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4. Buckwold, V. E.; Wei, J.; Wenzel-Mathers, M.; Russell, J.
solubility of 1 was below the limits of detection of the neph-
elometry assay (i.e., <15 µg/mL). However, compounds bearing
basic amine functionalities have improved solubilities relative
to 1, particularly at acidic pH values, but also at pH 7.4.
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Conclusion
We have extended our previously published work on host-
directed inhibitors of myxovirus replication by preparing
analogues that positively address the poor aqueous solubility of
1 (JMN3-003) while simultaneously improving its potency. The
compounds presented here furnish EC50 values as low as 1 nM
with aqueous solubilities ranging from 15–25 µg/mL at pH 7.4
to >300 µg/mL at pH 3.0. Additionally, we have developed two
complementary methods for the synthesis of each of the enan-
tiomers of the compounds discussed and have unequivocally
demonstrated that the (S)-enantiomer is more active in this
series than the (R)-enantiomer. Further work from our labora-
tories regarding the in vivo efficacy of these compounds is
underway.
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8. Yoon, J.-J.; Krumm, S. A.; Ndungu, J. M.; Hoffman, V.; Bankamp, B.;
Rota, P. A.; Sun, A.; Snyder, J. P.; Plemper, R. K.
Antimicrob. Agents Chemother. 2009, 53, 3860–3870.
9. Sun, A.; Yoon, J. J.; Yin, Y.; Prussia, A.; Yang, Y.; Min, J.;
Plemper, R. K.; Snyder, J. P. J. Med. Chem. 2008, 51, 3731–3741.
10.White, L. K.; Yoon, J.-J.; Lee, J. K.; Sun, A.; Du, Y.; Fu, H.;
Snyder, J. P.; Plemper, R. K. Antimicrob. Agents Chemother. 2007, 51,
11.Sun, A.; Chandrakumar, N.; Yoon, J.-J.; Plemper, R. K.; Snyder, J. P.
Bioorg. Med. Chem. Lett. 2007, 17, 5199–5203.
12.Krumm, S. A.; Ndungu, J. M.; Yoon, J.-J.; Dochow, M.; Sun, A.;
Natchus, M.; Snyder, J. P.; Plemper, R. K. PLoS One 2011, 6, e20069.
Supporting Information
13.Yoon, J.-J.; Chawla, D.; Paal, T.; Ndungu, M.; Du, Y.; Kurtkaya, S.;
Sun, A.; Snyder, J. P.; Plemper, R. K. J. Biomol. Screening 2008, 13,
Contains detailed synthetic procedures and characterization
data for molecules described herein, a more detailed
description of the laser nephelometry assay, and data tables
for the crystal structures of (S)-1 and (R)-1.
14.Sun, A.; Ndungu, J. M.; Krumm, S. A.; Yoon, J.-J.; Thepatchri, P.;
Natchus, M.; Plemper, R. K.; Snyder, J. P. ACS Med. Chem. Lett.
Supporting Information File 1
15.Pharmacokinetics Study of JMN3-003. Unpublished results.
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Detailed synthetic procedures and characterization data.
17.Nair, V. P.; Mustafa, S. M.; Mohler, M. L.; Yang, J.; Kirkovsky, L. I.;
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Acknowledgments
This work was supported, in part, by Public Health Service
Grants AI071002 and AI085328 (to R. K. P.) from the NIH/
NIAID and by Public Health Service Grant HG003918-02 (to
J.P.S.) from the NIH. We also thank Deborah Culver for solu-
bility testing and Dr. John Bacsa for helpful discussions of
crystal structures.
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