Design, Synthesis, and Mechanistic Study of 2-Pyridone-Bearing Phenylalanine Derivatives as Novel HIV Capsid Modulators
Abstract
:1. Introduction
2. Chemistry
3. Results and Discussion
3.1. In Vitro Anti-HIV Assays and SAR Analysis for HIV-1 Potency
3.2. Solubility of Representative Compounds
3.3. Binding Mode of FTC-2 within the Interprotomer Pocket
3.4. Computational Assessment of Drug-like Properties and Metabolic Stability
4. Conclusions
5. Experimental Section
5.1. Chemistry
5.1.1. General Procedure for the Synthesis of 2a and 2b
tert-butyl (S)-(1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (2a)
tert-butyl (S)-(3-(3,5-difluorophenyl)-1-((4-methoxyphenyl) (methyl)amino)-1-oxopropan-2-yl)carbamate (2b)
5.1.2. General Procedure for the Synthesis of 3a and 3b
(S)-2-amino-N-(4-methoxyphenyl)-N-methyl-3-phenylpropanamide (3a)
(S)-2-amino-3-(3,5-difluorophenyl)-N-(4-methoxyphenyl)-N-methylpropanamide (3b)
5.1.3. General Procedure for the Synthesis of 4a and 4b
(S)-2-(2-bromoacetamido)-N-(4-methoxyphenyl)-N-methyl-3-phenylpropanamide (4a)
(S)-2-(2-bromoacetamido)-3-(3,5-difluorophenyl)-N-(4-methoxyphenyl)-N-methylpropanamide (4b)
5.1.4. General Procedure for the Synthesis of FTC-1 and TC-1
tert-butyl (S)-(1-(2-((3-(3,5-difluorophenyl)-1-((4-methoxyphenyl)(methyl)amino)-1-oxopropan-2-yl)amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-4-yl)carbamate (FTC-1)
tert-butyl (S)-(1-(2-((1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-4-yl)carbamate (TC-1)
5.1.5. General Procedure for the Synthesis of FTC-2 and TC-2
(S)-2-(2-(4-amino-2-oxopyridin-1(2H)-yl)acetamido)-3-(3,5-difluorophenyl)-N-(4-methoxyphenyl)-N-methylpropanamide (FTC-2)
(S)-2-(2-(4-amino-2-oxopyridin-1(2H)-yl)acetamido)-N-(4-methoxyphenyl)-N-methyl-3-phenylpropanamide (TC-2)
5.1.6. General Procedure for the Synthesis of TD-1a–1l
(S)-N-(1-(2-((1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-4-yl)benzamide (TD-1a)
(S)-4-fluoro-N-(1-(2-((1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-4-yl)benzamide (TD-1b)
(S)-3-fluoro-N-(1-(2-((1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-4-yl)benzamide (TD-1c)
(S)-2-fluoro-N-(1-(2-((1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-4-yl)benzamide (TD-1d)
(S)-4-chloro-N-(1-(2-((1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-4-yl)benzamide (TD-1e)
(S)-4-bromo-N-(1-(2-((1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-4-yl)benzamide (TD-1f)
(S)-N-(1-(2-((1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-4-yl)-4-methylbenzamide (TD-1g)
(S)-4-methoxy-N-(1-(2-((1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-4-yl)benzamide (TD-1h)
methyl (S)-4-((1-(2-((1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-4-yl)carbamoyl)benzoate (TD-1i)
(S)-4-cyano-N-(1-(2-((1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-4-yl)benzamide (TD-1j)
(S)-N-(1-(2-((1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-4-yl)-2-naphthamide (TD-1k)
