Bio-Oriented Synthesis and Molecular Docking Studies of 1,2,4-Triazole Based Derivatives as Potential Anti-Cancer Agents against HepG2 Cell Line
Abstract
:1. Introduction
2. Results
2.1. Chemistry
2.2. Anti-proliferative Potential
2.3. Hemolytic Activity Potential
2.4. Structure–Activity Relationship of 7a–f
2.5. Molecular Docking
3. Materials and Methods
3.1. General
3.2. General Procedure for the Synthesis of Synthesized N-Arylated 5-Aryl-1,2,4-Triazole-Coupled Acetamide Scaffolds 7a–f
3.2.1. Synthesis of Methyl 2-(4-Isobutylphenyl)Propanoate (2)
3.2.2. Synthesis of 2-(4-Isobutylphenyl)Propanehydrazide (3)
3.2.3. Synthesis of 5-(1-(4- Isobutylphenyl)Ethyl)-1,2,4-Triazole -2-Thiol (4)
3.2.4. Synthesis of N–Aryl/Alkyl 2-Bromoroacetamides 6a–f
3.2.5. Synthesis of N-Arylated 5-(1-(4-Isobutylphenyl)Ethyl)-1,2,4-Triazole-2-yl- 2-Sulfanyl Coupled Acetamide Derivatives 7a–f
3.2.6. N-(2-Methylphenyl)-2-((5-(1-(4-isobutylphenyl)ethyl)-4-methyl-4H-1,2,4-triazol-3-yl)thio)Acetamide (7a)
3.2.7. N-(4-Bromo-2-Mthylphenyl)-2-((5-(1-(4-Isobutylphenyl)Ethyl)-4-Methyl-4H-1,2,4-Triazol-3-yl)Thio)Acetamide (7b)
3.2.8. N-(4-Ethylphenyl)-2-((5-(1-(4-Isobutylphenyl)Ethyl)-4-Methyl-4H-1,2,4-Triazol-3-yl)Thio)Acetamide (7c)
3.2.9. N-(2-Chlorophenyl)-2-((5-(1-(4-Isobutylphenyl)Ethyl)-4-Methyl-4H-1,2,4-Triazol-3-yl)Thio)Acetamide (7d)
3.2.10. N-(Phenyl)-2-((5-(1-(4-Isobutylphenyl)Ethyl)-4-Methyl-4H-1,2,4-Triazol-3-yl)Thio)Acetamide (7e)
3.2.11. N-(2,6-Dimethylphenyl)-2-((5-(1-(4-Isobutylphenyl)Ethyl)-4-Methyl-4H-1,2,4-Triazol-3-yl)Thio)Acetamide (7f)
3.3. Experimental Procedures for Biological Activities
3.3.1. Cell Culture and Treatment
3.3.2. Evaluation of Cell Viability
3.3.3. Hemolytic Activity Potential
3.4. Molecular Docking of Triazole-Coupled Acetamides
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Compound | Alkyl/Aryl | Cell Viability IC50 Value (µg/mL) | Hemolytic Activity (Mean% ± S.D) |
---|---|---|---|
7a | 2-methyl phenyl | 20.667 | 2.46 ± 0.31 |
7b | 2-methyl-4-bromo phenyl | 33.565 | 2.43 ± 0.11 |
7c | 4-ethyl phenyl | 39.002 | 4.32 ± 0.24 |
7d | 2-chloro phenyl | 39.667 | 7.33 ± 0.42 |
7e | phenyl | 39.105 | 4.19 ± 0.02 |
7f | 2,6-dimethyl phenyl | 16.782 | 1.19 ± 0.02 |
Sorafenib | 05.971 | ||
PBS | 0.00 ± 0.0 | ||
Triton-X-100 | 100 ± 0.0 |
Concentration (µg/mL) | 7a | 7b | 7c | 7d | 7e | 7f |
---|---|---|---|---|---|---|
200 | 89.40 ± 0.34 | 89.50 ± 0.06 | 87.51 ± 0.20 | 87.70 ± 0.18 | 88.00 ± 1.44 | 88.36 ± 0.31 |
100 | 88.17 ± 0.26 | 89.39 ± 0.91 | 78.82 ± 10.78 | 78.33 ± 0.78 | 87.34 ± 2.09 | 87.71 ± 1.34 |
