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This thesis describes the synthesis of a series of 5-alkideniminoxy-5-phenylhydantoins for the purpose of studying their anticonvulsant properties.

Recent years have seen a rapid increase in the search for new compounds to be employed in the treatment of convulsions associated with epilepsy and related ailments. The properties desired are a higher degree of effectiveness and lower toxicity than those already in use. This thesis describes the effect of methylation of the 5-alkylmercapto-5-phenylhydantoins.

CoordenaÃÃo de AperfeiÃoamento de NÃvel Superior / Segundo a OrganizaÃÃo Mundial de SaÃde (OMS, 2011), a epilepsia à uma das mais comuns doenÃas neurolÃgicas graves, afetando mais de 50 milhÃes de pessoas em todo o mundo. A principal manifestaÃÃo clÃnica de algumas epilepsias à a convulsÃo. Esta pode ser estudada em modelos animais pelo uso de diferentes estÃmulos. O Pentilenotetrazol (PTZ) à um antagonista GABA que mimetiza crise de ausÃncia e convulsÃes do tipo tÃnico-clÃnica em humanos. A Estricnina bloqueia a resposta inibitÃria da glicina, que age atravÃs de um receptor que se assemelha ao receptor GABAA. A Pilocarpina (PILO) à um agonista colinÃrgico que mimetiza epilepsia do lobo temporal em humanos. O Eletrochoque (ECS) à um procedimento que consiste na induÃÃo de convulsÃes generalizadas pela passagem de corrente elÃtrica pelo cÃrebro. Alpinia zerumbet, da famÃlia zingiberacea à uma espÃcie conhecida no Brasil por colÃnia que vem mostrando importantes efeitos depressores no SNC jà estudados por nosso grupo de pesquisa. O presente trabalho tem como objetivo investigar os efeitos da administraÃÃo aguda e repetida do Ãleo essencial de Alpinia zerumbet (OEAZ) em modelos animais de convulsÃo em camundongos (machos) por via intraperitoneal nas doses de 100 e 200 mg/Kg. OEAZ em tratamento agudo no modelo de PTZ 85 mg/kg, apresentou efeito neuroprotetor, tanto em latÃncia de convulsÃo (LC) quanto em latÃncia de morte (LM), apenas na dose 100 mg/kg. Jà em modelo de ESTRIC, em tratamento agudo, as duas doses estudadas mostraram efeito anticonvulsivante. Em modelo de PILO agudo nenhuma das doses ofereceu qualquer efeito neuroprotetor. No ECS, observa-se efeito anticonvulsivante, com relaÃÃo à reduÃÃo no tempo de estiramento, em ambas as doses comparadas ao controle. No entanto, apÃs administraÃÃo repetida por cinco dias o OEAZ apresentou efeitos anticonvulsivantes em todos os parÃmetros analisados de todos os testes de induÃÃo de convulsÃo, prolongando LC e LM com relaÃÃo ao grupo controle, podendo esta aÃÃo estar diretamente ligada aos constituintes do Ãleo, como monoterpenos. / According to the World Health Organization (WHO, 2011), epilepsy is one of the most common serious neurological diseases, affecting over 50 million people worldwide. The main clinical manifestation of some epilepsy is seizures. Seizures can be studied in animal models by using different stimuli. The pentylenetetrazol (PTZ) is a GABA antagonist that mimics absence seizures and tonic-clonic seizure in humans. The Strychnine blocks the inhibitory response of glycine, which acts via a receptor which resembles the GABAA receptor. The Pilocarpine (PILO) is a cholinergic agonist that mimics temporal lobe epilepsy in humans. The Electroshock (ECS) is a procedure which consists in induces the generalized seizures by the passage of electric current through the brain. Alpinia zerumbet, family zingiberacea is a specie known in Brazil as colony, showing significant CNS depressant effects already studied by our research group. The present study aims to investigate the effects of acute and repeated administration of the essential oil of Alpinia zerumbet (OEAZ) in animal models of seizures in mice (males) intraperitoneally at doses of 100 and 200 mg / kg. OEAZ in the acute treatment model PTZ 85 mg / kg, showed neuroprotective effect both in seizure latency (LC) and in death latency (ML), only at dose 100 mg / kg. On the other hand, when using model ESTRIC in acute treatment, both doses studied showed anticonvulsant effect. In a model of acute PILO none of doses offered any neuroprotective effect. In ECS was observed anticonvulsant effect with respect to reducing the time of stretching, at both doses, compared to the control. However, after repeated administration for five days the OEAZ showed anticonvulsant effects in all parameters of all tests seizure-inducing studied, prolonging LC and LM when compared with the control group, this action may be directly related to the constituents of the oil, as monoterpenes.

