Conformational analysis of phloroglucinols from hypericum Brasiliense by using x-ray diffraction and molecular modeling

Abstract

Neste trabalho, verificou-se a aplicabilidade de uma metodologia computacional para se predizer a estrutura de compostos orgânicos com atividade biológica. Para isso, selecionaramse três floroglucinóis, e compararam-se suas conformações obtidas por modelagem molecular e por difração de raios X. Os resultados mostraram que as conformações obtidas por análise conformacional com o método AM1 seguidas de otimização de geometria utilizando o método DFT (B3LYP/6-31G(d,p)) estão em boa concordância com os dados obtidos experimentalmente por difração de raios X, indicando que a metodologia empregada parece ser uma ótima ferramenta para predizer preferências conformacionais desta classe de compostos.In this work we intend to verify the applicability of a computational methodology to predict structural features of organic compounds with biological activity. We selected three phloroglucinols and compared their calculated conformational data with their X-ray crystallographic structure. The results showed that conformations obtained by conformational analysis with the AM1 method followed by geometry optimization by using the DFT B3LYP/6-31 G(d,p) basis set are in very good agreement with X-ray data, indicating that the methodology employed here seems to be a very useful tool in order to predict the conformational preference for this class of compounds.Keywords: conformational analysis, X-ray, molecular modeling, phloroglucinols IntroductionDespite the development of organic synthesis, biotechnology and combinatorial chemistry, natural plants are still a great source of bioactive compounds. However, just 8% of the Brazilian flora has been already studied in the search for new bioactive substances. 1,2 In the last decades several antibacterial compounds are being less effective in the treatment of infectious diseases due to multi-resistant bacteria.3 In this context medicinal plants are extremely important in the search of new molecules as therapeutic alternatives. The genus Hypericum seems to be a good choice for this problem. It is constituted by flavonoids, xantones and phloroglucinols with considerable pharmacological and biological effects.4,5 Phloroglucinol derivatives have been described in the literature as promising substances with Conformational Analysis of Phloroglucinols from Hypericum Brasiliense J. Braz. Chem. Soc. 838 high antibacterial activity. [6][7][8][9] The Hypericum brasiliense presents three phloroglucinols in its constitution and they are active against bacteria.10,11 These phloroglucinols are the japonicin A, the uliginosin B and the isouliginosin B (Figure 1).The study of conformations of bioactive compounds is very important in the design of new drugs, since that conformational profile may have direct implications in their activity. When the conformational properties of a drug are known to play an important role in establishing its therapeutic value, any newly designed analogue should have similar conformational properties to enhance the probability that it will bind to the receptor target.Nowada...