| dc.description.abstract | This work presents the results obtained in the studies of docking and QSAR carried out with a group of bis cationic bisamidines against Candida albicans, Cryptococcus neofarmans andPneumocystis carinii. As well as synthesis, structural determination and biological activity (antifungal and antitumor) of four new derivates S-isotioureidos. The results obtained in studies of docking carried out of bis cationic bisamidines groove binders, d(CGCGAATTCGCG) 2 and o(CGAATTCG) 2 DNA sequences showed that the employedmethodology can be a useful tool to predicting the conformational preference for this class of compounds. However, the calculated energies have not statistical correlation with the log DTm ofthe complexes ligant-B-ADN fragments, reflecting only a general affinity tendency between amidinic compounds to fragment of the B-ADN.The QSAR-2D studies indicated that the activity against C. albicans and C. neofarmans are correlated with lipophilic parameters. Althougt this isolated parameter can not explain the biological data in an appropriate way. The results obtained from 2D-QSAR studies corrobate ourprevious knowledge about the importance of isohelical conformation and complementarity to the minor groove of DNA in the biological activity of these compounds.The 3D-QSAR studies using CoMFA showed that the steric contribution is an important parameter for activity against C.albicans and C. neofarmans and that bulky groups in the amidinic group decrease the potency of these compounds. The proposed compounds (FB1 to FB4) based on previous computational studies werenot synthesized. On the other hand the synthesis of four novel S-isothioureids compounds, furan-2,5-diyldimethanediyl dicarbamimidothioate (Ia), furan-2,5-diildimethanediil bis(N, N'-dimetilcarbamimidothioate (Ib), oxybis(methanediylfuran-5,2-diylmethanediyl) bis(N, N-dimethylcarbamimidothioate (IIa) e xybis(methanediylfuran-5,2-diylmethanediyl) bis(Nmethylcarbamimidothioate)(IIb) were synthesized by an easy and efficient classical syntheticalroute. All the compounds were characterized by infrared, H1 NMR, C13 NMR and mass spectrometry. The furan-2,5-diildimetanol (2), [oxibis(metanodiilfuran-5,2-diil)]dimetanol (3), (4,4'-[furan-2,5-diilbis(metanodiiloxi)]dibenzonitrile) (7), Ia , Ib , IIa and IIb compounds showed activity against all the tested funguses. The compound 3 was more powerful by Paracoccidioides.The thioureids compounds tested are not toxic for healthy cells (IC50> 10-4 for BHK21) and they presented activity against all of carcinogenic tested cells. The Ib and IIb compounds presented similar activity against cell of mammary human carcinoma 4T1 (M). The compound IIawas more powerful front the tumorais cells of melanoma (MeWo). The Ia, Ib e IIb compounds were presented activity antitumoral similar by mouse's glioma C6. | |
