Structure–Activity Relationships of the Antimalarial Agent Artemisinin 10. Synthesis and Antimalarial Activity of Enantiomers of rac-5β-Hydroxy-d-Secoartemisinin and Analogs: Implications Regarding the Mechanism of Action
Abstract
:1. Introduction
2. Results
2.1. Chemistry
2.1.1. Ester Derivatives
2.1.2. Ketone Derivative
2.1.3. Exomethylene Derivative
2.1.4. Separation of the Two Enantiomers 2a and 2b
Mosher Ester Analysis
2.1.5. Rearrangement Chemistry
2.2. Antimalarial Activity
2.3. X-ray Crystallography
3. Discussion
4. Materials and Methods
4.1. Chemistry
4.1.1. General Information
4.1.2. Preparation and Characterization of Synthesized Compounds
Ethyl 2-(2-methyl-1,3-dioxolan-2-yl) acetate (3)
2-(2-Methyl-1,3-dioxolan-2-yl)acetaldehyde (4)
2-(1-Hydroxy-2-(2-methyl-1,3-dioxolan-2-yl)ethyl)cyclohexan-1-one (5)
2-(1-((Tert-butyldimethylsilyl)oxy)-2-(2-methyl-1,3-dioxolan-2-yl)ethyl)cyclohexan-1-one (6)
Tert-butyldimethyl(2-(2-methyl-1,3-dioxolan-2-yl)-1-(1-oxaspiro[2.5]octan-4-yl)ethoxy)silane (7)
(2-(1-((tert-butyldimethylsilyl)oxy)-2-(2-methyl-1,3-dioxolan-2-yl)ethyl)-1hydroperoxycyclohexyl)methanol (8)
3-Methyloctahydro-1h-3,9a-epidioxybenzo[c]oxepin-5-ol, (rac-2)
3-Methyloctahydro-1H-3,9a-epidioxybenzo[c]oxepin-5-yl pentanoate (9)
3-Methyloctahydro-1H-3,9a-epidioxybenzo[c]oxepin-5-yl benzoate (10)
3-Methyloctahydro-1H-3,9a-epidioxybenzo[c]oxepin-5-yl 4-fluorobenzoate (11)
3-Methyloctahydro-1H-3,9a-epidioxybenzo[c]oxepin-5-yl 4-methoxybenzoate (12)
3-Methyloctahydro-1H-3,9a-epidioxybenzo[c]oxepin-5-yl cinnamate (13)
3-Methyloctahydro-1H-3,9a-epidioxybenzo[c]oxepin-5-yl 4-chlorobenzoate (14)
3-Methylhexahydro-1H-3,9a-epidioxybenzo[c]oxepin-5(5aH)-one (15)
(3R,5R,5aR,9aS)-3-methyloctahydro-1H-3,9a-epidioxybenzo[c]oxepin-5-yl(R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (19a) and (3S,5S,5aS,9aR)-3-methyloctahydro-1H-3,9a-epidioxybenzo[c]oxepin-5-yl(R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (19b)
(3R,5R,5aR,9aS)-3-methyloctahydro-1H-3,9a-epidioxybenzo[c]oxepin-5-ol (2a)
(3S,5S,5aS,9aR)-3-methyloctahydro-1H-3,9a-epidioxybenzo[c]oxepin-5-ol (2b)
(3-Hydroxyhexahydrobenzofuran-7a(2H)-yl)methyl acetate (22)
(2-Acetyl-1-hydroxycyclohexyl)methyl acetate (29)
4.2. Single Crystal X-ray Diffraction Experiment
Compound rac-2
4.3. Antimalarial Activity Assay
4.3.1. Reagents and Materials
4.3.2. In Vitro Antimalarial Assay
4.3.3. In Vitro Cytotoxicity Assay
Neutral Red Assay
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Compound | R | % Yield | Compound | R | % Yield |
---|---|---|---|---|---|
9 | CH3(CH2)3CO | a 11 | 12 | p-MeOC6H4CO | d 68 |
10 | C6H5CO | b 42,c 70, d 74 | 13 | C6H5(CH)2CO | d 36 |
11 | p-FC6H4CO | d 70 | 14 | p-ClC6H4CO | d 49 |
Compound | Method | % Yield |
---|---|---|
15 | a | 40 |
b | 50 | |
c | 55 |
Structure | R | IC50 (ng/mL) | Relative Activity a | |||
---|---|---|---|---|---|---|
D-6 | W-2 | D-6 | W-2 | anal. (C, H) | ||
1 | (Artemisinin) | 7.05 | 5.08 | 100 | 100 | |
rac-2 | H | 1716.22 | 1778.35 | 0.6 | 0.43 | C11H18O4 |
2a | H | 1255.56 | 884.89 | 0.43 | 0.44 | C11H18O4 |
2b | H | NA b | NA b | C11H18O4 | ||
9 | CH3(CH2)3CO | 149.19 | 208.86 | 5.00 | 2.60 | C16H26O5 |
10 | C6H5CO | 152.81 | 120.97 | 10.40 | 9.50 | C18H22O5 |
11 | p-FC6H4CO | 80.72 | 97.54 | 20.81 | 12.41 | C18H21FO5 |
12 | p-MeOC6H4CO | 114.96 | 167.22 | 15.13 | 7.50 | C19H24O6 |
13 | C6H5(CH)2CO | 130.87 | 148.09 | 13.14 | 8.37 | C20H24O5 |
14 | p-ClC6H4CO | 144.65 | 119.95 | 12.18 | 10.58 | C18H21ClO5 |
15 | Ketone | 31.83 | 23.34 | 33.30 | 32.72 | C11H16O4 |
16 | Exomethylene | 344.84 | 346.31 | 3.05 | 2.18 | C12H18O3 |
19a | C6H5C(OCH3)(CF3)CO | 150.64 | 357.24 | 7.13 | 2.17 | C21H25F3O6 |
19b | C6H5C(OCH3)(CF3)CO | 2169.31 | 2255.40 | 0.50 | 0.34 | C21H25F3O6 |
22 | Scheme 5 | NA b | NA b | C12H20O3 | ||
29 | Scheme 6 | NA b | NA b | C11H18O4 |
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Jahan, M.; Leon, F.; Fronczek, F.R.; Elokely, K.M.; Rimoldi, J.; Khan, S.I.; Avery, M.A. Structure–Activity Relationships of the Antimalarial Agent Artemisinin 10. Synthesis and Antimalarial Activity of Enantiomers of rac-5β-Hydroxy-d-Secoartemisinin and Analogs: Implications Regarding the Mechanism of Action. Molecules 2021, 26, 4163. https://doi.org/10.3390/molecules26144163
Jahan M, Leon F, Fronczek FR, Elokely KM, Rimoldi J, Khan SI, Avery MA. Structure–Activity Relationships of the Antimalarial Agent Artemisinin 10. Synthesis and Antimalarial Activity of Enantiomers of rac-5β-Hydroxy-d-Secoartemisinin and Analogs: Implications Regarding the Mechanism of Action. Molecules. 2021; 26(14):4163. https://doi.org/10.3390/molecules26144163
Chicago/Turabian StyleJahan, Mohamed, Francisco Leon, Frank R. Fronczek, Khaled M. Elokely, John Rimoldi, Shabana I. Khan, and Mitchell A. Avery. 2021. "Structure–Activity Relationships of the Antimalarial Agent Artemisinin 10. Synthesis and Antimalarial Activity of Enantiomers of rac-5β-Hydroxy-d-Secoartemisinin and Analogs: Implications Regarding the Mechanism of Action" Molecules 26, no. 14: 4163. https://doi.org/10.3390/molecules26144163