Hybrides of Alkaloid Lappaconitine with Pyrimidine Motif on the Anthranilic Acid Moiety: Design, Synthesis, and Investigation of Antinociceptive Potency
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemical Synthesis
2.2. Biological Study
2.2.1. Analgesic Activity
2.2.2. Toxicity and Cytotoxicity Studies
2.3. Molecular Modeling of a Possible Mechanism of Antagonistic Effect of Lappaconitine 1 and New Lappaconitine Derivatives 10, 12, 15, on the Voltage-Gated Sodium Channel 1.7
3. Experimental Section
3.1. General Information
3.2. Syntheses and Spectral Data
3.2.1. Carbonylative Sonogashira Reaction
3.2.2. Procedures for Cross-Coupling Reactions
- (a)
- A mixture of alkynyl ketone 5 or 6 (0.3 mmol), 4-nitrobenzamidine hydrochloride 11 (72.5 mg, 0.36 mmol) and Et3N (90.9 mg, 0.9 mmol) was reflux under stirring in i-PrOH (8 mL) 8 h (TLC). After cooling (about 10 h), the precipitate was filtered, washed with CHCl3 (10 mL), the combined organic layer was concentrated under reduced pressure, and the residue was subjected to column chromatography (chloroform-EtOH). Fraction with Rf 0.4 (chloroform-EtOH, 20:1), was evaporated and dried in vacuo to give compounds 12, 13 as a yellow powders.
- (b)
- One-pot cross-coupling/cyclocondensation. To a stirred mixture of Pd(PPh3)2Cl2 (4.3 mg, 0.005 mmol), PPh3 (2.1 mg, 0.007 mmol), CuI (2.5 mg, 0.01 mmol) in benzene (5 mL) under argon flow was added Et3N (206 mg, 0.27 mL, 2 mmol) followed by freshly prepared 4-bromobenzoyl chloride 14 (132 mg, 0.6 mmol) in benzene (2 mL). The 5′-Ethynyllappaconitine 2 (304 mg, 0.5 mmol) in benzene (5 mL) was added dropwise during one hour. The reaction mixture was heated to 65 °C under stirring for 7 h (TLC-control). After removing the solvent in vacuo under argon, the crude material was dissolved in acetonitrile (7 mL), and acetamidine hydrochloride 9 (67 mg, 0.7 mmol) and anhydrous Na2CO3 (170 mg, 1.6 mmol), or guanidine hydrocarbonate 10 (41 mg, 0.7 mmol) and Et3N (162 mg, 1.6 mmol) were added. The reaction mixture was stirred under reflux for 8 h. After cooling (about 8 h) the precipitate was filtered, washed with CHCl3 (10 mL), the combined organic layer was washed with water (2 × 5 mL), dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography (chloroform-EtOH). The fraction with Rf 0.4 (chloroform-EtOH, 20:1), was collected evaporated and dried in vacuo to give compounds 15 or 16 as a yellow powders.
- (c)
- One-pot carbonylative cross-coupling/cyclocondensation. To solution of Et3N (101 mg, 1 mmol) in CH3CN (7 mL) PdCl2 (2 mg, 0.011 mmol), and Ad2PBn·HBr (7 mg, 0.017 mmol) were successively added under a stream of argon with stirring. The mixture was heated to 65 °C (bath) and Mo(CO)6 (158 mg, 0.59 mmol), phenylacetylene 18 (60 mg, 0.59 mmol) and 5′-iodolappaconitine 17 (236 mg, 0.33 mmol) were added. The reaction mixture was heated until 2 h at 65 °C, treated with amidinium salt 9 (0.46 mmol) and anhydrous Na2CO3 (106 mg, 1 mmol), or guanidine carbonate 10 (0.46 mmol) and Et3N (101 mg, 1 mmol) and stirred under reflux for 8 h. After completion based on TLC, the cooled mixture was filtered over Celite, the precipitate washed with CHCl3 (15 mL), the combined solvent was removed under reduced pressure, and the residue was subjected to column chromatography (chloroform-EtOH, 80:1). Fraction with Rf 0.4 (chloroform-EtOH, 20:1) was evaporated and dried in vacuo to give compounds 20, 21 as yellow powders.