(S)-N-(1-(2-((1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-4-yl)-4-nitrobenzamide (TD-1l)
5.1.7. Procedure for the Synthesis of TD-1m
(S)-4-amino-N-(1-(2-((1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-4-yl)benzamide (TD-1m)
5.2. In Vitro Anti-HIV Assay in MT-4 Cells
5.3. Solubility Studies
5.4. Molecular Docking Studies
5.5. Computational Assessment of Drug-like Properties, Metabolic Stability, and Toxicity
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
References
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Compound ID | R1 | R2 | EC50 a (μM) | CC50 b (μM) | SI c | ||
---|---|---|---|---|---|---|---|
HIV-1 IIIB | HIV-2 ROD | HIV-1 | HIV-2 | ||||
FTC-2 | F | H | 5.36 ± 0.98 | 15.56 ± 1.06 | >265.69 | >49.57 | >17.08 |
TC-2 | H | H | 29.07 ± 4.23 | 19.72 ± 6.42 | 261.13 ± 33.14 | 8.98 | 13.24 |
TD-1a | H | 16.81 ± 0.91 | 4.86 ± 1.71 | 86.54 ± 29.24 | 5.15 | 17.81 | |
TD-1b | H | >34.80 | 16.22 ± 17.16 | 34.80 ± 5.75 | N.D.d | 2.15 | |
TD-1c | H | 18.90 ± 2.66 | 6.59 ± 1.63 | 61.65 ± 8.44 | 3.26 | 9.36 | |
TD-1d | H | 17.88 ± 2.68 | 7.92 ± 0.83 | 81.42 ± 22.66 | 4.55 | 10.28 | |
TD-1e | H | >25.48 | >25.48 | 25.48 ± 2.90 | N.D. | N.D. | |
TD-1f | H | >23.51 | >23.51 | 23.51 ± 2.79 | N.D. | N.D. | |
TD-1g | H | 25.60 ± 7.51 | 20.48 ± 8.49 | 58.27 ± 4.85 | 2.28 | 2.85 | |
TD-1h | H | 29.62 ± 4.34 | 10.67 ± 3.66 | 53.13 ± 5.12 | 1.79 | 4.98 | |
TD-1i | H | 19.09 ± 5.08 | 15.25 ± 0.55 | 96.17 ± 19.83 | 5.04 | 6.31 | |
TD-1j | H | 16.77 ± 0.78 | 17.83 ± 2.79 | 137.19 ± 22.50 | 8.18 | 7.69 | |
TD-1k | H | >27.59 | >27.59 | 27.59 ± 3.18 | N.D. | N.D. | |
TD-1l | H | >31.87 | >31.87 | 31.87 ± 1.73 | N.D. | N.D. | |
TD-1m | H | >189.23 | 17.14 ± 2.49 | 189.23 ± 2.19 | N.D. | 11.04 | |
PF74 | - | - | 1.08 ± 0.24 | 5.76 ± 2.14 | >293.75 | >271.99 | >51.00 |
Compounds | Solubility (μg/mL) a | ||
---|---|---|---|
pH 2 | pH 7 | pH 7.4 | |
TD-1a | 2.69 ± 0.52 | 5.07 ± 2.60 | 8.66 ± 0.41 |
FTC-2 | 366.57 ± 58.39 | 261.19 ± 130.46 | 436.58 ± 51.87 |
PF74 | <1.12 b | 1.44 ± 0.10 c | 1.91 ± 0.56 |
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Zhang, X.; Sun, L.; Xu, S.; Shao, X.; Li, Z.; Ding, D.; Jiang, X.; Zhao, S.; Cocklin, S.; Clercq, E.D.; et al. Design, Synthesis, and Mechanistic Study of 2-Pyridone-Bearing Phenylalanine Derivatives as Novel HIV Capsid Modulators. Molecules 2022, 27, 7640. https://doi.org/10.3390/molecules27217640
Zhang X, Sun L, Xu S, Shao X, Li Z, Ding D, Jiang X, Zhao S, Cocklin S, Clercq ED, et al. Design, Synthesis, and Mechanistic Study of 2-Pyridone-Bearing Phenylalanine Derivatives as Novel HIV Capsid Modulators. Molecules. 2022; 27(21):7640. https://doi.org/10.3390/molecules27217640
Chicago/Turabian StyleZhang, Xujie, Lin Sun, Shu**g Xu, **aoyu Shao, Ziyi Li, Dang Ding, **angyi Jiang, Shujie Zhao, Simon Cocklin, Erik De Clercq, and et al. 2022. "Design, Synthesis, and Mechanistic Study of 2-Pyridone-Bearing Phenylalanine Derivatives as Novel HIV Capsid Modulators" Molecules 27, no. 21: 7640. https://doi.org/10.3390/molecules27217640