Antimalarial activity of phenazines from lapachol, β-lapachone and its derivatives against Plasmodium falciparum in vitro and Plasmodium berghei in vivo

The antimalarial activity of benzo[a]phenazines synthesized from 1,2-naphthoquinone, lapachol, β-lapachone and several derivatives have been tested against Plasmodium falciparum in vitro using isolates of parasites with various susceptibilities to chloroquine and/or mefloquine. Parasite growth in the presence of the test drugs was measured by incorporation of [3H]-hipoxanthine in comparison to controls with no drugs, always testing in parallel chloroquine, a standard antimalarial. Among seven benzophenazines tested, four had significant in vitro activities; important, the parasites resistant to chloroquine were more susceptible to the active phenazines in vitro. The doses of phenazines causing 50% inhibition of parasite growth varied from 1.67 to 9.44 μM. The two most active ones were also tested in vivo against Plasmodium berghei in mice, in parallel with lapachol and β-lapachone. The 3-sulfonic acid-β-lapachone-derived phenazine was the most active causing up to 98% inhibition of parasitaemia in long term treatment (7 doses) subcutaneouly, whereas the phenazine from 3-bromo-β-lapachone was inactive. Thus, these simple phenazines, containing polar (–Br,–I) and ionizable (–SO3H, –OH) groups, easily synthesized from cheap, natural or synthetic precursors (lapachol and β-lapachone), at rather low cost, provide prototypes for development of new antimalarials aiming the chloroquine resistant parasites.