synthesis and biological acvies of mefloquine analogsccc.chem.pitt.edu/wipf/topics/mo.pdf ·...
TRANSCRIPT
Synthesis and Biological Ac2vi2es of Mefloquine Analogs
Ting2ng Mo Research Topic Seminar
April 25 2009
Tingting Mo @ Wipf Group Page 1 of 9 4/27/2009
Outline
1. Background • An2malarial drug Mefloquine • Our Analogs 2. Efforts towards synthesis of our analogs • Asymmetric route • Racemic synthesis through WiJg rearrangement 3. Synthesis of our analogs and their biological ac2vi2es 4. Effort towards synthesis of a new analog 5. Conclusions
N
HN
HO
CF3
1
2
3
45
6
7
8
Tingting Mo @ Wipf Group Page 2 of 9 4/27/2009
Development of Mefloquine
Ridley, R. G. Nature. 2002, 415, 686
Tingting Mo @ Wipf Group Page 3 of 9 4/27/2009
Mechanism of Mefluoquine
Ridley, R. G. Nature. 2002, 415, 686
Tingting Mo @ Wipf Group Page 4 of 9 4/27/2009
Molecular Electronic Proper2es • H bond: alipha2c nitrogen to hydroxyl hydrogen
• Quinoline ring plane is suscep2ble to nucleophilic aYack (posi2ve poten2al)
• Electron withdrawing groups should be placed at both the 2 and 8 posi2ons
• Electronic features rather than steric factors control the an2malarial potency
N
R3
R2
R1
NH
HO
compd activity (MfI) R1 R2 R3
1a
1d
1f
1g
1c
1e
1b
1.00 (dl-erythro) CF3 CF3 H
CF3 CF3
CF3
0.81 (dl-threo)
0.81 CF3
H
OCH3
0.17 CF3 Cl Cl
0.03 CF3 Cl H
NC
NC
CF3 Me H
CF3 F H
MfI: molar ratio of the CD50 of mefloquine to the CD50 of the test compound
NC: noncurative dose
BhaYacharjee, A. K.; Karle, J. M. J. Med. Chem. 1996, 39, 4622
Tingting Mo @ Wipf Group Page 5 of 9 4/27/2009
Different Ac2vi2es Between Enan2omers
N
NH
HO
CF3
CF3
(+)-enantiomer
(+)-(11R, 2'S)
N
NH
HO
CF3
CF3
(-)-enantiomer
(-)-(11S, 2'R)
Adenosine A1 Adenosine A2 Adenosine A3
Source rat brain human human
Results (Ki)
(+)enantiomer
(-)enantiomer
6.4 µM
202 nM
1.8 µM 7.7 µM
6.8 µM4.4 nM
D-2 clone W-6 clone
IC50 (nM) IC50 (nM)compound
(+)enantiomer
(-)enantiomer
23.4
42.3
4.09
6.61
ratio ratio
1.81 1.69
(‐)‐enan2omer binds to central nervous system adenosine receptors, it’s believed to result in the neuropsychiatric symptoms
(+)‐enan2omer is more potent than the (‐)‐enan2omer by a factor of 1.69‐1.81
Shepherd, J. Interna7onal patent WO98/39003. 1998 Karle, J. M.; Olmeda, R.; Gerena, L.; Milhoust, W. K. Exp. Parasitol. 1993, 76, 345
Tingting Mo @ Wipf Group Page 6 of 9 4/27/2009
Side Effects of Mefloquine • Severe central nervous system (CNS) events requiring hospitaliza2on occur in 1:10,000 pa2ents
• Milder CNS events occur in up to 25% of pa2ents • Dose effect: the higher incidence of adverse events observed when the drug is used at the higher doses needed for treatment
• The drug crosses the blood‐brain barrier and accumulates as much as 30‐fold in the CNS than in the plasma
Phillips‐Howard, P. A.; Kuile, F. O. Drug Saf. 1995, a370 Pham, Y. T.; Nosten, F.; FarinoJ, R.; White, N. J.; Gimenez. F. Int. J. Clin. Pharmacol. Ther. 37:58
Tingting Mo @ Wipf Group Page 7 of 9 4/27/2009
Ameliora2on of Neurotoxicity
• Administra2on of neuroprotec2ve drugs
• Reformula2on of mefloquine as a pure isomer
• Reengineering of the mefloquine molecule to yield deriva2ves that are less neurotoxic but retain their an2malarial ac2vity
Speich, R.; Haller, A. N. Engl. J. Med, 1994, 331, 57 Shepherd, J. Interna7onal patent WO98/39003. 1998
Tingting Mo @ Wipf Group Page 8 of 9 4/27/2009
Acknowledgement
• Professor Peter Wipf • Akira Nakamura, Chenbo Wang and other group members
• Damodaran Krishnan
• John B. Williams
• Steven Geib • Walter Reed Army Ins2tute of Research
Tingting Mo @ Wipf Group Page 9 of 9 4/27/2009