50 | 75.18 ± 5.99 | 88.64 ± 1.11 | 73.66 ± 15.54 | 76.69 ± 5.63 | 74.24 ± 13.16 | 86.57 ± 0.56 |
25 | 63.98 ± 1.67 | 31.90 ± 0.30 | 22.82 ± 0.29 | 19.52 ± 1.44 | 24.01 ± 6.12 | 85.90 ± 0.30 |
12.5 | 27.70 ± 6.46 | 25.23 ± 4.67 | 19.14 ± 1.25 | 19.11 ± 17.71 | 20.99 ± 3.13 | 33.96 ± 2.47 |
6.25 | 21.44 ± 6.24 | 24.75 ± 4.62 | 17.35 ± 1.32 | 17.32 ± 1.40 | 20.52 ± 7.11 | 19.55 ± 4.07 |
3.125 | 11.57 + 8.85 | 10.33 + 0.96 | 15.40 ± 2.01 | 14.27 ± 4.27 | 18.65 ± 0.50 | 8.40 ± 4.54 |
DMSO (-ve Control) | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 |
Targets | Protein Kinase B (Akt) (PKB) | c-Kit Tyrosine Kinase (c-Kit) | Human Aurora B Kinase (AURKB) | Phosphatidylinositol 3-Kinase Alpha (PI3Kalpha) | Signal Transducer and Activator of Transcription 3 (STAT3) |
---|---|---|---|---|---|
PDB ID | 2X39 | 1T46 | 4AF3 | 4FA6 | 6NJS |
Center of docking | X:43 | X:28 | X:21 | X:44 | X:13 |
Coordinates | Y:31 | Y:26 | Y:-22 | Y:14 | Y:56 |
Z:111 | Z:39 | Z:-10 | Z:31 | Z:0.32 | |
Reference Ligand | X39 | STI | VX6 | 0TA | KQV |
Ligands | Mol. Dock Score (Kcal/mol) | Mol. Dock Score (Kcal/mol) | Mol. Dock Score (Kcal/mol) | Mol. Dock Score (Kcal/mol) | Mol. Dock Score (Kcal/mol) |
7a 7b | −166.843 −166.371 | −173.411 −167.882 | −145.234 −138.33 | −139.389 −136.267 | −125.105 −120.348 |
7c | −162.234 | −167.814 | −137.943 | −134.596 | −118.623 |
7d | −154.675 | −158.747 | −132.083 | −124.135 | −107.246 |
7e | −156.207 | −161.394 | −136.421 | −131.706 | −113.82 |
7f | −170.066 | −176.749 | −149.617 | −149.36 | −125.441 |
Reference Molecules | −130.624 | −181.533 | −144.231 | −112.819 | −197.521 |
Ligand | (ACE) (kcal/mol) | Category | Types | Interacting Residues |
---|---|---|---|---|
7a | −173.411 | H-bond | Alkyl | LEU595, LYS623, VAL654, LEU644, LEU595,LEU644, CYS673, CYS809, and VAL668. |
Hydrophobic | Pi-alkyl | TYR672. | ||
7b | −167.882 | H-bond | Sulfur-X | CYS809. |
Hydrophobic | C-alkyl Pi-alkyl | LEU595, VAL654, LEU644, CYS809, LEU595, ILE808, LEU644, AL654. TYR672, HIS790, and PHE811. | ||
7c | −167.814 | H-bond | Conventional | GLU640. |
Hydrophobic | Pi-Alkyl | HIS790. | ||
Hydrophobic | C-alkyl | VAL643, VAL603, LYS623, VAL668, LEU783, CYS788, LYS623, LEU644, VAL668, ALA621, and CYS788. | ||
7d | −158.747 | H-bond | Conventional | GLU640 and ASP810. |
Hydrophobic | C-alkyl Pi-alkyl | ILE808. VAL603, VAL643, LEU783, CYS788, CYS809, LEU595, VAL603, VAL643, and LEU783. | ||
7e | −161.394 | H-bond | Conventional | CYS673, |
Hydrophobic | C-alkyl Pi-alkyl | LEU595, VAL654, LEU644, CYS809, LYS623, LEU644, LEU644, TYR672, and VAL668. | ||
