Phenoxypropoxybiguanides, Prodrugs of DHFR−Inhibiting Diaminotriazine Antimalarials

• Published in: Journal of medicinal chemistry Vol. 44; no. 23; pp. 3925 - 3931
• Main Authors: Jensen, Norman P, Ager, Arba L, Bliss, Robert A, Canfield, Craig J, Kotecka, Barbara M, Rieckmann, Karl H, Terpinski, Jacek, Jacobus, David P
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 08.11.2001; Amer Chemical Soc
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Antimalarials - toxicity; Antiparasitic agents; Biological and medical sciences; Chemistry, Medicinal; Drug Evaluation, Preclinical; Female; Folic Acid Antagonists - chemical synthesis; Folic Acid Antagonists - chemistry; Folic Acid Antagonists - pharmacology; Folic Acid Antagonists - toxicity; Guanidines - chemical synthesis; Guanidines - chemistry; Guanidines - pharmacology; Guanidines - toxicity; Life Sciences & Biomedicine; Malaria - drug therapy; Male; Medical sciences; Mice; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Plasmodium berghei; Plasmodium falciparum - drug effects; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacology; Prodrugs - toxicity; Proguanil - analogs & derivatives; Proguanil - chemical synthesis; Proguanil - chemistry; Proguanil - pharmacology; Proguanil - toxicity; Science & Technology; Structure-Activity Relationship; Tetrahydrofolate Dehydrogenase - metabolism; Triazines - chemical synthesis; Triazines - chemistry; Triazines - pharmacology; Triazines - toxicity; PS-15; IN-VITRO ACTIVITIES; PLASMODIUM-FALCIPARUM; INVITRO; RESISTANCE; MALARIA; MODEL; METABOLITE; WR99210; Antimalarial; Nitrogen heterocycle; Chloroquine; Plasmodium falciparum; Plasmodium berghei; Biguanides; Structure activity relation; Chlorine Organic compounds; Six membered ring; Parasiticid; Dihydrofolate reductase; Chemical synthesis; Protozoa; Apicomplexa; Enzyme; Rodentia; Pyrimethamine; Enzyme inhibitor; Parasitosis; Prodrug; In vitro; Infection; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Animal; Triazine derivatives; Benzenic compound; Oxidoreductases
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm010089z

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.