3.2.3. 4β-{2′-Acetylamino-5′-[11′-(4-fluorophenyl)-9′-(4-nitrophenyl)-pyrimidine-7′-yl]benzoate}-1α,14α,16β-trimethoxy-20-ethylaconitane-8,9-diol (12)
3.2.4. 4β-{2′-Acetylamino-5′-[11′-(4-methoxyphenyl)-9′-(4-nitrophenyl)-pyrimidine-7′-yl]benzoate}-1α,14α,16β-trimethoxy-20-ethylaconitane-8,9-diol (13)
3.2.5. 4β-{2′-Acetylamino-5′-[11′-(4-bromophenyl)-9′-(methyl)pyrimidine-7′-yl]benzoate}-1α,14α,16β-trimethoxy-20-ethylaconitane-8,9-diol (15)
3.2.6. 4β-{2′-Acetylamino-5′-[9′-(amino)-11′-(4-bromophenyl)pyrimidine-7′-yl]benzoate}-1α,14α,16β-trimethoxy-20-ethylaconitane-8,9-diol (16)
3.2.7. 4β-{2′-Acetylamino-5′-[9′-(methyl)-11′-(phenyl)pyrimidine-7′-yl]benzoate}-1α,14α,16β-trimethoxy-20-ethylaconitane-8,9-diol (20)
3.2.8. 4β-{2′-Acetylamino-5′-[9′-(amino)-11′-(phenyl)pyrimidine-7′-yl]benzoate}-1α,14α,16β-trimethoxy-20-ethylaconitane-8,9-diol (21)
3.3. Biological Evaluation
3.3.1. Pharmacology
Animals
Analgesic Tests
3.4. Cell Culture and Determination of Cytotoxicity
3.5. Molecular Docking Study
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Compound | Dose (mg/kg) | Acetic Acid-Induced Writhing Test | Dose (mg/kg) | Acetic Acid-Induced Writhing Test | ||
---|---|---|---|---|---|---|
Control | Mean ± SD (MPE, %) a | Control | Mean ± SD (MPE, %) a | |||
9 | 25 | 11.5 ± 0.63 | 11.2 ± 1.25 | 5 | 12.0 ± 0.4 | 10.5 ± 0.67 |
10 | 25 | 11.5 ± 0.63 | 8.2 ± 0.86 | 5 | 12.0 ± 0.4 | 4.3 ± 1.21 * (63) |
12 | 25 | 11.5 ± 0.63 | 4.8 ± 1.2 * (60) | 5 | 12.0 ± 0.4 | 4.4 ± 0.9 * (64) |
13 | 25 | 11.5 ± 0.63 | 5.5 ± 1.4 * (54) | 5 | 12.0 ± 0.4 | 4.6 ± 0.5 * (61) |
15 | 25 | 11.5 ± 0.63 | 7.2 ± 0.98 * (37) | 5 | 12.0 ± 0.4 | 3.4 ± 1.28 * (70) |
16 | 25 | 11.5 ± 0.63 | 8.0 ± 1.61 | 5 | 12.0 ± 0.4 | 8.9 ± 1.08 |
20 | 25 | 11.5 ± 0.63 | 10.7 ± 0.28 | 5 | 12.0 ± 0.4 | 9.7 ± 0.8 |
21 | 25 | 11.5 ± 0.63 | 7.0 ± 1.69 * (39) | 5 | 12.0 ± 0.4 | 10.4 ± 0.84 |
1 | 25 | - | ND | 5 | 12.0 ± 0.4 | 5.7 ± 1.25 * (50) |
Diclofenac sodium | 10 | 11.5 ± 0.63 | 3.1 ± 0.7 * (74) | 10 | 11.5 ± 0.63 | 3.1 ± 0.7 * (74) |
Compound | Dose (mg/kg) | Acetic Acid-Induced Writhing Test (Oral Administration) | Dose (mg/kg) | Acetic Acid-Induced Writhing Test (Intraperitoneal) | ||
---|---|---|---|---|---|---|
Control | Mean ± SD (MPE, %) a | Control | Mean ± SD (MPE, %) a | |||
10 | 1 | 11.0 ± 0.87 | 6.6 ± 1.75 * (40) | 1 | 11.5 ± 0.63 | 7.4 ± 0.80 * (63) |
12 | 1 | 11.0 ± 0.87 | 9.5 ± 1.0 * (21) | 1 | 11.5 ± 0.63 | 9.0 ± 1.1 * (28) |
