Síntese, estudos de relações estrutura-atividade e da atividade antifúngica de novos agentes quimioterápicos para tratamento de doenças infecciosas emergentes

Abstract

The present dissertation presents the results obtained from synthesis of seven bis-, tri- and tetrabranched functionalized derivatives, the influence of the branching, the methylation levels at the nitrogen atoms of the thioureido moiety, on the antifungal activity was investigated. Allcompounds are symmetrical and similar to dendrimeric precursors or dendrons and they are named as P. The investigation of biological activity against pathogenic fungi from gender Candida spp., Cryptococcus neoformans and Saccharomices cerevisae are reported. The cytotoxic studies against several tumoral species are also described.Six w,w`-bis-S-thioureido substituted nitrogen mustard analogues with different nitrogen methylation levels at thioureido moiety, were synthesized and studied: tri(2-thioureídoethyl)amine (P1), tri(2-(1-methyl-2-thioureidoethyl)amine (P2), tri(2-(1,3-dimethyl)-thioureidoethyl)amine (P3), N,N,N´,N´- tetrakis (2-thioureidoethyl)ethylenediamine (P4),N,N,N,N-tetrakis(2-methyl-thioureido -ethyl)ethylenediamine (P5) and N,N,N,N-tetrakis(2-1,3- dimethyl-thioureido-ethyl)ethylene-diamine (P6). All of them are novel, but not P1, ever prepared and studied against leukemia. One novel thio-ether analogue was also prepared: 1,7-bis-(2-1,3-dimethyl-thioureido-ethyl)-4-thia-heptano (P7). All prepared substances were characterized by spectrometric methods (Infrared, 1H and 13C -NMR). The tribranched and non-methylated derivative P1 was the most active antifungal agent showing activity in very low concentrations against C. albicans and C. glabrata. P1 might bepotentially used as topical agent for the treatment of candidosis. The other thioureido derivatives P3 and P6 showed broad-spectrum of antifungal activity against C.albicans, C. glabrata, C. krusei, C. neoformans and S. cerevisae. P5 was active only against C. glabrata. Remarkably, P6 was active against C. glabrata, and such as P6 and P7 were the only agents enough efficient to inhibit C. parapsilosis. In fact, P7 also showed broad-spectrum of antifungal activity inhibitingC.albicans, C. glabrata, C. krusei, C. neoformans and S. cerevisae.The tri-branched and monomethylated amino analogue P2 was inactive against all species tested, such as P4, the tetra-branched and non-methylated amino analogue. It was expected that P4 would be more active than it really is and maybe this is due to the occurrence ofintramolecular hydrogen bonds - between the nitrogen and the hydrogen atoms of two different thioureido groups - which were noticed only in the infrared spectra for P4. In fact, these intramolecular interactions are very favorable in compounds with low alkylation level, high polarity and high symmetry compounds such as P4, and besides P4 has two pairs of nitrogenhydrogen groups (NH) to make two mutual intramolecular hydrogen bond interactions. Therefore, if the thioureido groups are involved in very strong intramolecular interactions, there is no freethioureido group to make the biological interaction which is responsible for the antifungal activity. P1 e P2 were also tested against some tumor species - human gastric adenocarcinome (AGS), murin colon carcinome (CT26WT), female mamarian human carcinome (MCF-7) and mouseglioma (C6) but, the average found MIC 10-4 to 10-5 mol/L - in not good enough to make these molecules promising novel antineoplastic agents. The attempts for their partition coefficient (log P) measurements by RP-HPLC technique are also described and the results show that the usual standardization with common and ordinary compounds with well-known partition coefficients is not suitable for the present studied with high branched and polifunctionalized molecules. The thin layer chromatography or even the usual shake-flask methodologies might be alternatives and they are going to be tested.