A method for unsymmetric disulfide synthesis from carboxylic acids under photoredox conditions has been developed. N-Perthiophthalimide derivatives (Harpp reagents) are used as disulfurating reagents in a decarboxylative disulfuration. Though significant sulfide formation was observed when using less sterically-hindered (primary and secondary) Harpp reagents, tertiary Harpp reagents affording corresponding disulfides in good yields. At first glance, the reaction was expected to go through radical substitution directly on the Harpp reagent to obtain the observed disulfide and a phthalimidyl radical that would reoxidize the reduced photocatalyst. However, computational studies suggest a high barrier and endergonic reaction for such a mechanism due to the high energy of the liberated phthalimidyl radical (N-H BDE in phthalimide is predicted to be ~120 kcal/mol). Supported by calculation and experiments, an alternative mechanism was proposed: perthyl radicals generated from single electron reduction of Harpp reagent dimerized to form tetrasulfides, which are known to undergo efficient radical substitution to afford disulfides. Mechanistic studies on previously reported sulfurations using N-thiophthalimide derivatives suggested a similar mechanism - specifically that disulfides generated in situ undergo radical substitution to provide the sulfide products. Direct C-H disulfuration using Harpp reagents under a variety of conditions was also investigated, but found to have very limited substrate scope. It would appear that the instability of the disulfurating reagents, be they Harpp reagents or tetrasulfides generated therefrom, under the various oxidative conditions prevented the development of a general approach.

Orientador: Man Chin Chung / Resumo: A doença de Alzheimer (DA) é a principal e mais comum causa de demência senil, contribuindo com 50-75% dos casos diagnosticados. Nos países desenvolvidos, a DA é quarta causa de morte, ficando atrás somente de doenças cardiovasculares, câncer e acidente vascular cerebral. A projeção da Organização Mundial de Saúde (OMS) é que até 2050 o número de idosos aumente 21% no mundo. A DA é uma doença neurodegenerativa progressiva, na qual os pacientes diagnosticados mostram uma extensa perda de sinapses e neurônios no hipocampo e nos córtex frontal e temporal, comprometendo de forma gradual suas funções cognitivas, como a memória, capacidade de aprendizado, raciocínio, assim como o comprometimento da comunicação e habilidade realização de atividades diárias. Atualmente não há tratamento capaz de curar ou modificar de maneira eficaz a doença, apenas medicamentos (donepezila, rivastigmina, galantamina e memantina) que melhoram alguns sintomas manifestados pelos pacientes. A redução do processo de neuroinflamação e estresse oxidativo associados ao envelhecimento e aos marcadores da DA, como a formação de placas senis e emaranhados neurofibrilares, contribui na plasticidade sináptica, cognição e memória e atenuando os efeitos associados à perda de neurônios dos pacientes acometidos pela DA. Neste trabalho foram planejados e obtidos oito compostos intermediários e nove compostos finais inéditos, planejados através da estratégia de hibridização molecular do ácido lipóico ou ácido ferúlico ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Alzheimer's disease (AD) is the main and most common cause of senile dementia, accounting for 50-75% of diagnosed cases. In developed countries, AD is the fourth leading cause of death, leading only to cardiovascular disease, cancer and stroke. The projection of the World Health Organization (WHO) is that by 2050 the number of elderly people increase by 21% in the world. AD is a progressive neurodegenerative disease, in which the diagnosed patients show an extensive loss of synapses and neurons in the hippocampus and in the frontal and temporal cortex, gradually impairing their cognitive functions, such as memory, learning ability, reasoning, and communication impairment and ability to perform daily activities. Currently there is no treatment capable of curing or effectively modifying the disease, only medications (tacrine, donepezil, rivastigmine, galantamine and memantine) that improve some of the symptoms manifested by the patients. The reduction of neuroinflammation and oxidative stress associated with aging and AD markers, such as the formation of senile plaques and neurofibrillary tangles, contribute to synaptic plasticity, cognition and memory and attenuate the effects associated with the loss of neurons in patients with AD. In this work, eight intermediate compounds and nine unpublished final compounds were obtained through the molecular hybridization strategy of lipoic acid or ferulic acid with phthalimide derivatives. All compounds were chemically characterized by 1... (Complete abstract click electronic access below) / Doutor

