Design, Synthesis and Molecular Docking Studies of Pyrazoline Derivatives as PI3K Inhibitors
- Authors: Kumar R.1, Kumar A.1, Kumar A.2, Singh A.3, Kumar P.2
-
Affiliations:
- Department of Pharmaceutical Sciences and Natural Products,, Central University of Punjab
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab
- Department of Pharmaceutical Sciences and Natural Product, Central University of Punjab
- Issue: Vol 27, No 2 (2024)
- Pages: 256-272
- Section: Chemistry
- URL: https://kazanmedjournal.ru/1386-2073/article/view/644608
- DOI: https://doi.org/10.2174/1386207326666230504163312
- ID: 644608
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Full Text
Abstract
Aim:Design, synthesis and molecular docking studies of quinoline/naphthalene containing pyrazoline derivatives as PI3K inhibitors.
Background:Phosphatidylinositol 3-kinases (PI3Ks) belong to the family of enzymes, which are associated with various cellular functions such as cell growth, proliferation, differentiation etc. Overexpression or any changes in these functions may result in various abnormalities, which in turn cause cancer.
Objectives:To perform synthesis and molecular docking studies of quinoline/naphthalene containing pyrazoline derivatives as PI3K inhibitors.
Methods:2-Chloroquinoline-3-carbaldehyde was synthesized by a reaction of acetanilide and POCl3. The latter was reacted with substituted acetophenones to synthesize chalcones, which were reacted with substituted phenyl hydrazines to yield pyrazoline derivatives (Series I). Similarly, pchloro benzaldehyde was reacted with 2-acetonapthone to yield chalcone with substituted phenyl hydrazines to yield pyrazoline derivatives (Series II).
Results:The synthetic compounds were subjected to molecular modelling experiments using Schrodinger 2016 software and evaluated in silico for their PI3K binding affinities. All the compounds had better docking scores than AMG-319 (-4.36 Kcal/mol) and comparable docking scores with PI-103 (-6.83 Kcal/mol).
Conclusion:Compounds 5 and 3 had the best docking scores (-7.85 and -7.17 Kcal/mol, respectively). The synthesized compounds have better docking scores than the reference drug AMG-319. As a result, they might be used as lead molecules in investigating PI3K inhibitors.
Keywords
About the authors
Rohit Kumar
Department of Pharmaceutical Sciences and Natural Products,, Central University of Punjab
Email: info@benthamscience.net
Arvind Kumar
Department of Pharmaceutical Sciences and Natural Products,, Central University of Punjab
Email: info@benthamscience.net
Adarsh Kumar
Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab
Email: info@benthamscience.net
Ankit Singh
Department of Pharmaceutical Sciences and Natural Product, Central University of Punjab
Email: info@benthamscience.net
Pradeep Kumar
Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab
Author for correspondence.
Email: info@benthamscience.net
References
- Nagai, H.; Kim, Y.H. Cancer prevention from the perspective of global cancer burden patterns. J. Thorac. Dis., 2017, 9(3), 448-451.
- Kuszyk, B.S.; Corl, F.M.; Franano, F.N.; Bluemke, D.A.; Hofmann, L.V.; Fortman, B.J.; Fishman, E.K. Tumor transport physiology: Implications for imaging and imaging-guided therapy. AJR Am. J. Roentgenol., 2001, 177(4), 747-753. doi: 10.2214/ajr.177.4.1770747 PMID: 11566666
- Rosielle, D.A.; Atwood, M.; Marks, S.; Rilling, W.S. Palliative care and symptom management, Interventional oncology: Principles and practice of image-guided. 2016, 294-314.
