Design, Synthesis, and In Vitro Evaluation of Novel Indolyl DiHydropyrazole Derivatives as Potential Anticancer Agents
Abstract
:1. Introduction
2. Materials and Methods
2.1. Molecular Modeling Studies
2.1.1. Ligand Preparation
2.1.2. Protein Preparation
2.1.3. Active Site Prediction
2.1.4. Receptor Grid Generation
2.1.5. Molecular Docking Study
2.2. Synthesis of Pyrazoline Derivatives of Indole
2.2.1. One-Pot Synthesis of Pyrazolines (3a–k)
2.2.2. Procedure for the Synthesis of 5-(1H-Indol-3-yl)-3-substituted-N-(pyridin-2-yl)-4,5-dihydro-1H-pyrazole-1-carboxamide (4a–t)
2.3. Anti-Proliferative Activity
2.3.1. Cell Culture
2.3.2. Cytotoxicity Assay
3. Results and Discussion
3.1. Molecular Modeling Studies
3.2. Chemistry
3.3. Anti-Proliferative Activity
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
Sample Availability
References
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Compound | R | R1 | Glide g-Score | Glide h-Bond | Glide Energy |
---|---|---|---|---|---|
4a | H | Pyridin-2-yl | −4.825 | −0.25 | −36.657 |
4b | 2-Cl | Pyridin-2-yl | −4.901 | −0.219 | −37.331 |
4c | 3-Cl | Pyridin-2-yl | −5.84 | −0.268 | −38.583 |
4d | 3-CH3 | Pyridin-2-yl | −5.071 | −0.221 | −37.89 |
4e | 3-OCH3 | Pyridin-2-yl | −4.892 | −0.17 | −38.54 |
4f | 4-OCH3 | Pyridin-2-yl | −4.982 | −0.216 | −38.981 |
4g | 2-OH | Pyridin-2-yl | −5.835 | −0.529 | −39.868 |
4h | 3-OH | Pyridin-2-yl | −6.255 | −0.562 | −38.825 |
4i | 4-OH | Pyridin-2-yl | −4.81 | −0.161 | −36.75 |
4j | 2-NO2 | Pyridin-2-yl | −4.876 | −0.237 | −38.004 |
4k | 3-NO2 | Pyridin-2-yl | −4.939 | −0.314 | −39.227 |
4l | 2-Cl | Pyridin-3-yl | −4.932 | −0.157 | −41.181 |
4m | 2-OH | Pyridin-3-yl | −5.137 | −0.329 | −37.86 |
4n | 3-OH | Pyridin-3-yl | −6.069 | −0.449 | −38.018 |
4o | 4-Cl | Pyridin-4-yl | −4.882 | −0.569 | −41.003 |
4p | 4-OCH3 | Pyridin-4-yl | −4.816 | −0.282 | −36.142 |
4q | 2-OH | Pyridin-4-yl | −5.022 | −0.556 | −41.616 |
4r | 3-OH | Pyridin-4-yl | −6.152 | −0.458 | −38.088 |
4s | 2-OH | Phenyl | −5.299 | −0.32 | −38.74 |
4t | 4-OH | Phenyl | −6.17 | −0.32 | −43.506 |
Compound | R | R1 | Amino Acid Residues (H-Bond Length Å) | No. of H-Bonding Interactions |
---|---|---|---|---|
4a | H | Pyridin-2-yl | Ile 262 (2.54) | 1 |
4b | 2-Cl | Pyridin-2-yl | Phe 115 (1.47) | 1 |
4c | 3-Cl | Pyridin-2-yl | Arg 236 (1.94), Phe 115 (1.06) | 2 |
4d | 3-CH3 | Pyridin-2-yl | Ile 262 (2.05) | 1 |
4e | 3-OCH3 | Pyridin-2-yl | Ile 262 (2.85), Phe 115 (3.02) | 2 |
4f | 4-OCH3 | Pyridin-2-yl | Asn 121 (2.42) | 1 |
4g | 2-OH | Pyridin-2-yl | Ile 262 (1.65, 2.76), Gln 234 (2.12) | 3 |
4h | 3-OH | Pyridin-2-yl | Leu 116 (1.95, 1.72), Gln 118 (2.02) | 3 |
4i | 4-OH | Pyridin-2-yl | Gln 235 (3.00) | 1 |
4j | 2-NO2 | Pyridin-2-yl | Arg 236 (2.99) | 1 |
4k | 3-NO2 | Pyridin-2-yl | Arg 236 (3.13) | 1 |
4l | 2-Cl | Pyridin-3-yl | Leu 116 (2.20) | 1 |
4m | 2-OH | Pyridin-3-yl | Gln 118 (2.65) | 1 |
4n | 3-OH | Pyridin-3-yl | Asn 232 (3.25), Glu 211 (3.09), Arg 236 (2.04), Ile 262 (2.01) | 4 |
4o | 4-Cl | Pyridin-4-yl | Gln 234 (2.01), Ile 262 (3.33) | 4 |
4p | 4-OCH3 | Pyridin-4-yl | Ile 262 (2.85), Phe 115 (3.02) | 2 |
4q | 2-OH | Pyridin-4-yl | Leu 116 (1.95, 1.72), Ile 262 (1.65, 2.76) | 4 |
