Antimaláricos potenciais: planejamento e síntese de fármacos dirigidos de antimetabólicos de serina / New potential antimalarials: design and synthesis of targeted serine antimetabolic drugs

De acordo com a Organização Mundial da Saúde, AIDS, malária e tuberculose são as três maiores doenças infectantes do mundo, atingindo principalmente crianças. Regiões paupérrimas e de clima tropical, como a África sub-saariana, são as mais atingidas. Este quadro agrava-se com a disseminação de cepas do Plasmodium falcíparum resistentes à cloroquina e multi-resistentes. Além disso, alguns fármacos utilizados na terapêutica da malária apresentam vários efeitos adversos, comprometendo o tratamento. Trata-se de um grande desafio e o seu enfrentamento requer estratégias. O desenvolvimento de novos quimioterápicos deve fundamentar-se em diferenças bioquímicas e morfológicas entre as células do hospedeiro e do parasita. A biossíntese de fosfolipídeos de membrana em parasitas do grupo Apicomplexa é de extrema importância para a maturação e a reprodução do parasita e constitui-se em bom alvo para novos antimaláricos, uma vez que é encontrada somente em parasitas. Hemácias infectadas têm sua absorção modificada em relação aos eritrócitos não-infectados, conferindo seletividade a substâncias como lipídeos. O trabalho em questão propõe a síntese de antimetabólitos da serina, visando à inibição das enzimas fosfatidilserina síntase e serina descarboxilase, fundamentais para a biossíntese de fosfolipídeos de membrana desses parasitas. Cinco derivados heterocíclicos da serine foram sintetizados: derivados diidroimidazólico, diidroxazólico, diidroxazínico, diidropirimidínico e diidrooxatiólico. Também, o transportador fosfolipídico com o ácido esteárico foi sintetizado. Os antimetabólitos serão acoplados a esse e outros fosfolípídeos, obtendo-se fármacos dirigidos específicos direcionados seletivamente a eritrócitos infectados...

Regulation of MAL1+ gene expression encoding maltase in Schizosaccharomyces pombe by added inositol.

In this study, the effects of inositol addition on maltase activity and expression of MAL1+ gene encoding maltase in Schizosaccharomyces pombe were investigated. The maximum specific maltase activity was observed, when the concentration of inositol reached 6.0 microg/ml in the synthetic medium containing 2.0% glucose. At 1.0 microg/ml inositol concentration, the maltase activity continuously decreased, as initial glucose concentration was higher than 0.1%. mRNA encoding maltase and phosphatidylinositol (PI) content were higher in the cells grown in the synthetic medium with 6.0 microg/ml of inositol and 2.0% glucose than those with 1.0 microg/ml of inositol. These results demonstrated that higher inositol concentration in the synthetic medium could derepress MAL1+ gene expression in S. pombe and PI might be involved in derepression of MAL1+ gene expression in S. pombe probably by PI-type signalling pathway.

Effect of haloperidol on phospholipid biosynthesis in rat brain.

Haloperidol, a butyrophenone used in the treatment of various psychoses has been clinically used and studied extensively. At the molecular level it is known to preferentially block D2 type of dopamine receptors but its other effects are unknown. We studied the effect of this drug on phospholipid biosynthesis in vitro by following incorporation of 32P into individual classes of phospholipids. It was observed that haloperidol inhibits the biosynthesis of almost all major phospholipids including phosphatidyl inositol at fairly low concentrations. It cannot be concluded from the present experiment which step the inhibition may be taking place but acyl transfer reaction is likely to be involved because the drug effects almost all the phospholipids. It is suggested that long-term use of the drug can effect the organization of synaptic membrane.

