Antimalarial activity of phenazines from lapachol, beta-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, beta-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 [(3)H]-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 microM. The two most active ones were also tested in vivo against Plasmodium berghei in mice, in parallel with lapachol and beta-lapachone. The 3-sulfonic acid-beta-lapachone-derived phenazine was the most active causing up to 98% inhibition of parasitaemia in long term treatment (7 doses) subcutaneously, whereas the phenazine from 3-bromo-beta-lapachone was inactive. Thus, these simple phenazines, containing polar (-Br,-I) and ionizable (-SO(3)H, -OH) groups, easily synthesized from cheap, natural or synthetic precursors (lapachol and beta-lapachone), at rather low cost, provide prototypes for development of new antimalarials aiming the chloroquine resistant parasites.
Centro de Pesquisas René Rachou, Fiocruz and Departamento de Parasitologia-Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil.
Valter F
VF
de Andrade-Neto
Marília O F
MO
Goulart
Jorge F
JF
da Silva Filho
Matuzalém J
MJ
da Silva
Maria do Carmo F R
Mdo C
Pinto
Antônio V
AV
Pinto
Mariano G
MG
Zalis
Luzia H
LH
Carvalho
Antoniana U
AU
Krettli
D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D010619:Phenazines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D010962:Plasmodium berghei / Q000187:drug effects* / Q000502:physiology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000502:physiology
D000962:Antimalarials; D009285:Naphthoquinones; D010619:Phenazines; C014638:beta-lapachone