assays auf ihre 5-LO-, 12-LO- und COX-1-Hemmung getestet. Unselektive Verbindungen wurden zusätzlich auf ihre cPLA2-Hemmaktivität untersucht. Die aus den biochemischen Assays hervorgegangenen Daten lieferten zwei entscheidende Ergebnisse: \- Bei den unselektiven Verbindungen handelte es sich ausschließlich um Verbindungen mit vinyloger Säurehalogenidstruktur. Sie hemmen alle gleichzeitig die cPLA2. \- Die Verbindungen mit vinyloger Carbonsäurestruktur weisen dagegen unterschiedliche Selektivitäten auf. Die erhoffte Steigerung der 5-LO- Aktivität in den nanomolaren Bereich konnte dabei nicht erreicht werden. Die Synthese der Arylbenzochinone führte zur Identifizierung des für die 5-LO- Hemmung entscheidenden Pharmakophors. Die biochemischen Daten ermöglichten ein Einteilung der neuen Strukturen anhand ihrer Hemmselektivitäten. Im Rahmen dieser Arbeit konnten neue Inhibitoren der folgenden Klassen gewonnen werden: Selektive 5-LO-Inhibitoren, selektive COX-1-Inhibitoren, duale 5-LO-/COX-1-Inhibitoren und duale 12-LO-/COX-1-Inhibitoren. Für die einzelnen Klassen konnten Struktur-Wirkungs-Beziehungen diskutiert werden. Weiterhin wurde im Rahmen der Untersuchungen die Bestimmung der Lipophilie mittels eines HPLC-Verfahrens vorgenommen. Eine Korrelation mit den biochemischen Daten zeigte sich dabei nicht. Die Messung der Antioxidativen Aktivität (AOA) nach der Methode von Popov et al. hat starke Antioxidantien unter den neuen Verbindungen hervorgebracht, deren Kapazität weit über der des Vitamin C liegt. Eine Korrelation zwischen AOA und Enzymhemmung besteht nicht, so dass bestätigt werden konnte, dass es sich bei der Verbindungsklasse der Aryl-1,4 -benzochinon-Derivate nicht um 5-LO-Inhibitoren vom Redox-Typ handelt. Vielmehr sind AOA und 5-LO-Aktivität zwei voneinander unabhängige Eigenschaften eines Moleküls., The aim of the present thesis was the further development of the model compound 1 [2-(3,5-di-tert- butyl-4-hydroxyphenyl)-3-hydroxy-1,4-naphthoquinone] by variation of segments A, B, and C. These variations were supposed to increase 5-lipoxygenase (5-LO) inhibitory activity towards the submicromolecular range. In addition the influence on the further enzymes relevant for eicosanoid synthesis (12-LO and COX-1) was studied. The results were discussed due to their structure- activity-relationship. Segment A: The integration of heteroatoms in this segment led to the arylquinoline-5,8-diones, arylisoquinoline-5,8-diones and arylbenzo[b]thiophene-4,7-diones. Segment B: The main aim of the variation of segment B was to reach a selectivity shift towards 12-LO-inhibition. Therefore salicylic and cinnamic acid structures as well as propionic acid and coumarin structures were inserted. Segment C: For segment C the vinylogous carboxylic acid structure was variated. Besides halogene atoms (F, Cl, Br, I, CN) malonic acid derivatives and thiols were introduced in this position. In addition known 5-LO-inhibitors were developed further: The cysteine derivative was transformed into tricyclic benzothiazines, the 1,2-naphthoquinones into benzo[a]phenazines and the benzo[b]naphtho[2,1-d]furan was cleaved to the dihydroxylated aryl-1,4-naphthoquinone. All substances were tested in cell based in vitro assays for their 5-LO, 12-LO and COX-1 inhibition. Unselective compounds were also tested for their cPLA2 (cytosolic phospholipase A2) inhibition. The obtained data led to two important results: \- All unselective compounds possess a vinylogous carboxylic acid chloride function and simultaneously inhibit cPLA2. \- Compounds with a vinylogous carboxylic acid function show different selectivities. An increase in 5-LO-activity towards the nanomolecular range could not be achieved. The synthesis of the arylbenzoquinones issued in the identification of the minimum structure necessary for 5-LO-inhibition. The biochemical data made it possible to distinguish the new substances due to their selectivities. In this work new inhibitors of the following categories were obtained: Selective 5-LO- and selective COX-1-inhibitors as well as dual 5-LO/COX-1- and 12-LO/COX-1-inhibitors. For each category structure-activity-relationships were discussed. In addition the lipophilicity of the substances was determined by using a HPLC-method. There was no correlation observed between biochemical data and lipophilicity. The antioxidative activity (AOA) was detected by using the method of Popov et al. By this method strong antioxidants were identified among the new compounds whose activity was significant increased in comparison with vitamin C. Meanwhile no correlation between AOA and enzyme inhibition was observed. This confirmed that the anellated aryl-1,4-benzoquinone derivatives are no redox inhibitors. AOA and 5-LO-inhibitory activity are two independent properties of a substance.