-
Bioorganic & Medicinal Chemistry Dec 2019The series of des-Cl (unsubstituted) and m-Cl phenyl analogues of PYR with various flexible 6-substituents were synthesized and studied for the binding affinities with...
The series of des-Cl (unsubstituted) and m-Cl phenyl analogues of PYR with various flexible 6-substituents were synthesized and studied for the binding affinities with highly resistant quadruple mutant (QM) DHFR. The derivatives carrying 4 atoms linker with a terminal carboxyl substituted on the aromatic ring exhibited good inhibition to the QM enzyme and also showed effective antimalarial activities against resistant P. falciparum bearing the mutant enzymes with relatively low cytotoxicity to mammalian cells. The X-ray crystallographic analysis of the enzyme-inhibitor complexes suggested that the hydrophobic substituent at 6-position was accommodated well in the hydrophobic pocket and the optimal length of the flexible linker could effectively promote the binding of the terminal carboxyl group to the key amino acid residues, Arg59 and Arg122.
Topics: Animals; Antimalarials; Chlorocebus aethiops; Drug Design; Drug Resistance; Folic Acid Antagonists; Models, Molecular; Molecular Structure; Plasmodium falciparum; Protein Conformation; Pyrimethamine; Tetrahydrofolate Dehydrogenase; Vero Cells
PubMed: 31685330
DOI: 10.1016/j.bmc.2019.115158 -
Lancet (London, England) Nov 1981
Topics: Drug Combinations; Drug Therapy, Combination; Humans; Malaria; Plasmodium falciparum; Pyrimethamine; Sulfadoxine; Sulfanilamides
PubMed: 6118530
DOI: No ID Found -
The New England Journal of Medicine Sep 1969
Topics: Bone Marrow; Bone Marrow Cells; Culture Techniques; Folic Acid; Folic Acid Antagonists; Humans; Malaria; Polycythemia; Pyrimethamine
PubMed: 5800521
DOI: 10.1056/NEJM196909042811024 -
The American Journal of Tropical... Mar 1992Central nervous system toxoplasmosis is a major opportunistic infection in patients with acquired immunodeficiency syndrome. The standard therapy for this infection is...
Central nervous system toxoplasmosis is a major opportunistic infection in patients with acquired immunodeficiency syndrome. The standard therapy for this infection is pyrimethamine (PYR) and sulfonamides. To assess in vivo if PYR alone could adequately treat toxoplasmosis, a murine model of acute toxoplasmosis was used. The CD1 strain of mice was infected intraperitoneally with 10(4) parasites of the RH strain of Toxoplasma gondii. Pyrimethamine was administered in mouse chow at concentrations of 0, 0.03125, 0.0625, 0.125, 0.25, or 1.0 mg of PYR/g of food, which provides the following daily PYR dosages: 0, 6.25, 12.5, 25, 50, and 200 mg/kg/day. No sulfonamides were administered. Serum PYR levels proved more accurate than mg of PYR/g of food in predicting survival. Mice with serum PYR levels greater than or equal to 500 ng/ml (2 microM) survived and had no parasites present on peritoneal lavage. Mice with serum PYR levels less than 100 ng/ml (0.4 microM) had a 100% mortality rate and the average parasite count was 3 x 10(7) organisms in the lavage fluid. At a PYR level of 370 ng/ml, six of 11 mice survived and the lavage fluid contained 2.5 x 10(5) organisms. Previously, using 3H-uracil in an in vitro assay, PYR at a concentration of 500 ng/ml was shown to be as effective in inhibiting Toxoplasma growth as the combination of PYR (100 ng/ml) and sulfonamides 25 micrograms/ml). These data suggest the potential usefulness of PYR for monotherapy of toxoplasmosis and are consistent with previously described in vitro assays.
Topics: Acute Disease; Animals; Biological Availability; Mice; Pyrimethamine; Toxoplasmosis, Animal; Toxoplasmosis, Cerebral
PubMed: 1558268
DOI: 10.4269/ajtmh.1992.46.288 -
Organic & Biomolecular Chemistry Mar 2003Pyrimethamine acts against malarial parasites by selectively inhibiting their dihydrofolate reductase-thymidylate synthase. Resistance to pyrimethamine in Plasmodium...
Pyrimethamine acts against malarial parasites by selectively inhibiting their dihydrofolate reductase-thymidylate synthase. Resistance to pyrimethamine in Plasmodium falciparum is due to point mutations in the DHFR domain, initially at residue 108 (S108N), with additional mutations imparting much greater resistance. Our previous work, the development of a simple rational drug design strategy to overcome such resistance, used suitable meta-substituents in the pyrimethamine framework to avoid the unfavorable steric clash with mutant side chains at position 108. Interestingly, the meta-chloro analog of pyrimethamine not only overcame the resistance due to S108N, but also that contributed by the more remote mutation, C59R. The present work improves on this by means of other meta-substituents. Against wild type DHFR, double mutant types A16V + S108T and C59R + S108T, and the highly pyrimethamine/cycloguanil-resistant quadruple-mutant form N51I + C59R + S108N + I164L, pyrimethamine itself gave Ki values of 1.5, 2.4, 72.3 and 859 nM, respectively. The meta-substituted analogs, especially the meta-bromo analog, were much more powerful inhibitors of these DHFRs, including the quadruple-mutant form (meta-bromo analog, Ki 5.1 nM). For comparison, the dihydropyrazine antifolate, WR99210, gave Ki values of 0.9, 3.2, 0.8 and 0.9 nM, respectively. Ki values were also measured against recombinant human DHFR, as were their activities against the growth of Plasmodium falciparum cultures bearing the double mutations (FCB and K1 strains) and quadruple mutation (V1/S) and the wild type (3D7). The meta-analogs were highly active against all of these, with the meta-bromo again being the strongest, having an IC50 of 37 nM against V1/S, compared to > 5000 nM for pyrimethamine itself and 1.1 nM for WR99210.
