1. NMR Shielding and Antimalarial Drugs Angel C. de Dios Georgetown University 13

2. Chloroquine Resistance, 2002 http://www.cdc.gov/ travel/diseases/maps

3. Antimalarial Drugs Pagola, S.; Stephens, P. W.; Bohle, D. S.; Kosar, A. D.; Madsen, S. K. Nature, 404, 307 (2000) Leed, A.; DuBay, K.; Ursos, L. M. B.; Sears, D. N.; de Dios, A. C.; Roepe, P. D. Biochemistry, 41, 10245 (2002) Red Blood Cell Hemoglobin Digestion Heme Hemozoin

4. Casabianca, L. B.; de Dios, A. C. J. Phys. Chem. A, 108 (40), 8505 -8513, (2004) Chloroquine Amodiaquine Quinine

5. Quinine carbon 8 J. Phys. Chem. A, 108 (40), 8505 -8513, 2004

6. Quinine observed chemical shift Carbon310 mM9.5 mM dd mm 2148.03148.27147.81148.30 3120.48120.60120.38120.63 4147.11146.87147.37146.87 5102.12102.25102.00102.29 6160.23160.32160.17160.38 7123.87123.53124.18123.55 8131.51131.83131.24131.87 9127.42127.52127.34127.57 10144.62144.87144.43144.93 Casabianca, L. B.; de Dios, A. C. J. Phys. Chem. A, 108 (40), 8505 -8513, (2004)

7. Casabianca, L. B.; de Dios, A. C. Magn. Reson. Chem., 44, 276-282 (2006) Interactions between drug molecules

8. Leed, A.; DuBay, K.; Ursos, L. M. B.; Sears, D. N.; de Dios, A. C.; Roepe, P. D. Biochemistry, 41, 10245 (2002) de Dios, A.C.; Casabianca, L.B.; Kosar, A.; Roepe, P.D. Inorg. Chem., 43, 8078-8084, (2004) Solution structures of drug-heme complex

9. Biochemistry, 41 (32), 10245 -10255, (2002)

10. Tumambac, G. E.; Wolf, C. J. Org. Chem. 69, 2048 (2004) Tumambac, G. E.; Wolf, C. J. Org. Chem. 70, 2930 (2005) Experimental Chemical Shift* Carbon III Difference 2165.5152.2-13.3 3119.8119.4-0.4 4147.9137.5-10.4 5125.3126.41.1 6128.4127.8-0.6 7125.1129.84.7 8129.4120.8-8.6 9126.4128.92.5 10146.7140.9-5.8 1,8-bis(2-isopropyl-4-quinolyl)naphthalene Chemical shifts and  electron density Search for a Quantitative Structure-Activity Relationship (QSAR)

11. Ramsey’s Equations for Calculating Chemical Shielding Ramsey, N. F. Phys. Rev. 1950, 78, 699-703. de Dios, A.C. Prog. NMR Spectrosc. 1996, 29, 229-278.

12. Shielding Tensors in Aromatic Rings

13. Strub, H.; Beeler, A. J.; Grant, D. M.; Michl, J.; Cutts, P. W.; Zilm, K. W. J. Am. Chem. Soc., 105, 3333, (1983)

14. Calculated Shielding Differences Casabianca, L.B.; Faller, C.M. Faller; de Dios, A.C. J. Phys. Chem. A, 110, 234-240, (2006)

15. Quinine

16. Maps of  11 “  -electron density” B A

17. Heme

18. Heme-Drug

19. Heme-Drug Solution Structures Leed, A.; DuBay, K.; Ursos, L. M. B.; Sears, D. N.; de Dios, A. C.; Roepe, P. D. Biochemistry 41, 10245 (2002) de Dios, A. C.; Casabianca, L. B.; Kosar, A. D.; Roepe, P. D. Inorg. Chem. 43, 8078 (2004) Electron-RichElectron-Poor

20. Substituted Aminoquinolines Log K values from Kaschula, C. H.; Egan, T. J.; Hunter, R.; Basilico, N.; Parapini, S.; Taramelli, D.; Pasini, E.; Monti, D. J. Med. Chem. 45, 3531 (2002)

21. de Dios, A.C.; Tycko, R.; Ursos, L.M.B.; Roepe, P.D. J. Phys. Chem. A, 107 (30), 5821 -5825, (2003) Solid State NMR Studies

22. de Dios, A.C.; Tycko, R.; Ursos, L.M.B.; Roepe, P.D. J. Phys. Chem. A, 107 (30), 5821 -5825, (2003)

23. de Dios, A.C.; Tycko, R.; Ursos, L.M.B.; Roepe, P.D. J. Phys. Chem. A, 107 (30), 5821 -5825, (2003)

24. de Dios, A.C.; Tycko, R.; Ursos, L.M.B.; Roepe, P.D. J. Phys. Chem. A, 107 (30), 5821 -5825, (2003)

25. de Dios, A.C.; Tycko, R.; Ursos, L.M.B.; Roepe, P.D. J. Phys. Chem. A, 107 (30), 5821 -5825, (2003)

26. Acknowledgements National Institutes of Health National Institutes of Health Georgetown University Georgetown University Luce Foundation Luce Foundation ARCS Foundation ARCS Foundation Prof. Paul Roepe, PhD Leah Casabianca Lyann Ursos, PhD Alison Leed Kateri DuBay Devin Sears, PhD Caitlyn Faller Prof. Christian Wolf, PhD NIH (Robert Tycko’s group)