Uma nova família de barbituratos, ácidos 5-cloro-5-benzilbarbitúricos, foi preparada usando um método simples e eficiente a partir de aldeídos aromáticos e ácido barbitúrico, seguido de redução e cloração usando ácido tricloroisocianúrico, com rendimento global de 53 a 70%. Por avaliação in vivo com camundongos, os produtos apresentaram atividade tranqüilizante.A new family of barbiturates, 5-chloro-5-benzylbarbituric acids, was prepared using a simple efficient synthetic method from aromatic aldehydes and barbituric acid, followed by reduction and chlorination with trichloro-isocyanuric acid, affording overall yields of 53 to 70%. The in vivo evaluation with mice showed that these compounds present tranquilizing activity.Keywords: 5-chloro-5-benzylbarbituric acids, tranquilizers, benzylidenebarbiturates, trichloroisocyanuric acid, rota-rod tests IntroductionBarbiturates are very well known drugs with activity at the central nervous system (CNS), with specific activity as anticonvulsants, anxiolytics, tranquilizers and sedatives-hypnotics. 1 The mechanism of action of barbiturates at the CNS is not well known, but it has been shown that they are able to interfere with acetylcholine, norepinephrine and glutamate activity and also that they can inhibit the calcium uptake of nerve terminals, thus allowing their use as analgesics. 2,3 In fact, today barbiturates are commonly used to induce anesthesia in surgery procedures. They are also known as GABA-mimetics, thus functioning as agonists of GABA receptors. 3,4 For many years the barbiturates were the main drugs used to cause effects on the CNS. However, after the discovery of the very effective benzodiazepines, their use became less common simply because benzodiazepines have less potential for lethal overdoses. 5,6 The main cause of death by overdoses of barbiturates is respiratory failure, because they are very potent respiratory depressants. Today, the main uses of barbiturates are the induction of anesthesia and for the treatment of refractory status epilepticus. 7 Regarding the significant historical and actual use of barbiturates as neurological drugs, and the importance of this type of disease in the actual condition of mankind, we developed a very simple new family of barbiturates with CNS activity. Interestingly, 5-chlorobarbituric acid and their derivatives have been rarely investigated. The only similar compounds that have been reported as anticonvulsants are the 5-chloro-5-phenyl barbiturates. 8 Surprisingly, 5-benzyl-5-chlorobarbituric acids have not been reported in the literature. We developed a very simple and efficient method for the preparation of this new family of barbiturates as potential tranquilizers. Results and DiscussionOur strategy for the preparation of 5-benzyl-5-chlorobabiturates was based on the use of benzylidenebarbiturates as intermediates, which are very easy to prepare. [9][10][11][12] Benzylidenebarbiturates are employed in several well known reactions in the literature 10,13-17 and have even been used as methionine aminopeptidas...
Neurotoxic organophosphorus compounds (OPs), which are used as pesticides and chemical warfare agents lead to more than 700,000 intoxications worldwide every year. The main target of OPs is the inhibition of acetylcholinesterase (AChE), an enzyme necessary for the control of the neurotransmitter acetylcholine (ACh). The control of ACh function is performed by its hydrolysis with AChE, a process that can be completely interrupted by inhibition of the enzyme by phosphylation with OPs. Compounds used for reactivation of the phosphylated AChE are cationic oximes, which usually possess low membrane and hematoencephalic barrier permeation. Neutral oximes possess a better capacity for hematoencephalic barrier permeation. NMR spectroscopy is a very confident method for monitoring the inhibition and reactivation of enzymes, different from the Ellman test, which is the common method for evaluation of inhibition and reactivation of AChE. In this work (1)H NMR was used to test the effect of neutral oximes on inhibition of AChE and reactivation of AChE inhibited with ethyl-paraoxon. The results confirmed that NMR is a very efficient method for monitoring the action of AChE, showing that neutral oximes, which display a significant AChE inhibition activity, are potential drugs for Alzheimer disease. The NMR method showed that a neutral oxime, previously indicated by the Ellman test as better in vitro reactivator of AChE inhibited with paraoxon than pralidoxime (2-PAM), was much less efficient than 2-PAM, confirming that NMR is a better method than the Ellman test.
This work describes the design, synthesis and in vivo evaluation of new central nervous system depressing agents that show low levels of acute toxicity, high solubility in water, and exhibit anxiolytic and hypnotic effects. These new compounds are sodium 2-benzyl-2-chloromalonates, which were designed using molecular modelling techniques and synthesized in four steps, with an overall yield between 41% and 65%. In vivo tests with mice, including pentobarbitalinduced sleep, rotarod, open field and elevated plus maze tests, were executed, and the results indicated that some of these agents induce activities similar to those induced by diazepam but with lower hypnotic potency and with greater anxiolytic potency. These compounds were also orally administered to mice in doses of 2 g/kg, and their effects were evaluated for 14 days. The mice did not show signs of intoxication, confirming that sodium 2-benzyl-2-chloromalonates exhibit low levels of acute toxicity. These observations indicate that sodium 2benzyl-2-chloromalonates and their analogues are efficient and safer central nervous system depressing drugs relative to the existing standard of care.
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