- Laird, P.W. Cancer epigenetics. Hum. Mol. Genet., 2005, 14(S1), R65-R76. doi: 10.1093/hmg/ddi113 PMID: 15809275
- Chaffer, C.L.; Weinberg, R.A. A perspective on cancer cell metastasis. Science, 2011, 331, 1559-1564. doi: 10.1126/science.1203543 PMID: 21436443
- Lu, P.; Weaver, V.M.; Werb, Z. The extracellular matrix: A dynamic niche in cancer progression. J. Cell Biol., 2012, 196(4), 395-406. doi: 10.1083/jcb.201102147 PMID: 22351925
- Hejmadi, M. Introduction to cancer biology; Bookboon, 2014, pp. 1-48.
- Akinleye, A.; Avvaru, P.; Furqan, M.; Song, Y.; Liu, D. Phosphatidylinositol 3-kinase (PI3K) inhibitors as cancer therapeutics. J. Hematol. Oncol., 2013, 6(1), 88. doi: 10.1186/1756-8722-6-88 PMID: 24261963
- Kong, D.; Yamori, T. Phosphatidylinositol 3-kinase inhibitors: Promising drug candidates for cancer therapy. Cancer Sci., 2008, 99(9), 1734-1740. doi: 10.1111/j.1349-7006.2008.00891.x PMID: 18616528
- Aly, R.M.; Serya, R.; Amira, M.; Al-Ansary, G.H.; Abou El Ella, D.A. Quinoline-based small molecules as effective protein kinases inhibitors. J. Am. Sci., 2016, 12, 10-32.
- Jain, S.; Chandra, V.; Kumar Jain, P.; Pathak, K.; Pathak, D.; Vaidya, A. Comprehensive review on current developments of quinoline-based anticancer agents. Arab. J. Chem., 2019, 12(8), 4920-4946. doi: 10.1016/j.arabjc.2016.10.009
- Qian, Y.; Zhang, H.J.; Zhang, H.; Xu, C.; Zhao, J.; Zhu, H.L. Synthesis, molecular modeling, and biological evaluation of cinnamic acid metronidazole ester derivatives as novel anticancer agents. Bioorg. Med. Chem., 2010, 18(14), 4991-4996. doi: 10.1016/j.bmc.2010.06.003 PMID: 20594859
- Wang, H.H.; Qiu, K.M.; Cui, H.E.; Yang, Y.S. Yin-Luo; Xing, M.; Qiu, X.Y.; Bai, L.F.; Zhu, H.L. Synthesis, molecular docking and evaluation of thiazolyl-pyrazoline derivatives containing benzodioxole as potential anticancer agents. Bioorg. Med. Chem., 2013, 21(2), 448-455. doi: 10.1016/j.bmc.2012.11.020 PMID: 23245802
- Shahavar Sulthana, S.; Arul Antony, S.; Balachandran, C.; Syed Shafi, S. Thiophene and benzodioxole appended thiazolyl-pyrazoline compounds: Microwave assisted synthesis, antimicrobial and molecular docking studies. Bioorg. Med. Chem. Lett., 2015, 25(14), 2753-2757. doi: 10.1016/j.bmcl.2015.05.033 PMID: 26028159
- Altıntop, M.D.; Özdemir, A.; Turan-Zitouni, G.; Ilgın, S.; Atlı Ö.; Demirel, R.; Kaplancıklı Z.A. A novel series of thiazolylpyrazoline derivatives: Synthesis and evaluation of antifungal activity, cytotoxicity and genotoxicity. Eur. J. Med. Chem., 2015, 92, 342-352. doi: 10.1016/j.ejmech.2014.12.055 PMID: 25576739
- Kim, J.; Hong, S.; Hong, S. Discovery of new aminopyrimidine-based phosphoinositide 3-kinase beta (PI3Kβ) inhibitors with selectivity over PI3Kα. Bioorg. Med. Chem. Lett., 2011, 21(23), 6977-6981. doi: 10.1016/j.bmcl.2011.09.118 PMID: 22030027
