Synthesis and In Silico Docking of New Pyrazolo[4,3-e]pyrido[1,2-a]pyrimidine-based Cytotoxic Agents
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis
2.2. Biological Evaluation
3. Materials and Methods
3.1. General
3.2. Synthesis
3.2.1. 5-Amino-3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile (3)
3.2.2. 3-Methyl-5-{[(1E)-1-methyl-3-oxobut-1-en-1-yl]amino}-1-phenyl-1H-pyrazole-4-carbonitrile (5)
3.2.3. General Procedure for the Synthesis of Compounds 7a–l
8-Acetyl-4-amino-7-(4-chlorophenyl)-3,9-dimethyl-1-phenyl-1,7-dihydropyrazolo[4,3-e] Pyrido[1,2-a]pyrimidine-6-carbonitrile (7a)
8-Acetyl-4-amino-3,9-dimethyl-7-(4-methylphenyl)-1-phenyl-1,7-dihydropyrazolo[4,3-e] Pyrido1,2-a]pyrimidine-6-carbonitrile (7b)
8-Acetyl-4-amino-3,9-dimethyl-1,7-diphenyl-1,7-dihydropyrazolo[4,3-e]Pyrido[1,2-a]pyrimidine-6-carbonitrile (7c)
8-Acetyl-4-Amino-7-(4-methoxyphenyl)-3,9-dimethyl-1-phenyl-1,7-dihydropyrazolo[4,3-e] Pyrido[1,2-a]pyrimidine-6-carbonitrile (7d)
8-Acetyl-4-amino-7-(4-bromophenyl)-3,9-dimethyl-1-phenyl-1,7-dihydropyrazolo[4,3-e] Pyrido[1,2-a]pyrimidine-6-carbonitrile (7e)
8-Acetyl-4-amino-7-(4-fluorophenyl)-3,9-dimethyl-1-phenyl-1,7-sihydropyrazolo[4,3-e] Pyrido[1,2-a]pyrimidine-6-carbonitrile (7f)
8-Acetyl-4-amino-3,9-dimethyl-7-(4-nitrophenyl)-1-phenyl-1,7-dihydropyrazolo[4,3-e] Pyrido[1,2-a]pyrimidine-6-carbonitrile (7g)
8-Acetyl-4-amino-7-(3,4-dimethoxyphenyl)-3,9-dimethyl-1-phenyl-1,7-dihydropyrazolo[4,3-e] Pyrido[1,2-a]pyrimidine-6-carbonitrile (7h)
8-Acetyl-4-amino-7-(3,4-dichlorophenyl)-3,9-dimethyl-1-phenyl-1,7-dihydropyrazolo[4,3-e] Pyrido[1,2-a]pyrimidine-6-carbonitrile (7i)
8-Acetyl-4-amino-3,9-dimethyl-7-(5-nitro-2-thienyl)-1-phenyl-1,7-dihydropyrazolo[4,3-e] Pyrido[1,2-a]pyrimidine-6-carbonitrile (7j)
8-Acetyl-4-amino-3,9-dimethyl-7-(2-naphthyl)-1-phenyl-1,7-dihydropyrazolo[4,3-e] Pyrido[1,2-a]pyrimidine-6-carbonitrile (7k)
8-Acetyl-4-amino-3,9-dimethyl-1-phenyl-7-pyridin-3-yl-1,7-dihydropyrazolo[4,3-e] Pyrido[1,2-a]pyrimidine-6-carbonitrile (7l)
3.3. Cytotoxicity Assay (SRB Assay)
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 | A375 | HT29 | MCF-7 | A2780 | FaDu | NIH 3T3 | HEK293 |
---|---|---|---|---|---|---|---|
3, 5 | >30 | >30 | >30 | >30 | >30 | >30 | >30 |
7a | 19.3 ± 3.0 | 29.9 ± 1.4 | 17.2 ± 1.4 | 18.0 ± 3.0 | >30 | 23.0 ± 1.4 | 15.8 ± 2.0 |
7b | 12.9 ± 1.6 | 17.5 ± 1.8 | 12.2 ± 1.3 | 14.6 ± 2.2 | 22.3 ± 2.7 | 21.3 ± 0.9 | 12.4 ± 0.9 |
7c | 19.3 ± 3.8 | >30 | 19.5 ± 1.1 | 25.4 ± 2.5 | >30 | >30 | 7.7 ± 1.1 |
7d | 21.5 ± 3.6 | 28.3 ± 3.5 | 18.4 ± 2.3 | 21.7 ± 3.9 | >30 | >30 | 16.7 ± 1.2 |
7e | 9.4 ± 1.2 | 13.3 ± 1.8 | 9.2 ± 0.7 | 9.1 ± 1.6 | 13.5 ± 1.5 | 12.3 ± 0.7 | 6.6 ± 0.6 |
7f | 18.1 ± 3.3 | 24.7 ± 4.4 | 19.2 ± 1.3 | 19.2 ± 3.9 | >30 | 24.1 ± 2.8 | 14.7 ± 1.4 |
7g | 16.2 ± 2.0 | 25.9 ± 3.4 | 15.7 ± 2.2 | 14.5 ± 2.2 | >30 | >30 | 17.0 ± 1.3 |
7h | 22.1 ± 4.9 | >30 | 25.1 ± 2.8 | 27.5 ± 8.1 | >30 | >30 | 24.0 ± 3.4 |
7i–l | n.s. | n.s. | n.s. | n.s. | n.s. | n.s. | n.s. |
DX | n.d. | 0.9 ± 0.01 | 1.1 ± 0.3 | 0.01 ± 0.01 | n.d. | 0.4 ± 0.07 | n.d. |
Compound | Free Binding Energy (Kcal·mol−1) | |||||
---|---|---|---|---|---|---|
DHFR (5HQY) | VEGFR2 (5EW3) | HER-2 (3RCD) | hCA-IX (5FL4) | CDK6 (3NUP) | LOX5 (3V99) | |
7e | −8.5 | −6.6 | −7.3 | −7.2 | −7.1 | −8.5 |
Ref. ligand | −8.3 | −7.3 | −7.2 | −7.0 | −6.8 | −6.0 |
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Horchani, M.; Heise, N.V.; Hoenke, S.; Csuk, R.; Harrath, A.H.; Ben Jannet, H.; Romdhane, A. Synthesis and In Silico Docking of New Pyrazolo[4,3-e]pyrido[1,2-a]pyrimidine-based Cytotoxic Agents. Int. J. Mol. Sci. 2021, 22, 10258. https://doi.org/10.3390/ijms221910258
Horchani M, Heise NV, Hoenke S, Csuk R, Harrath AH, Ben Jannet H, Romdhane A. Synthesis and In Silico Docking of New Pyrazolo[4,3-e]pyrido[1,2-a]pyrimidine-based Cytotoxic Agents. International Journal of Molecular Sciences. 2021; 22(19):10258. https://doi.org/10.3390/ijms221910258
Chicago/Turabian StyleHorchani, Mabrouk, Niels V. Heise, Sophie Hoenke, René Csuk, Abdel Halim Harrath, Hichem Ben Jannet, and Anis Romdhane. 2021. "Synthesis and In Silico Docking of New Pyrazolo[4,3-e]pyrido[1,2-a]pyrimidine-based Cytotoxic Agents" International Journal of Molecular Sciences 22, no. 19: 10258. https://doi.org/10.3390/ijms221910258