7f | −176.749 | H-bond | Conventional H-bond Pi-sigma | GLU640, ASP810, And HIS790. |
Hydrophobic | Alkyl | VAL603, LYS623, VAL643, LEU783, CYS788, LYS623, LEU644, VAL668, CYS809, ILE571, and CYS788. | ||
Reference Ligand | H-bond | Conventional | ALA232, GLU236, MET282, ASP293, GLU279, | |
STI | −181.533 | Other | C-H bond | MET229, GLY159, |
Hydrophobic | C-alkyl | VAL166, LEU158, ALA179, LYS181, and LEU183. |
Ligand | (ACE) (kcal/mol) | Category | Types | Interacting Residues |
---|---|---|---|---|
7a | −166.843 | H-bond | Conventional C-H bond | GLY164. SER9. |
Other Hydrophobic | Pi-sulfur C-alkyl | PHE163. VAL166, LYS181, and EU183. | ||
7b | −166.371 | H-bond | Conventional | CYS809. |
Hydrophobic | C-alkyl | LYS181, VAL166, and LEU296. | ||
7c | −162.234 | Hydrophobic | Alkyl | LYS181, VAL166, and LEU183. |
7d | −154.675 | H-bond | Conventional | GLY161, LEU158. |
Hydrophobic | C-H bond C-alkyl Pi-alkyl | ASP293. VAL166, LYS181. PHE239, and PHE439. | ||
7e | −156.207 | H-bond | C-H bond | CYS673. |
Hydrophobic | Alkyl | LEU296. | ||
7f | −170.066 | H-bond | Conventional C-H bond | GLY161, ASP293, and ARG6. ASP293. |
Hydrophobic | C-alkyl | LYS181 and LEU183. | ||
Reference Ligand | H-bond | Conventional | ALAA232, ASPA293, META282, GLUA279, GLUA236 | |
X39 | −130.624 | Other | C-H bond | MET229, GLY159, |
Hydrophobic | C-alkyl | VAL166, LEU A183, LEU A158, ALA179, LYS and A181. |
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Akhter, N.; Batool, S.; Khan, S.G.; Rasool, N.; Anjum, F.; Rasul, A.; Adem, Ş.; Mahmood, S.; Rehman, A.u.; Nisa, M.u.; et al. Bio-Oriented Synthesis and Molecular Docking Studies of 1,2,4-Triazole Based Derivatives as Potential Anti-Cancer Agents against HepG2 Cell Line. Pharmaceuticals 2023, 16, 211. https://doi.org/10.3390/ph16020211
Akhter N, Batool S, Khan SG, Rasool N, Anjum F, Rasul A, Adem Ş, Mahmood S, Rehman Au, Nisa Mu, et al. Bio-Oriented Synthesis and Molecular Docking Studies of 1,2,4-Triazole Based Derivatives as Potential Anti-Cancer Agents against HepG2 Cell Line. Pharmaceuticals. 2023; 16(2):211. https://doi.org/10.3390/ph16020211
Chicago/Turabian StyleAkhter, Naheed, Sidra Batool, Samreen Gul Khan, Nasir Rasool, Fozia Anjum, Azhar Rasul, Şevki Adem, Sadaf Mahmood, Aziz ur Rehman, Mehr un Nisa, and et al. 2023. "Bio-Oriented Synthesis and Molecular Docking Studies of 1,2,4-Triazole Based Derivatives as Potential Anti-Cancer Agents against HepG2 Cell Line" Pharmaceuticals 16, no. 2: 211. https://doi.org/10.3390/ph16020211