Currently L-DOPA is the drug most commonly used for the treatment of Parkinson’s disease (PD). However, the long-term use of L-DOPA is associated with the development of motor fluctuations and dyskinesias. Treatment mainly addresses the dopaminergic features of the disease and leaves its progressive course unaffected. An optimal treatment would be a combination of both motor and non-motor symptom relief with neuroprotective properties. Two drug targets have attracted the attention for PD treatment, namely monoamine oxidase B (MAOB) and adenosine A2A receptors. MAO-B inhibitors enhance the elevation of dopamine levels after L-DOPA treatment, improve motor functions and may also possess neuroprotective properties. The antagonistic interaction between A2A and dopamine receptors in the striatopallidal pathway, which modulates motor behaviour, has also become a potential strategy for PD treatment. Blockade of the A2A receptor exerts both anti-symptomatic and neuroprotective activities and offer benefit for motor symptoms and motor complications. This thesis seeks to synthesize novel drug treatments for PD by exploring both MAO-B inhibitors and adenosine A2A receptor antagonists and to assess the prospects for drug modification to increase activity. MAO-B inhibitors - Based on a recent report that the phthalimide moiety may be a useful scaffold for the design of potent MAO-B inhibitors, the present study examines a series of 5-sulfanylphthalimide analogues as potential inhibitors of both human MAO isoforms. The results document that 5- sulfanylphthalimides are highly potent and selective MAO-B inhibitors with all of the examined compounds possessing IC50 values in the nanomolar range. The most potent inhibitor, 5- (benzylsulfanyl)phthalimide, exhibits an IC50 value of 0.0045 μM for the inhibition of MAO-B with a 427–fold selectivity for MAO-B compared to MAO-A. We conclude that 5-sulfanylphthalimides represent an interesting class of MAO-B inhibitors and may serve as lead compounds for the design of antiparkinsonian therapy. It has recently been reported that nitrile containing compounds frequently act as potent MAO-B inhibitors. In an attempt to identify additional potent and selective inhibitors of MAO-B and to contribute to the known structure-activity relationships of MAO inhibition by nitrile containing compounds, the present study examined the MAO inhibitory properties of series of novel sulfanylphthalonitriles and sulfanylbenzonitriles. The results document that the evaluated compounds are potent and selective MAO-B inhibitors with most homologues possessing IC50 values in the nanomolar range. In general, the sulfanylphthalonitriles exhibited higher binding affinities for MAO-B than the corresponding sulfanylbenzonitrile homologues. Among the compounds evaluated, 4-[(4-bromobenzyl)sulfanyl]phthalonitrile is a particularly promising inhibitor since it displayed a high degree of selectivity (8720-fold) for MAO-B over MAO-A, and potent MAO-B inhibition (IC50 = 0.025 μM). Based on these observations, this structure may serve as a lead for the development of therapies for neurodegenerative disorders such as Parkinson’s disease. Adenosine A2A receptor antagonism - Most adenosine A2A receptor antagonists belong to two different chemical classes, the xanthine derivatives and the amino-substituted heterocyclic compounds. In an attempt to discover high affinity A2A receptor antagonists for PD and to further explore the structure-activity relationships of A2A antagonism by the xanthine class of compounds, this study examines the A2A antagonistic properties of series of (E)-8-styrylxanthine, 8-(phenoxymethyl)xanthine and 8-(3- phenylpropyl)xanthine derivatives. The results document that among these series, the (E)-8- styrylxanthines are the most potent antagonists with the most potent homologue, (E)-1,3-dietyl- 7-methyl-8-[(3-trifluoromethyl)styryl]xanthine, exhibiting a Ki value of 11.9 nM. This compound was also effective in reversing haloperidol-induced catalepsy in rats. The importance of substitution at C8 with the styryl moiety was demonstrated by the finding that none of the 8- (phenoxymethyl)xanthines and 8-(3-phenylpropyl)xanthines exhibited high binding affinities for the A2A receptor. It was also concluded that (E)-8-styrylxanthines are potent A2A antagonists with particularly the 1,3-dietyl-7-methylxanthine substitution pattern being most appropriate for high affinity binding. Conclusion - The results of these studies have established that all of the sulfanylphthalimides, sulfanylphthalonitriles and sulfanylbenzonitriles examined display significant MAO-B inhibitory properties in vitro with IC50 values in the low μM to nM range. Good A2A receptor affinity was demonstrated by the xanthines containing a styryl moiety, while the phenoxymethyl and phenylpropyl xanthines exhibited poor activity. / Thesis (PhD (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2013

