Antimalarial activity of imidazo[2,1-a]isoindol-5-ol derivatives and related compounds

The synthesis of several series of imidazo[2,1-a]isoindol-5-ol derivatives and the results of their evaluation against Plasmodium falciparum are presented and discussed. The effects of electron-withdrawing or-donating substituents on different parts of the molecule, as well as those produced by the incorporation of an additional fused ring, were analyzed. Several compounds showed significant antimalarial activity in vitro with IC50 values as low as 60 nM and a certain efficacy in vivo by reducing parasitemia in Plasmodium berghei mouse models. Benzyl and β-naphthylmethyl derivatives of imidazo[2,1-a]isoindol-5-ol with potent in vitro antiplasmodial effects (IC50 = 60 nM) and promising antimalarial efficacy in vivo (87% inhibition of parasitemia) are described. [Display omitted] ▸ 29 imidazoisoindoles, imidazobenzimidazoles and isoindolinones synthesized. ▸ IC50 values against 3D7 Plasmodium falciparum ranged between 60 nM and >35 mM. ▸ 7 imidazoisoindoles assayed on mice infected with Plasmodium berghei. ▸ Up to 87% parasitemia inhibition on the 5th day, after 4 daily i.p. 25 mg/kg/day.