This investigation deals with the synthesis of 2-alkylpyridine and 2-alkylpyrazine derivatives of 2,3-dichloro-1,4-naphthoquinone. These compounds will be tested for physiological activity by Parke-Davis and Company.

The purpose of this investigation was the synthesis of some 1,4-naphthoquinones and 1,4-anthraquinones. It will be shown that some of these substituted quinones exhibit physiological properties.

Thesis (MTech(Chemistry))--Cape Technikon, Cape Town,1995 / The naphtho[2,3-c]pyran occurs frequently in nature as derivatives of the 5,10 quinones. The most common examples include the eleutherins and protoaphins. These naturally occurring compounds have been found to possess antibiotic activity through the process of bioactivation. The possibility of appropriately substituted compounds functioning as bioreductive alkylating agents provides a logical model that has a great deal of predictive power. The thesis deals with the synthesis of some naphtho[2,3-c]pyrans to be tested biologically; the challenge being to design compounds in a biologically inactive form which become activated only subsequent to an in-vivo transformation. Chapter One describes and compares a high yielding synthesis of a naphtho[2,3c] pyran, hongconin, to a previous route.,a Racemic hongconin (29) has been synthesised from adduct (43) formed by reaction between 1-methoxycyclohexa1,4- diene (41) and 1,4-benzoquinone (42). The key steps includes Fries and Claisen rearrangements, base and cerium(lVj initiated pyran ring formation, C-4 pyran ring hydroxylation and silver(ll) mediated oxidation. The target compound (29) was tested in vitro for antimicrobial activity and compared to the results obtained for isoeleutherin (2) and its 9-demethoxy analoque (30). The spectral data, melting points and yields of the individual compounds is as described in Chapter Two.

Thesis (Ph.D.)--Murdoch University, 2007. / Thesis submitted to the Division of Science and Engineering. Includes bibliographical references (leaves 210-214)

Thesis (Ph. D.)--University of Texas at El Paso, 2009. / Title from title screen. Vita. CD-ROM. Includes bibliographical references. Also available online.

The antimycobacterial activity of twenty South African medicinal plants were investigated using two methods commonly used; the conventional agar plate method and the BACTEC radiometric method. Fourteen of the twenty acetone extracts of medicinal plants used to treat pulmonary diseases showed inhibitory activity at a concentration of 0.5 mg/ml against a sensitive strain of Mycobacterium tuberculosis using the conventional agar plate method. These fourteen extracts were also tested against M tuberculosis by the BACTEC radiometric method against a sensitive as well as a strain resistant to the drugs isoniazid and rifampin. Eight plants showed activity against both the strains at a concentration of 1.0 mg/ml. Susceptibility testing of M tuberculosis by the agar plate method is reliable, economical, and reproducible whereas the BACTEC radiometric method is much faster and probably more accurate than the agar plate method. A cytotoxicity assay of the fourteen plants on primary vervet monkey kidney cells showed that the crude acetone extracts of E. natalensis was the least cytotoxic extract with significant antimycobacterial properties. It was therefore, chosen for the isolation of active compound(s). An antibacterial assay of the water and acetone extracts of the roots of E. natalensis showed that they inhibited the growth of Gram-positive bacteria at concentrations ranging between 0.1 and 6.0 mg/ml. The water extract did not exert any inhibitory action on Gram-negative bacteria while the acetone extract showed inhibitory activity at a concentration of 5.0 mg/ml. The MIC of diospyrin, isolated from E. natalensis, was found to be 100 µg/ml for a drug-sensitive and a number of drug-resistant strains of M. tuberculosis and Gram-positive bacterial species. An antiviral investigation of the crude extracts of E. natalensis showed that the water extract of the roots of the plant inhibited the replication of herpes simplex virus type 1 moderately at a concentration of 0.2 mg/ml whereas, acetone extract at concentrations ranging from 0.1 to 0.02 mg/ml. Diospyrin exhibited no inhibitory effect against the virus. The MIC of 7-methyljuglone, isolated from E. natalensis, was found to be 50 µg/ml for both drug-sensitive and drug-resistant strains of M. tuberculosis. The compound inhibited the growth of Gram-positive bacterial species at concentrations ranging from 50 to 100 µg/ml. No inhibitory effect of the compound was observed on any Gram-negative bacteria at the highest concentration tested. A significant synergistic effect of the two naphthoquinones was observed against M tuberculosis and some of the bacterial species. MICs obtained were 10 µg/ml and 50 µg/ml for M tuberculosis and the bacterial species respectively. No synergistic effect was observed on any Gram-negative bacterial species investigated. In view of the encouraging results obtained from this study on the biological activity of the two naphthoquinones; diospyrin and 7 -methyljuglone, it appears that the compounds deserve further investigation in order to explore its potential as antimycobacterial agents. / Thesis (DPhil (Plant Physiology))--University of Pretoria, 2007. / Plant Science / unrestricted

This thesis describes a series of pyridine-N-oxide derivatives of naphthoquinone that were prepared by the author. These compounds will be tested for medicinal activity by Parke-Davis and Company.

This paper deals with the preparation of pyridinium derivatives of naphthoquinone. The starting material was 2,3-dichloro-1,4-naphthoquinone, and it was reacted with pyridine and 4-n-alkyl-pyridine derivatives.

