Structure–Activity Relationship of N-Phenylthieno[2,3-b]pyridine-2-carboxamide Derivatives Designed as Forkhead Box M1 Inhibitors: The Effect of Electron-Withdrawing and Donating Substituents on the Phenyl Ring
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis of N-Phenylthieno[2,3-b]pyridine-2-carboxamide Derivatives
2.2. Determination of FOXM1’s Relative Expression
2.3. Cytotoxic Activity Determination
2.4. Molecular Docking in FOXM1’s DNA-Binding Domain
3. Materials and Methods
3.1. Organic Synthesis: General
3.2. General Method for the Synthesis of the Final Derivatives (FDI-6 and 1–18): Conventional Heating
3.2.1. 3-Amino-N-(4-fluorophenyl)-6-(thiophen-2-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxamide (FDI-6)
3.2.2. 3-Amino-N-(4-fluoro-2-nitrophenyl)-6-(thiophen-2-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxamide (3)
3.2.3. 3-Amino-N-(4-chlorophenyl)-6-(thiophen-2-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxamide (5)
3.2.4. 3-Amino-N-(4-chloro-2-cyanophenyl)-6-(thiophen-2-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxamide (6)
3.2.5. 3-Amino-N-(4-chloro-2-nitrophenyl)-6-(thiophen-2-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxamide (7)
3.2.6. 3-Amino-N-(4-bromophenyl)-6-(thiophen-2-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxamide (9)
3.2.7. 3-Amino-N-(4-bromo-2-cyanophenyl)-6-(thiophen-2-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxamide (11)
3.2.8. 3-Amino-N-(4-bromo-2-nitrophenyl)-6-(thiophen-2-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxamide (12)
3.2.9. 3-Amino-N-(4-bromo-2-(trifluoromethyl)phenyl)-6-(thiophen-2-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxamide (13)
3.2.10. 3-Amino-N-(4-iodophenyl)-6-(thiophen-2-yl)-4-(trifluoromethyl)-thieno[2,3-b]pyridine-2-carboxamide (14)
3.2.11. 3-Amino-N-(4-iodo-2-methylphenyl)-6-(thiophen-2-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxamide (15)
3.2.12. 3-Amino-N-(2-cyano-4-iodophenyl)-6-(thiophen-2-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxamide (16)
3.2.13. 3-Amino-N-(4-iodo-2-nitrophenyl)-6-(thiophen-2-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxamide (17)
3.2.14. 3-Amino-N-(4-iodo-2-(trifluoromethyl)phenyl)-6-(thiophen-2-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxamide (18)
3.3. General Method for the Synthesis of the Final Derivatives (FDI-6 and, 1–18): Microwave Heating
3.3.1. 3-Amino-N-(4-fluoro-2-methylphenyl)-6-(thiophen-2-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxamide (1)
3.3.2. 3-Amino-N-(2-cyano-4-fluorophenyl)-6-(thiophen-2-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxamide (2)
3.3.3. 3-Amino-N-(4-fluor-2-(trifluoromethyl)phenyl)-6-(thiophen-2-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxamide (4)
3.3.4. 3-Amino-N-(4-chloro-2-(trifluoromethyl)phenyl)-6-(thiophen-2-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxamide (8)
3.3.5. 3-Amino-N-(4-bromo-2-methylphenyl)-6-(thiophen-2-yl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxamide (10)
3.4. Western Blotting
3.5. Cell-Proliferation-Inhibition (MTT) Assay
3.6. Molecular Docking
3.7. MEP Maps
4. 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 | MDA-MB-231 IC50 (μM) a |
---|---|
FDI-6 | 11.67 ± 1.35 |
1 | 171.5 ± 1.49 |
6 | 8.75 ± 1.27 |
16 | 4.61 ± 1.34 |
| |||
---|---|---|---|
Compound | S (kcal/mol) a | R1 | R2 |
FDI-6 | −5.3383 | -F | -H |
1 | −5.6402 | -F | -CH3 |
2 | −5.4899 | -F | -CN |
3 | −5.9180 | -F | -NO2 |
4 | −5.4391 | -F | -CF3 |
5 | −5.5565 | -Cl | -H |
6 | −7.2807 | -Cl | -CN |
7 | −6.1224 | -Cl | -NO2 |
8 | −5.5823 | -Cl | -CF3 |
9 | −5.6117 | -Br | -H |
10 | −5.8423 | -Br | -CH3 |
11 | −5.9348 | -Br | -CN |
12 | −6.1845 | -Br | -NO2 |
13 | −5.7709 | -Br | -CF3 |
14 | −5.6386 | -I | -H |
15 | −5.5661 | -I | -CH3 |
16 | −5.8317 | -I | -CN |
17 | −5.7237 | -I | -NO2 |
18 | −5.7932 | -I | -CF3 |
MEP Values (kJ/mol) a | |||
---|---|---|---|
| | | |
FDI-6 | −112.0 | 44.0 | −50.0 to 17.4 |
5 | −117.4 | 83.4 | −65.0 to 4.1 |
9 | −111.4 | 81.4 | −65.0 to 0.4 |
14 | −109.0 | 77.4 | −69.7 to −14.7 |
2 | −128.7 | 108.2 | −5.0 to 37.5 |
6 | −154.1 | 110.0 | −7.0 to 50.0 |
11 | −165.0 | 98.8 | −18.1 to 51.3 |
16 | −160.0 | 108.8 | −23.2 to 54.7 |
1 | −167.6 | 75.3 | −104 to 59 |
7 | −151.0 | 119.3 | −7.0 to 30.4 |
1 | −157.1 | 76.4 | −72.0 to 3.0 |
17 | −146.3 | 112.0 | −36.4 to 58.1 |
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Huerta-García, C.S.; Pérez, D.J.; Velázquez-Martínez, C.A.; Tabatabaei Dakhili, S.A.; Romo-Mancillas, A.; Castillo, R.; Hernández-Campos, A. Structure–Activity Relationship of N-Phenylthieno[2,3-b]pyridine-2-carboxamide Derivatives Designed as Forkhead Box M1 Inhibitors: The Effect of Electron-Withdrawing and Donating Substituents on the Phenyl Ring. Pharmaceuticals 2022, 15, 283. https://doi.org/10.3390/ph15030283
Huerta-García CS, Pérez DJ, Velázquez-Martínez CA, Tabatabaei Dakhili SA, Romo-Mancillas A, Castillo R, Hernández-Campos A. Structure–Activity Relationship of N-Phenylthieno[2,3-b]pyridine-2-carboxamide Derivatives Designed as Forkhead Box M1 Inhibitors: The Effect of Electron-Withdrawing and Donating Substituents on the Phenyl Ring. Pharmaceuticals. 2022; 15(3):283. https://doi.org/10.3390/ph15030283
Chicago/Turabian StyleHuerta-García, César Sebastian, David J. Pérez, Carlos A. Velázquez-Martínez, Seyed Amirhossein Tabatabaei Dakhili, Antonio Romo-Mancillas, Rafael Castillo, and Alicia Hernández-Campos. 2022. "Structure–Activity Relationship of N-Phenylthieno[2,3-b]pyridine-2-carboxamide Derivatives Designed as Forkhead Box M1 Inhibitors: The Effect of Electron-Withdrawing and Donating Substituents on the Phenyl Ring" Pharmaceuticals 15, no. 3: 283. https://doi.org/10.3390/ph15030283