Topics: Animals; Antimalarials; Drug Resistance; Folic Acid Antagonists; Humans; Models, Molecular; Molecular Structure; Plasmodium falciparum; Point Mutation; Pyrimethamine; Tetrahydrofolate Dehydrogenase
PubMed: 12929634
DOI: 10.1039/b211636g -
Transactions of the Royal Society of... 1991
Topics: Adult; Animals; Drug Combinations; Humans; Malaria, Falciparum; Pyrimethamine; Sulfadoxine
PubMed: 1755076
DOI: 10.1016/0035-9203(91)90261-v -
Lancet (London, England) Jul 1973
Topics: Half-Life; Humans; Leucovorin; Leukemia; Meningitis; Pyrimethamine; Time Factors
PubMed: 4124093
DOI: 10.1016/s0140-6736(73)93118-8 -
American Journal of Clinical Pathology Jul 1995Pyrimethamine is an antiparasitic agent currently used for therapy of central nervous system toxoplasmosis, a disease seen with increasing frequency in association with... (Comparative Study)
Comparative Study
Pyrimethamine is an antiparasitic agent currently used for therapy of central nervous system toxoplasmosis, a disease seen with increasing frequency in association with the AIDS epidemic. Monitoring of pyrimethamine levels may be particularly important because patients may be treated with high doses of the drug for extended periods of time. The authors have developed and validated both a new enzyme inhibition assay that can be run on an automated analyzer and an improved high performance liquid chromatography (HPLC) method. The calibration range of both methods is 100 to 3,000 micrograms/L. Both demonstrate good linearity, specificity, and precision, and correlate well with one another (r = 0.99). The CVs of the enzyme inhibition assay were < or = 8.6% and those of the HPLC method were < or = 5.4%. No interference was noted for a variety of drugs likely to be used concomitantly with or in lieu of pyrimethamine with the exception of a minor interference from trimethoprim in the enzyme inhibition assay. The major advantage of the enzyme inhibition assay is its ease of automation. The major advantages of the HPLC assay are its precision and relative simplicity. These methods should facilitate therapeutic monitoring of pyrimethamine.
Topics: Calibration; Chromatography, High Pressure Liquid; Clinical Enzyme Tests; Drug Monitoring; Enzyme Inhibitors; Folic Acid Antagonists; Humans; Linear Models; Pyrimethamine; Toxoplasmosis, Cerebral
PubMed: 7611189
DOI: 10.1093/ajcp/104.1.82 -
The Journal of Infectious Diseases Mar 1988
Topics: Acquired Immunodeficiency Syndrome; Acute Disease; Encephalitis; Humans; Pyrimethamine; Toxoplasmosis
PubMed: 3343528
DOI: 10.1093/infdis/157.3.580 -
The American Journal of Tropical... Sep 1977The experiments described in this report have dealt with the dimensions of therapeutic potentiation achieved when combinations of pyrimethamine and sulfadiazine were...
The experiments described in this report have dealt with the dimensions of therapeutic potentiation achieved when combinations of pyrimethamine and sulfadiazine were administered to rhesus monkeys infected with a drug-susceptible strain of Plasmodium cynomolgi or its pyrimethamine-resistant variant and to owl monkeys infected with strains of P. falciparum and P. vivax of varying degrees of resistance to this pyrimidine. These evaluations showed: 1) that when delivered in combination, the activities of both pyrimethamine and sulfadiazine against infections with any of the above strains were enhanced significantly; 2) that in infections with the Ro and Ro/PM strains of P. cynomolgi and the Vietnam Palo Alto strain of P. vivax, concomitant delivery of the two agents resulted in a 32-fold increase in the activity of pyrimethamine and a 50- to 100-fold increase in the activity of sulfadizine; 3) that as a result of this synergism, infections with the pyrimethamine resistant Ro/PM and Palo Alto strains could be cured with a fraction of the maximum tolerated dose of this drug; 4) that in marked contrast to the above result, infections with the Malayan Camp and Vietnam Smith strains of P. falciparum could not be cured regularly by combination regimens which included the maximally tolerated dose of pyrimethamine. This poor response has been attributed to the high levels of pyrimethamine-resistance possessed by these strains. It is believed that the comparatively small but not insignificant incidences of treatment failures associated with delivery of pyrimethamine-sulfonamide combinations to both patients and human volunteers infected with multidrug-resistant strains of P. falciparum rest on a similar basis.
Topics: Animals; Drug Resistance, Microbial; Drug Synergism; Drug Therapy, Combination; Haplorhini; Macaca mulatta; Malaria; Plasmodium; Plasmodium falciparum; Plasmodium vivax; Pyrimethamine; Sulfadiazine
PubMed: 410317
DOI: 10.4269/ajtmh.1977.26.837