Evaluation of potent inhibitors of dihydrofolate reductase in a culture model for growth of Pneumocystis carinii.

Antimicrobial Agents and Chemotherapy
M BartlettS F Queener

Abstract

Many antifolates are known to inhibit dihydrofolate reductase from murine Pneumocystis carinii, with 50% inhibitory concentrations (IC50s) ranging from 10(-4) to 10(-11) M. The relationship of the potency against isolated enzyme to the potency against intact murine P. carinii cells was explored with 17 compounds that had proven selectivity for or potency against P. carinii dihydrofolate reductase. Pyrimethamine and one analog were inhibitory to P. carinii in culture at concentrations two to seven times the IC50s for the enzyme, suggesting that the compounds may enter P. carinii cells in culture. Methotrexate was a potent inhibitor of P. carinii dihydrofolate reductase, but the concentrations effective in culture were more than 1,000-fold higher than IC50s for the enzyme, since P. carinii lacks an uptake system for methotrexate. Analogs of methotrexate in which chlorine, bromine, or iodine was added to the phenyl ring had improved potency against the isolated enzyme but were markedly less effective in culture; polyglutamation also lowered the activity in culture but improved activity against the enzyme. Substitution of a naphthyl group for the phenyl group of methotrexate produced a compound with improved activity against the en...Continue Reading

References

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Citations

Mar 6, 2008·PLoS Neglected Tropical Diseases·Ernest J MuiRima McLeod
Apr 25, 2012·Journal of Molecular Modeling·Osvaldo A Santos-FilhoNubia Boechat
Sep 21, 2016·Journal of Molecular Graphics & Modelling·Sedat KarabulutJerzy Leszczynski
Sep 21, 2001·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·J A Fishman
May 21, 1998·Antimicrobial Agents and Chemotherapy·J A Fishman
Jun 13, 1998·Antimicrobial Agents and Chemotherapy·J A Fishman
May 26, 2018·Future Microbiology·Ayla Debraekeleer, Han Remaut
Jan 1, 1997·Antimicrobial Agents and Chemotherapy·M J O'GaraS F Queener

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