The antimalarial triazine WR99210 and the prodrug PS-15: Folate reversal of in vitro activity against Plasmodium falciparum and a non-antifolate mode of action of the prodrug

American Journal of Tropical Medicine and Hygiene

Volumn 60, Issue 6, 1999, Pages 943-947

  Kinyanjui, Samson M ^a   Mberu, Edward K ^b   Winstanley, Peter A ^c   Jacobus, David P ^d   Watkins, William M ^b  

^a KENYA MEDICAL RESEARCH INSTITUTE   (Kenya)

^b KEMRI WELLCOME TRUST RESEARCH PROGRAMME   (Kenya)

^c UNIVERSITY OF LIVERPOOL   (United Kingdom)

^d Jacobus Pharmaceutical Co Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4,6 DIAMINO 1,2 DIHYDRO 2,2 DIMETHYL 1 [3 (2,4,5 TRICHLOROPHENOXY)PROPOXY] 1,3,5 TRIAZINE; ANTIMALARIAL AGENT; DIHYDROFOLATE REDUCTASE; FOLIC ACID; FOLINIC ACID; N [3 (2,4,5 TRICHLOROPHENOXY)PROPOXY] N' ISOPROPYLIMIDOCARBONIMIDIC DIAMIDE; PYRIMETHAMINE;

ARTICLE; BINDING AFFINITY; DRUG ACTIVITY; DRUG ANTAGONISM; DRUG MECHANISM; DRUG PROTEIN BINDING; GROWTH INHIBITION; MALARIA; MICROBIAL GROWTH; NONHUMAN; PLASMODIUM FALCIPARUM;

EID: 0033027433     PISSN: 00029637     EISSN: None     Source Type: Journal    
DOI: 10.4269/ajtmh.1999.60.943     Document Type: Article

References (21)

1. Watkins WM, Mberu EK, Winstanley PA, Plowe CV, 1997. The efficacy of antifolate antimalarial combinations in Africa: a predictive model based on pharmacodynamic and pharmacokinetic analyses. Parasitol Today 13: 459-461.
2. Rieckmann KH, 1973. The in vitro activity of experimental antimalarial compounds against strains of P. falciparum with varying degrees of sensitivity to pyrimethamine and chloroquine. Chemotherapy of malaria and resistance to Antimalarials. World Health Organ Tech Rep Ser 529: 58.
3. Canfield GJ, Rozman RS, 1974. Clinical testing of new antimalarial compounds. Bull World Health Organ 50: 203-212.
4. Knight DJ, Mamalis P, 1982. The antimalarial activity of N-benzyl-oxydihydrotriazines. III. The activity of 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(2,4,5-trichloropropyloxy)-1,3,5- triazinehydrobromide (BRL 51084) and hydrochloride (BRL 6231). Ann Trop Med Parasitol 76: 1-7.
5. Childs GE, Lambros C, 1994. Analogues of N-benzyloxydihydrotriazines - in vitro antimalarial activity against Plasmodium falciparum. Ann Trop Med Parasitol 80: 111-181.
6. Canfield CJ, Milhous WK, Ager AL, Rossan RN, Sweeney TR, Lewis NJ, Jacobus DP, 1993. PS-15: a potent, orally active antimalarial from a new class of folic acid antagonists. Am J Trop Med Hyg 49: 121-126.
7. Yeo EAT, Rieckmann KH, 1994. The activity of PS-15 in combination with sulfamethoxazole. Trop Med Parasitol 45: 136-137.
8. Canfield CJ. 1986. New antimalarials under development. Bruce-Chwatt LJ, ed. Chemotherapy of Malaria. Revised second edition. Geneva: World Health Organization Monograph Series, No. 27, 99-100.
9. Canfield CJ, Pudney M, Gutteridge WE. 1995. Interactions of atovoquone and other antimalarial drugs against Plasmodium falciparum in vitro. Exp Parasitol 80: 373-381.
10. Chulay JD, Watkins WM, Sixsmith DG, 1984. Synergistic antimalarial activity of pyrimethamine and sulfadoxine against Plasmodium falciparum in vitro. Am J Trop Med Hyg 33: 325-330.
11. Watkins WM, Sixsmith DG, Chulay JD, Spencer HC, 1985. Antagonism of sulfadoxine and pyrimethamine antimalarial activity in vitro by p-aminobenzoic acid, p-aminobenzoylglutamic acid and folic acid. Mol Biochem Parasitol 32: 25-38.
12. Milhous WK, Wetherly NF, Bowdre JH, Desjardins RE, 1985. In vitro activities and mechanisms of resistance to antifol antimalarial drugs. Antimicrob Agents Chemother 27: 525-530.
13. Krungkrai J, Webster HK, Yuthavong Y, 1989. De novo and salvage biosynthesis of pteroylpentaglutamate in the human malarial parasite Plasmodium falciparum. Mol Biochem Parasitol 32: 25-38.
14. Trager W, Jensen JB, 1976. Human malaria in continuous culture. Science 193: 673-675.
15. Desjardins RE, Canfield CJ, Haynes JD, Chulay JD, 1979. Quantitative assessment of antimalarial activity by a semi-automated microdilution technique. Antimicrob Agents Chemother 16: 710-718.
16. Sixsmith DG, Watkins WM, Chulay JD, Spencer HC, 1984. In vitro antimalarial activity of tetrahydrofolate dehydrogenase inhibitors. Am J Trop Med Hyg 33: 772-776.
17. Watkins WM. Sixsmith DG, Chulay JD, 1984. The activity of proguanil and its metabolites cycloguanil and p-chlorophenylbiguanide against Plasmodium falciparum in vitro. Ann Trop Med Parasitol 78: 273-278.
18. McCormick GJ, Canfield CJ, Willet GP, 1971. In vitro evaluation of antimalarial activity of folic acid inhibitors. Exp Parasitol 30: 88-93.
19. Yeo AET, Seymour KK, Rieckmann KH, Christopherson RI, 1997. Effects of folic and folinic acids on the activities of cycloguanil and WR99210 against Plasmodium falciparum in erythrocytic culture. Trop Med Parasitol 91: 17-23.
20. Fidock DA, Wellems TE, 1997. Transformation with human dihydrofolate reductase renders malaria parasites insensitive to WR99210 but does not affect the intrinsic activity of proguanil. Proc Natl Acad Sci USA 94: 10931-10936.
21. Yeo AET, Seymour KK, Rieckmann KH, Christopherson RI, 1997. Effect of dual combination of antifolates with atovoquone or dapsone on nucleotide levels in Plasmodium falciparum. Biochem Pharmcol 53: 943-950.