- Giordanetto, F.; Wållberg, A.; Ghosal, S.; Iliefski, T.; Cassel, J.; Yuan, Z.Q.; von Wachenfeldt, H.; Andersen, S.M.; Inghardt, T.; Tunek, A.; Nylander, S. Discovery of phosphoinositide 3-kinases (PI3K) p110β isoform inhibitor 4-2-hydroxyethyl(1-naphthylmethyl)amino-6-(2S)-2-methylmorpholin-4-yl-1H-pyrimidin-2-one, an effective antithrombotic agent without associated bleeding and insulin resistance. Bioorg. Med. Chem. Lett., 2012, 22(21), 6671-6676. doi: 10.1016/j.bmcl.2012.08.102 PMID: 23010262
- Ciraolo, E.; Morello, F.; Hirsch, E. Present and future of PI3K pathway inhibition in cancer: perspectives and limitations. Curr. Med. Chem., 2011, 18(18), 2674-2685. doi: 10.2174/092986711796011193 PMID: 21649577
- Che, H.; Guo, H.; Si, X.; You, Q.; Lou, W. PP121, a dual inhibitor of tyrosine and phosphoinositide kinases, inhibits anaplastic thyroid carcinoma cell proliferation and migration. Tumour Biol., 2014, 35(9), 8659-8664. doi: 10.1007/s13277-014-2118-3 PMID: 24867098
- Herko, A.; Mavis, C.; Czuczman, M. S.; Hernandez, F. AMG 319, a novel inhibitor of phosphoinositide-3 kinase delta (PI3Kd), demonstrates activity in lymphoma pre-clinical models. Am. Soc. Hematol., 2012, 3718-3718. doi: 10.1182/blood.V120.21.3718.3718
- Gaonkar, S.L.; Vignesh, U.N. Synthesis and pharmacological properties of chalcones: A review. Res. Chem. Intermed., 2017, 43(11), 6043-6077. doi: 10.1007/s11164-017-2977-5
- Joshi, V.D.; Kshirsagar, M.D.; Sarita, S. Synthesis and antimicrobial activities of various pyrazolines from chalcones. Int. J. Chemtech Res., 2012, 4, 971-975.
- Van Den Driessche, G.; Fourches, D. Adverse drug reactions triggered by the common HLA-B*57:01 variant: a molecular docking study. J. Cheminform., 2017, 9(1), 13. doi: 10.1186/s13321-017-0202-6 PMID: 28303164
- Madhavi Sastry, G.; Adzhigirey, M.; Day, T.; Annabhimoju, R.; Sherman, W. Protein and ligand preparation: Parameters, protocols, and influence on virtual screening enrichments. J. Comput. Aided Mol. Des., 2013, 27(3), 221-234. doi: 10.1007/s10822-013-9644-8 PMID: 23579614
- Kumar, S.; Singh, J.; Narasimhan, B.; Shah, S.A.A.; Lim, S.M.; Ramasamy, K.; Mani, V. Reverse pharmacophore mapping and molecular docking studies for discovery of GTPase HRas as promising drug target for bis-pyrimidine derivatives. Chem. Cent. J., 2018, 12(1), 106. doi: 10.1186/s13065-018-0475-5 PMID: 30345469
- Sharma, V.; Sharma, P.C.; Kumar, V. In silico molecular docking analysis of natural pyridoacridines as anticancer agents. Adv Chem, 2016, 2016, 5409387. doi: 10.1155/2016/5409387
- Deep, A.; Singh, J.; Kumar, M.; Mansuri, R.; Sahoo, G.C. Inhibitor designing, virtual screening, and docking studies for methyltransferase: A potential target against dengue virus. J. Pharm. Bioallied Sci., 2016, 8(3), 188-194. doi: 10.4103/0975-7406.171682 PMID: 27413346
- Friesner, R.A.; Murphy, R.B.; Repasky, M.P.; Frye, L.L.; Greenwood, J.R.; Halgren, T.A.; Sanschagrin, P.C.; Mainz, D.T. Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J. Med. Chem., 2006, 49(21), 6177-6196. doi: 10.1021/jm051256o PMID: 17034125
