Triazine Inhibits Toxoplasma gondii tachyzoites in vitro and in vivo.
The triazine WR99210 [4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(2,4,5-trichlorophenoxypropyloxy)-1,3,5 triazine] inhibits Toxoplasma gondii in vitro at nanomolar levels (P < 0.05). The 50% inhibitory concentration (IC(50)) was approximately 50 nM. It is a potent inhibitor in vitro and is also effective in vivo. Administration of WR99210 parenterally (i.e., intraperitoneally) reduced the mean number of RH strain tachyzoites present in peritoneal fluid substantially 4 days after intraperitoneal infection of mice. There was a mean of approximately 35 million parasites in control mice as contrasted with approximately 2 million parasites in mice treated with 1.25 mg WR99210/kg of body weight in a representative experiment (P < 0.05). In addition the prodrug PS-15 N'-[3-(2,4, 5-trichlorophenoxy)propyloxy]-N9-(1-methylethyl) imidocarbonimidicdiamide is converted to 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(2,4,5-trichlorophenoxypropyloxy)-1,3,5 triazine in vivo when the prodrug is administered orally. PS-15 administered by gavage also reduced intraperitoneal RH strain T. gondii tachyzoite numbers. WR99210 has high efficacy and relatively low toxicity because of its substantial effect on T. gondii dihydrofolate reductase (DHFR) but not the mammalian host DHFR. Amino acid sequences of T. gondii, Plasmodium falciparum, and Homo sapiens DHFRs were compared. It is of interest that of the DHFR amino acids considered to be interacting with WR99210 in P. falciparum within interatomic distances within 3 to 5 A, four of eight were shared with T. gondii DHFR. H. sapiens also shared four amino acids thought to be interacting with WR99210. Efficacy of intraperitoneal administration of WR99210 and peroral administration of PS-15 demonstrate the potential usefulness of this class of compounds in treatment of toxoplasmosis administered either parenterally or perorally. The recent development program for this class of antimicrobials as antimalarials makes our proof of principle of improved efficacy of triazines (compared with the gold standard treatment, pyrimethamine) against T. gondii especially promising.
Mui
Ernest J
EJ
The University of Chicago, 5841 S. Maryland Avenue (MC2114), AMB S-208, Chicago, IL 60637, USA.
Jacobus
David
D
Milhous
Wilbur K
WK
Schiehser
Guy
G
Hsu
Honghue
H
Roberts
Craig W
CW
Kirisits
Michael J
MJ
McLeod
Rima
R
D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000469:parasitology; D005493:Folic Acid Antagonists; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D021261:Parasitic Sensitivity Tests; D016415:Sequence Alignment; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry; D014122:Toxoplasma / Q000187:drug effects* / Q000254:growth & development*; D014124:Toxoplasmosis, Animal / Q000188:drug therapy* / Q000469:parasitology; D014227:Triazines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
D000981:Antiprotozoal Agents; D005493:Folic Acid Antagonists; D014227:Triazines; D013762:Tetrahydrofolate Dehydrogenase