title: Phenoxypropoxybiguanides, prodrugs of DHFR-inhibiting diaminotriazine antimalarials.
abstract: A total of 34 analogues of the biguanide PS-15 (5s), a prodrug of the diaminotriazine WR-99210 (8s), have been prepared. Several of them, such as 5b (PS-33) and 5m (PS-26), maintain or exceed the in vivo activity of PS-15 while not requiring the use of highly regulated starting materials. The putative diaminotriazine metabolites of these new analogues (compounds 8) have also been prepared and shown to maintain the activity against resistant P. falciparum strains. The structure-activity relationships of biguanides 5 and putative metabolites 8 are discussed.
authors.affiliation: Jacobus Pharmaceutical, Box 5290, Princeton, New Jersey 08540, USA. romich@aol.com
authors.forename: N P
authors.initials: NP
authors.lastname: Jensen
authors.forename: A L
authors.initials: AL
authors.lastname: Ager
authors.forename: R A
authors.initials: RA
authors.lastname: Bliss
authors.forename: C J
authors.initials: CJ
authors.lastname: Canfield
authors.forename: B M
authors.initials: BM
authors.lastname: Kotecka
authors.forename: K H
authors.initials: KH
authors.lastname: Rieckmann
authors.forename: J
authors.initials: J
authors.lastname: Terpinski
authors.forename: D P
authors.initials: DP
authors.lastname: Jacobus
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D005260:Female; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D008288:Malaria / Q000188:drug therapy; D008297:Male; D051379:Mice; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D002727:Proguanil / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism*; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity
chemical_list: D000962:Antimalarials; D005493:Folic Acid Antagonists; D006146:Guanidines; C439961:PS 26 compound; C439960:PS 33 compound; D011355:Prodrugs; D014227:Triazines; C082651:PS 15; D013762:Tetrahydrofolate Dehydrogenase; D002727:Proguanil