4r | 3-OH | Pyridin-4-yl | Glu 211 (2.98), Arg 236 (2.62) | 2 |
4s | 2-OH | Phenyl | Gln 234 (3.44), Gln 118 (3.08), Thr 264 (2.89) | 3 |
4t | 4-OH | Phenyl | Gly 235 (2.93) | 1 |
Compound | R | R1 | IC50 (µM) | |||
---|---|---|---|---|---|---|
A-549 | MCF-7 | Hep G-2 | DU-145 | |||
4a | H | Pyridin-2-yl | 4.75 ± 0.21 | 54.32 ± 0.52 | 22.29 ± 0.30 | 19.53 ± 0.11 |
4b | 2-Cl | Pyridin-2-yl | 5.79 ± 0.13 | 59.01 ± 0.46 | 21.61 ± 0.25 | 19.68 ± 0.15 |
4c | 3-Cl | Pyridin-2-yl | 5.32 ± 0.17 | 60.64 ± 0.27 | 24.55 ± 0.26 | 16.54 ± 0.08 |
4d | 3-CH3 | Pyridin-2-yl | 7.89 ± 0.26 | 56.58 ± 0.36 | 26.32 ± 0.14 | 16.02 ± 0.26 |
4e | 3-OCH3 | Pyridin-2-yl | 5.78 ± 0.15 | 54.93 ± 0.31 | 32.57 ± 0.25 | 15.67 ± 0.21 |
4f | 4-OCH3 | Pyridin-2-yl | 6.83 ± 0.16 | 58.76 ± 0.34 | 34.95 ± 0.13 | 16.84 ± 0.18 |
4g | 2-OH | Pyridin-2-yl | 2.32 ± 0.11 | 43.59 ± 0.38 | 24.53 ± 0.17 | 14.53 ± 0.16 |
4h | 3-OH | Pyridin-2-yl | 4.56 ± 0.14 | 47.45 ± 0.28 | 26.30 ± 0.14 | 12.36 ± 0.15 |
4i | 4-OH | Pyridin-2-yl | 5.74 ± 0.012 | 52.18 ± 0.12 | 30.22 ± 0.19 | 13.50 ± 0.14 |
4j | 2-NO2 | Pyridin-2-yl | 7.77 ± 0.26 | 64.78 ± 0.46 | 35.50 ± 0.12 | 19.63 ± 0.15 |
4k | 3-NO2 | Pyridin-2-yl | 8.81 ± 0.13 | 75.36 ± 0.34 | 33.77 ± 0.15 | 16.76 ± 0.17 |
4l | 2-Cl | Pyridin-3-yl | 6.46 ± 0.22 | 45.30 ± 0.26 | 27.74 ± 0.26 | 19.75 ± 0.12 |
4m | 2-OH | Pyridin-3-yl | 3.92 ± 0.24 | 57.18 ± 0.31 | 21.60 ± 0.29 | 10.15 ± 0.13 |
4n | 3-OH | Pyridin-3-yl | 5.45 ± 0.14 | 55.74 ± 0.42 | 29.52 ± 0.21 | 13.99 ± 0.19 |
4o | 4-Cl | Pyridin-4-yl | 6.78 ± 0.16 | 54.84 ± 0.27 | 30.53 ± 0.19 | 14.65 ± 0.21 |
4p | 4-OCH3 | Pyridin-4-yl | 5.74 ± 0.15 | 54.23 ± 0.29 | 26.25 ± 0.24 | 15.52 ± 0.15 |
4q | 2-OH | Pyridin-4-yl | 2.86 ± 0.12 | 46.13 ± 0.34 | 21.12 ± 0.16 | 9.92 ± 0.13 |
4r | 3-OH | Pyridin-4-yl | 4.50 ± 0.18 | 56.50 ± 0.37 | 25.87 ± 0.15 | 12.16 ± 0.17 |
4s | 2-OH | Phenyl | 3.02 ± 0.14 | 48.67 ± 0.34 | 22.28 ± 0.17 | 10.47 ± 0.16 |
4t | 4-OH | Phenyl | 5.26 ± 0.19 | 66.53 ± 0.31 | 25.94 ± 0.12 | 12.19 ± 0.22 |
Isatin | -- | 4.96 ± 0.21 | 32.61 ± 0.25 | 28.29 ± 0.14 | 19.64 ± 0.12 |
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Venugopala, K.N.; Habeebuddin, M.; Aldhubiab, B.E.; Asif, A.H. Design, Synthesis, and In Vitro Evaluation of Novel Indolyl DiHydropyrazole Derivatives as Potential Anticancer Agents. Molecules 2021, 26, 5235. https://doi.org/10.3390/molecules26175235
Venugopala KN, Habeebuddin M, Aldhubiab BE, Asif AH. Design, Synthesis, and In Vitro Evaluation of Novel Indolyl DiHydropyrazole Derivatives as Potential Anticancer Agents. Molecules. 2021; 26(17):5235. https://doi.org/10.3390/molecules26175235
Chicago/Turabian StyleVenugopala, Katharigatta N., Mohammed Habeebuddin, Bandar E. Aldhubiab, and Afzal Haq Asif. 2021. "Design, Synthesis, and In Vitro Evaluation of Novel Indolyl DiHydropyrazole Derivatives as Potential Anticancer Agents" Molecules 26, no. 17: 5235. https://doi.org/10.3390/molecules26175235
APA StyleVenugopala, K. N., Habeebuddin, M., Aldhubiab, B. E., & Asif, A. H. (2021). Design, Synthesis, and In Vitro Evaluation of Novel Indolyl DiHydropyrazole Derivatives as Potential Anticancer Agents. Molecules, 26(17), 5235. https://doi.org/10.3390/molecules26175235