- Lenselink, E.B.; Louvel, J.; Forti, A.F.; van Veldhoven, J.P.D.; de Vries, H.; Mulder-Krieger, T.; McRobb, F.M.; Negri, A.; Goose, J.; Abel, R.; van Vlijmen, H.W.T.; Wang, L.; Harder, E.; Sherman, W.; IJzerman, A.P.; Beuming, T. Predicting binding affinities for GPCR ligands using free-energy perturbation. ACS Omega, 2016, 1(2), 293-304. doi: 10.1021/acsomega.6b00086 PMID: 30023478
- Kalra, S.; Joshi, G.; Munshi, A.; Kumar, R. Structural insights of cyclin dependent kinases: Implications in design of selective inhibitors. Eur. J. Med. Chem., 2017, 142, 424-458. doi: 10.1016/j.ejmech.2017.08.071 PMID: 28911822
- Nandhakumar, R.; Suresh, T.; Jude, A.L.C. Rajesh kannan, V.; Mohan, P.S. Synthesis, antimicrobial activities and cytogenetic studies of newer diazepino quinoline derivatives via VilsmeierHaack reaction. Eur. J. Med. Chem., 2007, 42(8), 1128-1136. doi: 10.1016/j.ejmech.2007.01.004 PMID: 17331623
- Hamama, W.S.; Ibrahim, M.E.; Gooda, A.A.; Zoorob, H.H. Recent advances in the chemistry of 2-chloroquinoline-3-carbaldehyde and related analogs. RSC Advances, 2018, 8(16), 8484-8515. doi: 10.1039/C7RA11537G PMID: 35539824
- Dhakshinamoorthy, A.; Alvaro, M.; Garcia, H. ClaisenSchmidt condensation catalyzed by metal-organic frameworks. Adv. Synth. Catal., 2010, 352(4), 711-717. doi: 10.1002/adsc.200900747
- Guo, S.; Wang, J.; Guo, D.; Zhang, X.; Fan, X. Synthesis of 3,5-disubstituted pyrazoles via cyclocondensation of 1,2-allenic ketones with hydrazines: Application to the synthesis of 5-(5-methyl-pyrazol-3-yl)-2′-deoxycytidine. RSC Advances, 2012, 2(9), 3772-3777. doi: 10.1039/c2ra20274c
- Johnson, M.; Younglove, B.; Lee, L.; LeBlanc, R.; Holt, H., Jr; Hills, P.; Mackay, H.; Brown, T.; Mooberry, S.L.; Lee, M. Design, synthesis, and biological testing of pyrazoline derivatives of combretastatin-A4. Bioorg. Med. Chem. Lett., 2007, 17(21), 5897-5901. doi: 10.1016/j.bmcl.2007.07.105 PMID: 17827004
- Havrylyuk, D.; Zimenkovsky, B.; Vasylenko, O.; Zaprutko, L.; Gzella, A.; Lesyk, R. Synthesis of novel thiazolone-based compounds containing pyrazoline moiety and evaluation of their anticancer activity. Eur. J. Med. Chem., 2009, 44(4), 1396-1404. doi: 10.1016/j.ejmech.2008.09.032 PMID: 19000643
- Roecker, A.J.; Coleman, P.J.; Mercer, S.P.; Schreier, J.D.; Buser, C.A.; Walsh, E.S.; Hamilton, K.; Lobell, R.B.; Tao, W.; Diehl, R.E.; South, V.J.; Davide, J.P.; Kohl, N.E.; Yan, Y.; Kuo, L.C.; Li, C.; Fernandez-Metzler, C.; Mahan, E.A.; Prueksaritanont, T.; Hartman, G.D. Kinesin spindle protein (KSP) inhibitors. Part 8: Design and synthesis of 1,4-diaryl-4,5-dihydropyrazoles as potent inhibitors of the mitotic kinesin KSP. Bioorg. Med. Chem. Lett., 2007, 17(20), 5677-5682. doi: 10.1016/j.bmcl.2007.07.074 PMID: 17766111
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