Currently L-DOPA is the drug most commonly used for the treatment of Parkinson’s disease (PD). However, the long-term use of L-DOPA is associated with the development of motor fluctuations and dyskinesias. Treatment mainly addresses the dopaminergic features of the disease and leaves its progressive course unaffected. An optimal treatment would be a combination of both motor and non-motor symptom relief with neuroprotective properties. Two drug targets have attracted the attention for PD treatment, namely monoamine oxidase B (MAOB) and adenosine A2A receptors. MAO-B inhibitors enhance the elevation of dopamine levels after L-DOPA treatment, improve motor functions and may also possess neuroprotective properties. The antagonistic interaction between A2A and dopamine receptors in the striatopallidal pathway, which modulates motor behaviour, has also become a potential strategy for PD treatment. Blockade of the A2A receptor exerts both anti-symptomatic and neuroprotective activities and offer benefit for motor symptoms and motor complications. This thesis seeks to synthesize novel drug treatments for PD by exploring both MAO-B inhibitors and adenosine A2A receptor antagonists and to assess the prospects for drug modification to increase activity. MAO-B inhibitors - Based on a recent report that the phthalimide moiety may be a useful scaffold for the design of potent MAO-B inhibitors, the present study examines a series of 5-sulfanylphthalimide analogues as potential inhibitors of both human MAO isoforms. The results document that 5- sulfanylphthalimides are highly potent and selective MAO-B inhibitors with all of the examined compounds possessing IC50 values in the nanomolar range. The most potent inhibitor, 5- (benzylsulfanyl)phthalimide, exhibits an IC50 value of 0.0045 μM for the inhibition of MAO-B with a 427–fold selectivity for MAO-B compared to MAO-A. We conclude that 5-sulfanylphthalimides represent an interesting class of MAO-B inhibitors and may serve as lead compounds for the design of antiparkinsonian therapy. It has recently been reported that nitrile containing compounds frequently act as potent MAO-B inhibitors. In an attempt to identify additional potent and selective inhibitors of MAO-B and to contribute to the known structure-activity relationships of MAO inhibition by nitrile containing compounds, the present study examined the MAO inhibitory properties of series of novel sulfanylphthalonitriles and sulfanylbenzonitriles. The results document that the evaluated compounds are potent and selective MAO-B inhibitors with most homologues possessing IC50 values in the nanomolar range. In general, the sulfanylphthalonitriles exhibited higher binding affinities for MAO-B than the corresponding sulfanylbenzonitrile homologues. Among the compounds evaluated, 4-[(4-bromobenzyl)sulfanyl]phthalonitrile is a particularly promising inhibitor since it displayed a high degree of selectivity (8720-fold) for MAO-B over MAO-A, and potent MAO-B inhibition (IC50 = 0.025 μM). Based on these observations, this structure may serve as a lead for the development of therapies for neurodegenerative disorders such as Parkinson’s disease. Adenosine A2A receptor antagonism - Most adenosine A2A receptor antagonists belong to two different chemical classes, the xanthine derivatives and the amino-substituted heterocyclic compounds. In an attempt to discover high affinity A2A receptor antagonists for PD and to further explore the structure-activity relationships of A2A antagonism by the xanthine class of compounds, this study examines the A2A antagonistic properties of series of (E)-8-styrylxanthine, 8-(phenoxymethyl)xanthine and 8-(3- phenylpropyl)xanthine derivatives. The results document that among these series, the (E)-8- styrylxanthines are the most potent antagonists with the most potent homologue, (E)-1,3-dietyl- 7-methyl-8-[(3-trifluoromethyl)styryl]xanthine, exhibiting a Ki value of 11.9 nM. This compound was also effective in reversing haloperidol-induced catalepsy in rats. The importance of substitution at C8 with the styryl moiety was demonstrated by the finding that none of the 8- (phenoxymethyl)xanthines and 8-(3-phenylpropyl)xanthines exhibited high binding affinities for the A2A receptor. It was also concluded that (E)-8-styrylxanthines are potent A2A antagonists with particularly the 1,3-dietyl-7-methylxanthine substitution pattern being most appropriate for high affinity binding. Conclusion - The results of these studies have established that all of the sulfanylphthalimides, sulfanylphthalonitriles and sulfanylbenzonitriles examined display significant MAO-B inhibitory properties in vitro with IC50 values in the low μM to nM range. Good A2A receptor affinity was demonstrated by the xanthines containing a styryl moiety, while the phenoxymethyl and phenylpropyl xanthines exhibited poor activity. / Thesis (PhD (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2013

Submitted by Irene Nascimento (irene.kessia@ufpe.br) on 2017-03-30T18:26:28Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) TESE PAULO ANDRÉ.pdf: 12707088 bytes, checksum: 1ef366976f050b974da19aa9ed860831 (MD5) / Made available in DSpace on 2017-03-30T18:26:29Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) TESE PAULO ANDRÉ.pdf: 12707088 bytes, checksum: 1ef366976f050b974da19aa9ed860831 (MD5) Previous issue date: 2016-07-27 / FACEPE / A identificação e utilização de estruturas privilegiadas como base para a obtenção de novas moléculas, tem se destacado como estratégia para a descoberta de novos fármacos. Como exemplos de estruturas privilegiadas podem ser citados os heterociclos ftalimida e isatina. Ambos são importantes grupos farmacofóricos conhecidos pelo amplo espectro de atividades biológicas que apresentam. Outro