R X Neurite Length, M (ng/ml) 1 Me (artemisinin) O NA 1.0 15 (CH2)3CH3 H,H 50 u 10–6 0.017 (CH2)3CH3 O 33 u 10–6 1.0 16 (CH2)3C6H5 H,H 16 u 10–6 0.019 (51 nM) (CH2)3C6H5 O 47 u 10–6 0.96 17 (CH2)3C6H4-p-Cl H,H 5 u 10–6 0.020 (CH2)3C6H4-p-Cl O 70 u 10–6 1.26 18 (CH2)3C6H4-p-F H,H 12 u 10–6 0.48 (CH2)3C6H4-p-F O 25 u 10–6 2.86 19 (CH2)3C6H4-p-OMe H,H 19 u 10–6 0.65 (1.6 µM) (CH2)3C6H4-p-OMe O 49.9 u 10–6 3.25 20 (CH2)3C6H3(3,4)-Cl2 H,H 21.3 u 10–6 2.51 (CH2)3C6H3(3,4)-Cl2 O 7.79 u 10–6 0.79 a IC
50 in Neuro 2a cell line, McLean and Edwards (University of Liverpool). b Standard in vitro antimalarial screening data, D-6 clone of P. falciparum.
FIGURE 9.12
Semisynthesis of potent, nontoxic antimalarials from artemisinic acid. (a) n-BuLi, TMSCl; RMgBr, 10 mole % CuI, THF; workup; (b) hv, oxygen, CH2Cl2, sens.; then H+; (c) NaBH4, BF3•OEt2, THF; (d) NaBH4, MeOH, THF, or DIBAH, ether, –78°C; (e) Et3SiH, BF3•OEt2, CH2Cl2.
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of artemisinic acid 2 followed by in situ addition of a Grignard reagent in the presence of cat- alytic copper (I) led to production of the desired intermediate acids 21 in excellent yield (HPLC).29 In the case of the aryl-containing side chains, only the desired diastereomer 22
was produced. After singlet oxygenation, the oxygenated material was then acidified in the same pot reaction, as others have demonstrated, to give the lactones 23. For the reduction of the lactone carbonyl, depending on the substituents, the carbonyl could be removed in a one-pot reaction (c) to give the 10-deoxoartemisinin analogs 15 to 20, or by a two step, more readily controlled procedure involving anhydrous conditions and lower temperatures. Thus, the lactol analogs 24, easily obtained by reduction of the corresponding lactones, could be reductively deoxygenated by treatment with triethylsilane in the presence of a Lewis acid such as boron trifluoride etherate.
Several accomplishments have been made in these studies:
1. A 3D-QSAR model for artemisinin pharmacophore has been developed. 2. The Meshnick hypothesis has been supported.
3. No quantitative structure–toxicity relationship could be determined, but the MOA and the mechanism of toxicity (MOT) were not identical and it, therefore, was possible to develop high-potency, low-toxicity antimalarials.
4. Oral activity was achievable by specific modifications.
5. A cost-effective approach to these analogs was developed. Future directions will focus on further optimization of the synthetic route and the search for more potent analogs.
ACKNOWLEDGMENTS: The many students who have contributed to this work are to be recognized: John Woolfrey, Jeff Vroman, Jason Bonk, Chad Haraldson, Rohit Duvadie, Maria Alvim- Gaston, Sanjiv Mehrotra, Fenglan Gao, Ranjan and Anita Srivastasva, Jayendra Bhonsle, and Baogen Wu. This work was financially supported at various times by the DoD (Walter Reed Army Institute of Research), NIH (Allergy and Infectious Diseases), and WHO (Special Programme for Tropical Diseases Research).
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