13 | 1 | 11.0 ± 0.87 | 8.3 ± 0.8 * (31) | 1 | 11.5 ± 0.63 | 8.5 ± 1.3 * (29) |
15 | 1 | 11.0 ± 0.87 | 3.6 ± 1.82 * (67) | 1 | 11.5 ± 0.63 | 9.0 ± 1.5 |
1 | 1 | 11.0 ± 0.87 | 9.1 ± 1.05 | 5 (for 15) | 11.5 ± 0.63 | 4.0 ± 0.89 * (64) |
Compound | Dose (mg/kg) | Hot Plate Test | Dose (mg/kg) | Hot Plate Test | ||
---|---|---|---|---|---|---|
Control | Mean ± SD (Protection, %) a | Control | Mean ± SD (Protection, %) a | |||
9 | 25 | 7.3 ± 0.71 | 8.9 ± 1.27 | 5 | 7.3 ± 0.71 | 8.6 ± 0.82 |
10 | 25 | 7.3 ± 0.71 | 11.2 ± 1.41 * (36) | 5 | 7.3 ± 0.71 | 11.7 ± 0.91 * (38) |
12 | 25 | 7.3 ± 0.71 | 10.3 ± 0.8 * (34) | 5 | 7.3 ± 0.71 | 10.3 ± 0.61 * (31) |
13 | 25 | 7.3 ± 0.71 | 10.1 ± 1.2 * (33) | 5 | 7.3 ± 0.71 | 10.0 ± 0.9 * (32) |
15 | 25 | 7.3 ± 0.71 | 9.3 ± 1.1 | 5 | 7.3 ± 0.71 | 11.0 ± 1.01 * (34) |
16 | 25 | 7.3 ± 0.71 | 8.4 ± 0.82 | 5 | 7.3 ± 0.71 | 8.1 ± 0.86 |
20 | 25 | 7.3 ± 0.71 | 8.0 ± 0.48 | 5 | 7.3 ± 0.71 | 8.9 ± 1.01 |
21 | 25 | 7.3 ± 0.71 | 10.6 ± 1.88 | 5 | 7.3 ± 0.71 | 9.7 ± 1.92 |
1 | - | - | - | 5 | 7.3 ± 0.71 | 12.3 ± 1.13 * (41) |
Diclofenac sodium | 10 | 7.3 ± 0.71 | 10.8 ± 0.9 * (37) | 10 | 7.3 ± 0.71 | 10.8 ± 0.9* (37) |
Sample Availability: Samples of the compounds 7, 8, 12, 13, 15, 16, 20–22 are available from the authors. |
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Cheremnykh, K.P.; Savelyev, V.A.; Borisov, S.A.; Ivanov, I.D.; Baev, D.S.; Tolstikova, T.G.; Vavilin, V.A.; Shults, E.E. Hybrides of Alkaloid Lappaconitine with Pyrimidine Motif on the Anthranilic Acid Moiety: Design, Synthesis, and Investigation of Antinociceptive Potency. Molecules 2020, 25, 5578. https://doi.org/10.3390/molecules25235578
Cheremnykh KP, Savelyev VA, Borisov SA, Ivanov ID, Baev DS, Tolstikova TG, Vavilin VA, Shults EE. Hybrides of Alkaloid Lappaconitine with Pyrimidine Motif on the Anthranilic Acid Moiety: Design, Synthesis, and Investigation of Antinociceptive Potency. Molecules. 2020; 25(23):5578. https://doi.org/10.3390/molecules25235578
Chicago/Turabian StyleCheremnykh, Kirill P., Victor A. Savelyev, Sergey A. Borisov, Igor D. Ivanov, Dmitry S. Baev, Tatyana G. Tolstikova, Valentin A. Vavilin, and Elvira E. Shults. 2020. "Hybrides of Alkaloid Lappaconitine with Pyrimidine Motif on the Anthranilic Acid Moiety: Design, Synthesis, and Investigation of Antinociceptive Potency" Molecules 25, no. 23: 5578. https://doi.org/10.3390/molecules25235578