Phenoxypropoxybiguanides, prodrugs of DHFR-inhibiting diaminotriazine antimalarials

A total of 34 analogues of the biguanide PS-15 (5s), a prodrug of the diami notriazine WR99210 (8s), have been prepared. Several of them, such as 5b (P S-33) and 5m. (PS-26), maintain or exceed the in vivo activity of PS-15 whi le not requiring the use of highly regulated starting materials. The putati ve diaminotriazine metabolites of these new analogues (compounds 8) have al so been prepared and shown to maintain the activity against resistant P. fa lciparum strains. The structure-activity relationships of biguanides 5 and putative metabolites 8 are discussed.