SÃntese e caracterizaÃÃo de novos derivados mesoiÃnicos para aplicaÃÃo de Ãptica nÃo-linear e atividade biolÃgica

AUTOR(ES)
DATA DE PUBLICAÇÃO

2004

RESUMO

Mesoionic compounds constitute a group of heterocyclic betaines stabilized by delocalisation of electrons and charge, the synthesis of which has proven of great interest. This stemmed from (a) their wide range of biological activity with a considerable possibility of obtaining pharmaceuticals; (b) their special physical properties for non-linear optics applications such as in telecommunications; (c) their value in synthesising diverse heterocyclic systems. On this basis, with the possibility of applications of their non-linear optical properties and of their biological activity we have synthesized and characterized fourteen new mesoionic derivatives, of which ten are 1,3-thiazolium-5-thiolates and four are 1,3-diazolium-5-thiolates; varying the electron-donating substituents in the negative region (associated with the HOMO) and varying electron-withdrawing substituents in the positive region (associated with the LUMO). The following synthetic route (figure 3.1) was utilized: (i) Strecker reaction with arene aldehydes (1), sodium cyanide and methyl ammonium chloride giving N-methyl-C-arylglycines (2) in good yields (ii) aroylation of (2) giving N-methyl-N-aroyl-C-arylglicines (3) and (iii) cyclodehydration of (3) with acetic anhydride or trifluoroacetic anhydride or DCC followed by 1,3-dipolar cycloaddition and cycloreversion with carbon disulphide forming mesoionic 1,3-thiazolium-5-thiolates MI-4.1, MI-4.2, MI-4.3, MI-4.4, MI-4.5, MI-4.6, MI-4.7, MI-4.8, MI-4.9 and MI-4.10 (iv) alkylation of MI-4.1 and MI-4.2 with methyl iodide yielded MI-5.1 and MI-5.2 in the form of iodides of S-methylated derivates (v) treatment of MI-5.1 and MI-5.2 with methylamine yielded mesoionic 1,3-diazolium-5-thiolates MI-6.1 and MI-6.2 (vi) alkylation of MI-6.1 and MI-6.2 with methyl iodide yielded MI-7.1 and MI-7.2 as iodides of S-methylated derivatives. Overall yields were good and products were recrystallized from ethanol/water. The chemical structures of the new mesoionic derivatives were fully elucidated using spectrometric techniques, viz, APT, DEPT, HETCOR or HMQC and HMBC; together with Mass spectrometry, IV spectroscopy and Elemental Analysis. The NMR techniques were especially valuable. The activity of the new mesoionic compounds against micro-organisms was tested by the method of diffusion on paper disks in gels (Muller Hinton method). The samples were dissolved in DMSO (15mg/ml) and the paper disks moistened with DMSO placed over each micro-organism in a gel medium in wells. The discs were inoculated with the solution of the mesoionic compounds which were at a concentration of 300μg/ml. After the incubation period the inhibition halos (if any) of the ten compounds were measured. Of the compounds tested only four had significant activity and these two were in the form of iodides of the Smethylated derivatives: these were the most active. They inhibited eight of the ten microorganisms tested, particularly Gram-positive bacteria and the filamentous fungus Monilia sitophila. The other two active compounds MI-6.1 and MI-6.2 are mesoionic 1,3-diazolium-5-thiolates. These were also active against Gram-positive bacteria and against the fungus Candida albicans though less active. The remaining six mesoionic compounds (MI-4.1), (MI-4.2), (MI-4.3), (MI-4.4), (MI-4.6) and (MI-4.7) all 1,3-thiazolium-5-thiolates were essentially inactive against the micro-organisms used. Study of the biological activity of mesoionic 2-(4-chlorophenyl)-3-methyl-4-(4-methoxyphenyl)-1,3-thiazolium-5-thiolate (MI-4.6), both in vivo and in vitro, indicated blood pressure reduction in normal unanesthetized rats as well as potent relaxation of the endothelium of rings of the upper mesenteric artery of rats and also led to the relaxation of the spontaneous muscle tone of and a non specific spasmolytic effect on the trachea of guinea pigs. For the optical studies we used the semi-empirical AM1 molecular orbital method implemented in the MOPAC93r2 program to calculate the optimised geometries of sixteen 1,3-thiazolium-5-thiolates (MI-4) as a function of different electron-donating groups (Rd), viz, OCH3, CH(CH3)2, CH3 compared with H, and of different electron-withdrawing groups (Ra) viz, NO2, CF3, Cl, compared with H. We also made calculations using the Hartree-Fock time-dependent method to obtain values of the static hyperpolarizability, β(0), of the sixteen compounds. The values obtained fall into the range 23,16 to 61,49 x 10-30 esu. Mesoionic (MI-4.10) had the highest value. If confirmed this is the largest β(0), value found in the mesoionic compounds already synthesized.

ASSUNTO(S)

biological activity physical properties compostos mesoiÃnicos Ãptica nÃo-linear quimica 1,3-tiazÃlio-5-tiolato atividade biolÃgica propriedades fÃsicas 1,3-thiazolium-5-thiolates mesoinic compounds non-linear optics

ACESSO AO ARTIGO

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