importante grupo farmacofórico que vem sendo bastante explorado e que está presente em moléculas quimicamente diversas e ativas para uma grande variedade de doenças é o heterociclo tiazol. Fazendo uso da estratégia de hibridização molecular foram obtidos inéditos compostos tiazóis derivados da ftalimida e da isatina. O presente trabalho está dividido em dois capítulos e explora duas das muitas atividades farmacológicas apresentadas pelos grupos farmacofóricos, a atividade antichagásica e a anticâncer. O primeiro capítulo apresenta o planejamento, a síntese, a caracterização estrutural, a avaliação quanto às propriedades antichagásicas de tiazóis derivados da ftalimida. Alguns dos compostos obtidos nessa primeira parte apresentaram potente inibição sobre a forma tripomastigota do parasito com baixa toxicidade em células esplênicas, e as relações estrutura-atividade resultantes são discutidas. Também são apresentadas alterações ultraestruturais que ftalil-1,3-tiazóis induzem sobre a morfologia do parasito, como o encurtamento do flagelo, condensação da cromatina, inchaço das mitocôndrias, alteração de reservosomos e dilatação do retículo endoplasmático. Juntos, estes dados revelam, pela primeira vez, uma nova série de compostos contendo ftalimido-tiazóis como base estrutural com potentes efeitos contra o T. cruzi e características de líder-similar ("lead-like") contra a doença de Chagas. Os resultados apresentados no primeiro capítulo foram publicados na European Journal of Medicinal Chemistry. O segundo capítulo apresenta o planejamento, a síntese empregada, a caracterização estrutural para a obtenção das séries de tiazóis inéditos derivados da isatina, assim como alguns resultados prévios de suas propriedades antitumorais. Nessa segunda parte da tese são apresentadas 29 moléculas, sendo 9 tiossemicarbazonas e 20 tiazóis. Nenhum dos compostos apresentou citotoxicidade na dose de 100 μM para células normais humanas. Embora não sejam conclusivos, resultados prévios indicam que alguns compostos intermediários apresentam importante atividade antitumoral, o que pode indicar que a síntese de derivados de tais compostos pode ser promissora para a obtenção de novos agentes antitumorais. De modo geral, pode-se concluir que a estratégia de utilização de estruturas privilegiadas como bases estruturais para a obtenção de novos compostos biologicamente ativos permitiu identificar potentes agentes antichagásicos, bem como encontrar um prévio direcionamento para síntese de novos protótipos a fármacos antitumorais. / The identification and use of privileged structures as a basis for obtaining new molecules, has excelled as a strategy for drug discovery. Examples of privileged structures can be cited the phthalimide and isatin heterocycles. Both are important pharmacophore groups known by the broad spectrum of biological activities that present. Another important pharmacophore which has been extensively explored and is present in various chemically active molecules and for a wide variety of diseases is the thiazole heterocycle. Making use of molecular hybridization strategy were obtained unpublished thiazoles compounds derived from phthalimide and isatin. This work is divided into two chapters and explores two of the many pharmacological activities presented by pharmacophore groups, the antichagasic and anti-cancer activity. The first chapter presents the planning, synthesis, structural characterization, antichagasic properties evaluation of phthalimido-thiazoles derivatives. Some of the compounds obtained in this first part showed potent inhibition on parasite trypomastigotes with low toxicity in spleen cells and the resulting structure-activity relationships are discussed. Also ultrastructural changes appear that phthalyl-1,3-thiazoles induce on the morphology of the parasite, such as the shortening of the flagellum, chromatin condensation, swelling of mitochondria, reservosomes change and dilatation of the endoplasmic reticulum. Together, these data revealed, for the first time, a novel series of phthalimido-thiazoles-structure-based compounds with potential effects against T. cruzi and lead-like characteristics against Chagas disease. The results showed in the first chapter were published in the European Journal of Medicinal Chemistry. The second chapter presents the planning, the synthesis used, the structural characterization to obtain the derivatives unpublished thiazoles series of isatin, as well as some preliminary results of its anti-tumor properties. In this second part of the thesis are displayed 29 molecules, 9 thiosemicarbazone and 20 thiazoles. Neither compound showed cytotoxicity in a dose of 100 uM to normal human cells. Although not conclusive, preliminary results indicate that some intermediates have significant antitumor activity, which may indicate that the synthesis of derivatives of such compounds can be promising for obtaining novel anticancer agents. In general, it can be concluded that the strategy of use of privileged structures as structural basis for obtaining new biologically active compounds identified potent antichagasic agents and find a previous guidance for synthesis of new prototypes to antitumor drugs.