Pathophysiology of cholesterol gallstone disease

The purpose of the present paper is to review the current knowledge about cholesterol gallstone disease. It is generally accepted that the formation of cholesterol gallstone requires three major pathogenic defect, namely, supersaturation, nucleation and crystal growth as well as disorder of gallbladder motility. The supersaturation is necessary but not sufficient to explain stone formation. It has been suggested that nucleation is the key factor for gallstone formation. However, those three factors are necessary for the formation of cholesterol gallstones, and the presence of just one or two factor does not lead to stones. We also touch briefly on the results form studies performed in Mexico in this area

Proteínas pulmonares asociadas a sustancias con actividad surfactante7 / Pulmonary proteins associated to substances with surfactant activity

La ausencia de surfactantes pulmonares trae como consecuencia el incremento de la tensión superficial a lo largo del epitelio alveolar, provocando un colapso alveolar y la lisis de las células epiteliales. Este proceso culmina con la aparición de un síndrome de insuficiencia respiratoria, que es la causa principal de morbimortalidad en niños prematuros. Recientemente, la aplicación de mezclas de agentes surfactantes con fines terapéuticos ha constituido un gran apoyo para la terapia respiratoria, ya que permite una evolución más rápida de los niños que padecen este síndrome. Por todo esto, resulta de gran importancia el conocimiento más detallado de la función, el metabolismo y la regulación de la expresión genética de las proteíinas surfactantes, para el diseño de nuevas y mejores estrategias terapéuticas para combatir este síndrome

Correlation between phospholipid biosynthesis and intracellular levels of cyclic adenosine monophosphate in Mycobacterium smegmatis.

The influence of intracellular levels of cAMP on phospholipid synthesis in Mycobacterium smegmatis has been examined under conditions of varying carbon source. A decreased phospholipid content was observed in glucose-grown cells, possibly due to decrease in intracellular cAMP levels caused by decreased/increased activity of adenylate cyclase and phosphodiesterase, respectively. The lowered phospholipid content was supported by decrease both in [14C]acetate incorporation and activities of key enzymes of phospholipid biosynthesis. These results in the light of our earlier observation of enhanced phospholipid synthesis in presence of increased levels of cAMP suggest a direct correlation between phospholipid biosynthesis and intracellular levels of cAMP in M. smegmatis.

Basic biochemical investigations as rationale for the design of original antimalarial drugs. An example of phospholipid metabolism

The future of antimalarial chemotherapy is particulary alarming in view of the spread of parasite cross-resistances to drugs that are not even structurally related. Only the availability of new pharmacological models will make it possible to select molecules with novel mechanisms of action, thus delaving resistance and allowing the development of new chemotherapeutic strategies. We reached this objective in mice. Our approach is hunged on fundamental and applied research begun in 1980 to investigate to phospholipid (PL) metabolism of intraerythrocytic Plasmodium. This metabolism is abundant, specific and indispensable for the production of Plasmodium membranes. Any drug to interfere with this metabolism blocks parasitic development. The most effective interference yet found involves blockage of the choline transporter, which supplies Plasmodium with choline for the synthesis of phosphatidylcholine, its major PL, this is a limiting step in the pathway. The drug sensitivity thereshold is much lower for the parasite, which is more dependent on this metabolism than host cells. The compounds show in vitro activity against P. falciparum at 1 to 10 nM. They show a very low toxicity against a lymphblastoid cell line, demonstrating a total abscence of correlation between growth inhibition of parasites and lymphoblastoid cells. They show antimalarial activity in vivo, in the P. berghei or P. chabaudi/mouse system, at doses 20-to 100-fold lower than their in acute toxicity limit. The bioavailability of a radiolabeled form of the product seemed to be advantageous (slow blood clearance and no significant concentration in tissues). Lastly, the compounds are inexpensive to produce. They are stable and water-soluble

Further studies on the influence of dibutyryl cAMP, theophylline and prostaglandin E1 on composition and biosynthesis of phospholipids in Microsporum gypseum.

Exogenous supplementation of dibutyryl cAMP and cAMP modulators like theophylline and prostaglandin E1 in the growth medium of Microsporum gypseum lead to increase in the levels of phosphatidylcholine and lysophosphatidylcholine and thereby in total phospholipid content. These observations were further confirmed by the increased incorporation of [32P]orthophosphoric acid into total phospholipid and [14C]choline into phosphatidylcholine and lysophosphatidylcholine. The activity of sn-glycerol-3-phosphate acyltransferase, the enzyme involved in phospholipid synthesis, was stimulated in the presence of dibutyryl cAMP, theophylline and PGE1 supporting the increased synthesis of phospholipids.