No derivatives of 5-phenylhydantoin with an oxygen atom attached directly in the five position of the hydantoin nucleus have been found in the literature. It was therefore considered of interest to synthesize a series of compounds of this type to determine the effect of the change of the position of the oxygen atom on anticonvulsant activity.

Epilepsy is a common neurological disorder for which the development of new and improved therapies is essential. Thus, the central theme of this thesis pertains to the design and synthesis of putative antiepileptic drugs. A substructure search was performed on a database of exogenous compounds to find those that contain a known sodium channel pharmacophore. The anticonvulsant activity of several compounds identified by this search was evaluated, resulting in the recognition of multiple molecular classes from which new anticonvulsant scaffolds could be derived. A series of analogues derived from uracil (an endogenous molecule) were synthesized and evaluated for anticonvulsant activity. Several of these analogues displayed promising activity and minimal toxicity, further supporting the theory that uracils could serve as potent, non-toxic, broad-range antiepileptic drugs capable of targeting both ictogenesis and epileptogenesis. A uracil QSAR model was also developed that could be used in the future to guide further analogue synthesis.

This thesis describes the attempt to synthesize some 5-hetero-substituted dihydro-4,6(1H,5H)-pyrimidinediones as possible anticonvulsants.

The purpose of this investigation was to complete the study of the 5-pyridylhydantoins by resynthesizing 5-(2-pyridyl)hydantoni and investigating its properties.

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissus damage or described in terms of such damage. Opioids are effective in treating moderate to severe pain, but opioid alone therapy is associated with several adverse effects, development of tolerance and addiction potential. One way to solve these problems is to administer opioids with adjuvant drugs. In this project several opioid molecules were combined with other adjuvant drugs in a single chemical entity to form a codrug. A series of codrugs were prepared by conjugation of an opioid with S-(-)-nornicotine, ketamine, norketamine and gabapentin. Several of the synthesized codrugs were evaluated for analgesic activity in the rats after oral administration. Codeine-S-(-)- nornicotine, 3-O-acetylmorphine-S-(-)-nornicotine, and N-ethoxycarbonylgabapentincodeine codrugs showed greater effectiveness as well as prolonged pain management properties as compared to the parent drugs. Stabilities of several synthesized codrugs were studied in aqueous solutions from pH 1.3-7.4, in simulated gastrointestinal fluids, in rat plasma and in brain homogenate. Only the ester-linked codrugs showed sign of hydrolysis in different solutions. Carbamate-linked codrugs didn’t cleave under any hydrolytic condition. Pharmacokinetic study was performed on the following three codrugs: 3-O-acetylmorphine-S-(-)-nornicotine, N-acetylgabapentin-codeine, and N-ethoxycarbonylgabapentin- codeine. The carbamate linkage in 3-O-acetylmorphine-S-(-)- nornicotine codrug did not cleave in vivo to produce parent drugs. The ester linkage in N-acetylgabapentin- codeine codrug cleaved in vivo to produce codeine and N-acetylgabapentin, but N-acetylgabapentin did not undergo hydrolysis to produce gabapentin. The ester linkage in N-ethoxycarbonylgabapentin-codeine codrug hydrolyzed slowly in plasma to produce N-ethoxycarbonylgabapentin and codeine and then the carbamate linkage in N-ethoxycarbonylgabapentin hydrolyzed even slowly to produce gabapentin. Produced codeine also metabolized to generate some amount of morphine. Thus, the design and synthesis of an opiate and gabapentin codrug was achieved which was stable enough in the gastrointestinal tract, showed enhanced analgesic effects as compared to the physical mixture of the parent drugs, and also produced the two parent drugs in blood plasma.