Activity of benzothiazoles and chemical derivatives on Plasmodium falciparum.
Malaria is a major health concern particularly in Africa which has about 90% of the worldwide annual clinical cases. The increasing number of drug-resistant Plasmodium falciparum justifies the search for new drugs in this field. Antimalarial activity of 2-substituted 6-nitro- and 6-amino-benzothiazoles and their anthranilic acids has been tested. An in vitro study has been performed on W2 and 3D7 strains of P. falciparum and on clinical isolates from malaria-infected patients. Toxicity has been assessed on THP1 human monocytic cells. For the most active drug candidates, the in vitro study was followed by in vivo assays on P. berghei-infected mice and by in vitro assays in order to determine the stage-dependency and the mechanism of action. Of 39 derivatives tested in vitro, 2 had specific antimalarial properties. Each compound was active on all stages of the parasite, but one was markedly active on mature schizonts, while the other was more active on young schizont forms. Both drugs were also active on mitochondrial membrane potential. In vivo data confirmed efficiency with a sustained decrease of parasitaemia. Products A12 and C7 may be considered as potential antimalarial worthy of further chemical and biological research.
Hout
S
S
Laboratoire de Parasitologie, Hygiène et Zoologie, Faculté de Pharmacie, Marseille cedex 05, France.
Azas
N
N
Darque
A
A
Robin
M
M
Di Giorgio
C
C
Gasquet
M
M
Galy
J
J
Timon-David
P
P
D000293:Adolescent; D000368:Aged; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D052160:Benzothiazoles; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005260:Female; D006801:Humans; D008018:Life Cycle Stages / Q000187:drug effects; D008288:Malaria / Q000188:drug therapy; D016778:Malaria, Falciparum / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000187:drug effects; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects*; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity
D000962:Antimalarials; D052160:Benzothiazoles; D013844:Thiazoles; C005465:benzothiazole