Síntese de derivados 1,2,3-triazólicos de isocumarinas e 3,4-diidroisocumarinas com potencial atividade antimalárica in vitro

Abstract

This work reports the synthesis of a new class of 3,4-dihydroisocoumarins and 1,2,3-triazoles to obtain substances with biological activities. Thirty-one compounds were synthesized by an unprecedented hybridization of isocoumarins/3,4- dihydroisocoumarins with 1,2,3-triazoles. These hybrids were obtained via a copper catalyzed 1,3-dipolar cycloaddition between azides (derived from isocoumarins or 3,4-dihydroisocoumarine) and terminal alkynes (derived from commercial benzyl alcohols). The isocoumarins were prepared using a Castro Stephens coupling as a key step of the synthetic route. The 3,4-dihydroisocoumarines were synthesized by the reduction of their corresponding synthetic precursors with sodium borohydride. The antimalarial activity of the novel hybrid compounds was evaluated in vitro against two strains of Plasmodium falciparum: the 3D7, sensitive to chloroquine, and the W2 resistant to chloroquine. The majority of the tested compounds were active [IC50 values in the range of 0.68 to 2.89 μM (strain W2) and 0.79 to 2.07 μM (strain 3D7)],], demonstrating their great potential as prototypes for the development of new substances with antimalarial activity. Besides, 22 new substances were also synthesized: 11 derived of them prepared from isocoumarins, and 11 derived from 3,4-dihydroisocoumarins. The synthesis routes used to obtain these compounds showed global yields that ranged from 22 to 55%.