RO-42-1611 (ARTEFLENE), A NEW EFFECTIVE ANTIMALARIAL - CHEMICAL-STRUCTURE AND BIOLOGICAL-ACTIVITY

The discovery of the natural peroxides qinghaosu (arteannuin A, artemi sinin) (1) and yingzhaosu A (3) from traditional Chinese herbal medici nes was a major advance in the search for new antimalarials (Fig. 1). Whereas qinghaosu can be produced from natural sources and has been we ll studied, yingzhaosu A has never been available for full evaluation as antimalarial. We have designed a synthesis of the novel ring system present in yingzhaosu A, the 2,3-dioxabicyclo[3.3.1]nonane and prepar ed a series of yingzhaosu A analogues which were tested against Plasmo dium berghei in mice. Structure-activity rules could be established an d used for lead optimization. The best antimalarial activity was obser ved for analogues having a keto group within the ring system and an al iphatic 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 the refore be expected to show improved pharmacokinetic properties. As one of the best compounds, Ro 42-1611 (arteflene) (26n, Fig.2) was select ed for detailed preclinical evaluation. Ro 42-1611 (arteflene) was fou nd negative in a battery of mutagenicity tests. It had low acute toxic ity after oral or subcutaneous administration. In a 4-week oral tolera nce study in rats, doses of up to 400 mg/kg/day were well tolerated. L aboratory and morphological changes were indicative of enzyme inductio n. All changes were reversible. In a 4-week oral tolerability study in dogs, doses of up to 700 mg/kg/day were similarly well tolerated. Rep roductive toxicology studies revealed a clear embryolethal effect in r ats at 20 mg/kg and a slight effect in rabbits at 40 mg/kg. This embry otoxicity was comparable to the effects seen with qinghaosu and its de rivatives, and while requiring further evaluation it was not considere d to be a handicap for a possible use in the treatment of malaria. In view of the novel chemical structure, potent biological activity and g ood tolerance, a full clinical development of Ro 42-1611 (arteflene) w as initiated.