Muitas naftoquinonas como o lapachol, podem ser encontradas em plantas da família Bignoniaceae e são conhecidas por desempenharem diversas atividades biológicas, acompanhadas, entretanto, por efeitos indesejáveis. A atividade citotóxica apresentada pelas naftoquinonas está relacionada ao aparecimento de espécies reativas de oxigênio in vivo que causam severo estresse oxidativo no interior das células. O isolapachol e a atovaquona são análogos estruturais do lapachol, sendo que a atovaquona é comercializada como fármaco para o tratamento de malária e certos tipos de pneumonia. Devido ao grande potencial biológico apresentado pelas naftoquinonas, várias tentativas no sentido de obtenção de derivados desprovidos de efeitos colaterais vêm sendo realizadas. Além disso, a determinação da segurança e eficácia dos fármacos está intimamente ligada ao estudo da formação de derivados in vivo por ocasião do metabolismo. A utilização de fungos filamentosos na predição do metabolismo que os fármacos sofreriam após administração oral, bem como de bactérias do trato gastrointestinal, pode contribuir substancialmente para a elucidação da rota metabólica de fármacos fornecendo informações sobre a geração de substâncias farmacologicamente ativas, inativas ou tóxicas e ainda sobre a produção de substâncias capazes de inibir a biotransformação de outros fármacos. Estudos de biotransformação também podem contribuir para a obtenção de novos esqueletos químicos. Dessa forma, o presente trabalho relata estudos do metabolismo microbiano do lapachol e do seu sal de potássio por bactérias do trato gastrointestinal e fungos filamentosos, além da correlação desses com as reações que ocorrem quando o isolapachol e a atovaquona são utilizados como substratos para os mesmos micro-organismos. Os experimentos de biotransformação utilizando lapachol e seu sal de potássio foram conduzidos por até dez dias, em diferentes meios de cultura, empregando-se quatro linhagens de bactérias presentes no trato gastrointestinal, além de 11 linhagens de fungos filamentosos. Foram obtidos sete metabólitos, sendo dois inéditos e dois anteriormente detectados em estudos sobre o metabolismo do lapachol em mamíferos. Durante a realização dos experimentos com o fungo filamentoso Aspergillus brasiliensis verificou-se a capacidade desse fungo em mimetizar uma reação muito importante em química orgânica, conhecida como oxidação de Hooker. As condições mais promissoras para a biotransformação do lapachol foram utilizadas nos estudos com a atovaquona e o isolapachol. A biotransformação da atovaquona possibilitou, pela primeira vez, a caracterização estrutural de um metabólito desse fármaco. Já os estudos realizados com o isolapachol permitiram inferências sobre a especificidade enzimática apresentada pelos micro-organismos avaliados. Todos os metabólitos obtidos foram submetidos aos ensaios de citotoxicidade frente a linhagens celulares normais e tumorais, o que possibilitou obter conclusões sobre a relação estrutura-atividade e sobre a citotoxicidade seletiva apresentada pelos metabólitos. Destaca-se o resultado obtido com um dos metabólitos do lapachol, ?-xiloidona, o qual se mostrou mais tóxico para a linhagem tumoral que o lapachol e não apresentou toxicidade frente à linhagem normal. O metabólito obtido a partir da biotransformação da atovaquona apresentou maior toxicidade não seletiva que a substância de partida. / Several naphthoquinones, as lapachol, can be found in the Bignoniaceae family and they present several biological activities with some unwanted effects. The cytotoxic activity displayed by naphthoquinones is correlated to the presence of reactive oxygen species, which are formed in vivo and cause severe oxidative stress within cells. Isolapachol and atovaquone are structural analogs of lapachol, and atovaquone is in the market as a drug for the treatment of malaria and some types of pneumonia. Because of the great biological potential presented by naphthoquinones, several studies have been carried out to obtain derivatives without side effects. Furthermore, the drug safety and efficacy are closely related to the study of the formation of in vivo derivatives during metabolism. The filamentous fungi and the bacteria from the gastrointestinal tract can be used in the prediction of drug metabolism after oral administration, which is an interesting tool to elucidation of the metabolic pathway of drugs, providing information on the generation of pharmacologically active, inactive or toxic substances and still on the production of compounds able to inhibit the biotransformation of other drugs. Biotransformation studies can also contribute to the obtention of new chemical skeletons (hits). Thus, the present work reports the study about the microbial metabolism of lapachol and its potassium salt by filamentous fungi and bacteria from the gastrointestinal tract, beyond the correlation of the reactions that occur when the isolapachol and atovaquone are used as substrates for the same microorganisms. The biotransformations of lapachol and its potassium salt were evaluated for up to ten days, in different culture media, catalyzed by four bacteria from the gastrointestinal tract and 11 filamentous fungi strains. Seven metabolites were obtained, from which two are new and two were previously detected in the mammals metabolism of lapachol. The filamentous fungus Aspergillus brasiliensis showed to be capable of mimicking the Hooker oxidation, an important organic chemistry reaction. The best conditions for the lapachol biotransformation have been used in the studies with isolapachol and atovaquone. The atovaquone biotransformation provided, for the first time, the structural characterization of a metabolite from this drug. The studies with isolapachol allowed inferences about the enzyme specificity shown by the evaluated microorganisms. All obtained metabolites were submitted to cytotoxicity assays against human cancer and tumoral cell lines. Several conclusions about the structure activity relationship and about the selective cytotoxicity showed by the metabolites were taken. It should be highlighted the obtained result with a lapachol metabolite, ?-xyloidone, which showed to be more toxic than lapachol against tumoral cell line and did not show cytotoxicity to normal cell line. The atovaquone metabolite displayed higher toxicity than pattern structure, and this activity was not selective.

Thesis (PhD.(Pharmacology)--Faculty of Health Sciences)-University of Pretoria, 2006. / Includes bibliographical references.