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ACS Medicinal Chemistry Letters
proval to the final version of the manuscript.
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ABBREVIATIONS
DHFR, dihydrofolate reductase; TS, thymidylate synthase; PYR,
pyrimethamine; DHPS, dihydropteroate synthase; DHF, dihydro-
folate; MOE, molecular operating environment; 3D-RISM, three-
dimensional reference interaction site model; SAR, structure-
activity relationship; ND, not determined
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a
Physiochemical properties were calculated using chemical de-
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excellent predicted physiochemical properties, including fa-
vorable size, solubility and permeability (Table 2). Ongoing
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ASSOCIATED CONTENT
Supporting Information
Parasitol 2015, 31 (12), 610-2.
(11) Sullivan, W. J., Jr.; Jeffers, V., Mechanisms of Toxoplasma
gondii persistence and latency. FEMS Microbiol Rev 2012, 36 (3),
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
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17-33.
Experimental procedures for molecular modeling, crystal-
lography, biological assays and chemical synthesis of all
compounds (PDF)
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Accession Codes
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AUTHOR INFORMATION
Corresponding Author
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17) McLeod, R.; Khan, A. R.; Noble, G. A.; Latkany, P.; Jalbr-
*
zikowski, J.; Boyer, K.; Toxoplasmosis Study, G., Severe sulfadiazine
hypersensitivity in a child with reactivated congenital toxoplasmic
chorioretinitis. Pediatr Infect Dis J 2006, 25 (3), 270-2.
Present Address
€
Atoms2Applications, Jersey City, NJ 07306
(
18) Allegra, C. J.; Kovacs, J. A.; Drake, J. C.; Swan, J. C.; Chabner,
B. A.; Masur, H., Potent in vitro and in vivo antitoxoplasma activity
of the lipid-soluble antifolate trimetrexate. J Clin Invest 1987, 79 (2),
478-82.
(19) Lamb, K. M.; N, G. D.; Wright, D. L.; Anderson, A. C., Eluci-
dating features that drive the design of selective antifolates using
crystal structures of human dihydrofolate reductase. Biochemistry
2013, 52 (41), 7318-26.
Author Contributions
M.E.W. designed and performed the computational experiments.
M.E.W., S.B.T. and G.A. designed the in vitro pharmacology
experiments. G.P. performed and analyzed the in vitro pharma-
cology experiments. S.B.T., M.E.W., Z.J., G.Y. and Y.Y. oversaw
and designed the synthetic chemistry. Z.J., G.Y. and Y.Y. per-
formed the synthetic chemistry. Y.L., H.L. and Z.C. performed all
crystallographic experiments. S.B.T. and M.E.W. wrote the man-
uscript with input from all authors. All authors have given ap-
(
20) Pelphrey, P. M.; Popov, V. M.; Joska, T. M.; Beierlein, J. M.;
Bolstad, E. S.; Fillingham, Y. A.; Wright, D. L.; Anderson, A. C.,
Highly efficient ligands for dihydrofolate reductase from Cryptospor-
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