Ro 42-1611 (arteflene), a new effective antimalarial: chemical structure and biological activity.

The discovery of the natural peroxides qinghaosu (arteannuin A, artemisinin) (1) and yingzhaosu A (3) from traditional Chinese herbal medicines was a major advance in the search for new antimalarials (Fig. 1). Whereas qinghaosu can be produced from natural sources and has been well studied, yingzhaosu A has never been available for full evaluation as anti-malarial. We have designed a synthesis of the novel ring system present in yingzhaosu A, the 2,3-dioxabicyclo[3.3.1]nonane and prepared a series of yingzhaosu A analogues which were tested against Plasmodium berghei in mice. Structure-activity rules could be established and used for lead optimization. The best anti-malarial activity was observed for analogues having a keto group within the ring system and an aliphatic or aromatic lipophilic tail as ring substituent. The optimized analogues possessed activity comparable to qinghaosu. In spite of the presence of a peroxide ring, the new compounds were chemically stable against common reagents. In contrast to qinghaosu and its derivatives, they were also stable against hydrolytic decomposition and could therefore be expected to show improved pharmacokinetic properties. As one of the best compounds, Ro 42-1611 (arteflene) (26n, Fig. 2) was selected for detailed preclinical evaluation. Ro 42-1611 (arteflene) was found negative in a battery of mutagenicity tests. It had low acute toxicity after oral or subcutaneous administration. In a 4-week oral tolerance study in rats, doses of up to 400 mg/kg/day were well tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)

Antimalarial activity of the bicyclic peroxide Ro 42-1611 (arteflene) in experimental models.

The sesquiterpene peroxide Ro 42-1611 (arteflene), a synthetic derivative of yingzhaosu, was evaluated extensively against various drug-sensitive and drug-resistant lines of Plasmodium falciparum in vitro and P. berghei in vivo in mice. The potential therapeutic and prophylactic activities were studied comparatively with the standard antimalarials chloroquine, mefloquine and quinine, as well as qinghaosu and the derivatives artemether and artesunic acid. Experimentally arteflene proved to be a highly effective antimalarial drug. In vivo it is active at low doses against blood stages of P. berghei in mice after oral or parenteral administration. It has a rapid onset of drug action and a long lasting suppressive effect when given after infection, as well as a good potential for prophylactic activity when given before infection. The suppressive and prophylactic properties are comparable to chloroquine and superior to qinghaosu, artemether and artesunic acid. In vitro the compound showed no signs of cross-resistance with existing antimalarials. It was consistently rather more active against drug-resistant than against drug-sensitive strains of P. falciparum. Drug interaction studies in vitro and in vivo with chloroquine, mefloquine and quinine revealed an additive to synergistic effect with arteflene. Antagonism with these drugs was not observed. Compared with standard antimalarials the activity of arteflene in vitro is lower than would be expected from the in vivo results. This may be due to pharmacokinetic properties of the compound and the formation of an active metabolite which sustains the activity of arteflene in vivo.

Parasitological evaluation of curative and subcurative doses of 9-acridanone-hydrazone drugs against Schistosoma mansoni in baboons, and observations on changes in serum levels of anti-egg antibodies detected by ELISA.

Derivatives in the class of 9-acridanone-hydrazones were found to be highly active against Schistosoma mansoni in baboons. Single doses of 25 mg/kg were fully effective. Data are presented showing changes detected by ELISA in antibody levels against schistosome eggs which correlated positively with the effect of chemotherapy. This approach may help to evaluate the effects of treatment of human schistosomiasis where the detection of low egg counts is problematic.