Síntese e avaliação da atividade Leishmanicida de híbridos moleculares Tetrahidropiranos/ Adutos de Morita-Baylishillman: Uma abordagem clássica na busca de antiparasitários

Abstract

This study had as principle the use of molecular hybridization like classical technique of drug discovery. This perspective was driven by simplicity in application of different biological effects of molecules known to be active against a potentially sensitive subject to these effects. Thus we propose the synthesis of molecular hybrids formed from two kinds of reaction products, with broad biological interest, namely: tetrahydropyrans coming from the Prins ciclization reaction and adducts of MoritaBaylis-Hillman reaction. The Barbier reaction was used to produce in 96% a intermediate homoallyl alcohol in 69%, as the starting reagent of Prins cyclization step. This, in turn, proved to be an efficient tool in the production of two tetrahydropyranic structures with yields of 80% and 88% being precursors of the prototypes tetrahydropyrans, molecules with antinociceptive activity strategically important in this work. In step Morita-Baylis-Hillman reaction, microwave irradiation was widely used in the majority of products formed, although in some cases it was used different conditions for optimization of reaction generating, in the analogous series, yields between 45% e 96%. The hybrid species were bioevaluated in vitro against the promastigotes shapes of Leishmania donovani observing the viability of the incubated species in presence of different concentrations of the hybrids and compared to the positive control, Amphotericin B®. The minimum inhibitory concentration (IC50) of each sample was obtained, where the most active compounds presented IC50 values between 2.22 and 7.09 µg / mL. In subsequent tests, these same, more active species were submitted to toxicity evaluation through hemolysis of red cells (HC50) showing higher selectivity indices to the control drug.