DESIGN SYNTHESIS OF NOVEL ACRIDINE TAGGED PYRAZOLE DERIVATIVES AS AURORA KINASE INHIBITORS

HARATHI PERKA; SATYAVATI D; DEEPAK REDDY GADE; VIVEKANANDA BOYA; RAJENDRA PRASAD VVS

doi:10.22159/ajpcr.2020.v13i5.36997

Authors

HARATHI PERKA Department of Pharmaceutical Chemistry, Teegala Krishna Reddy College of Pharmacy, Hyderabad, Telangana, India.
SATYAVATI D Department of Pharmacology, Brilliant Grammar School Educational Society’s Group of Institutions (Faculty of Engineering and Faculty of Pharmacy), Hyderabad, Telangana, India.
DEEPAK REDDY GADE Department of Pharmaceutical Chemistry, Vishnu Institute of Pharmaceutical and Educational Research, Narsapur, Telangana, India.
VIVEKANANDA BOYA Department of Pharmaceutical Chemistry, Teegala Krishna Reddy College of Pharmacy, Hyderabad, Telangana, India.
RAJENDRA PRASAD VVS Department of Pharmaceutical Chemistry, Vishnu Institute of Pharmaceutical and Educational Research, Narsapur, Telangana, India.

DOI:

https://doi.org/10.22159/ajpcr.2020.v13i5.36997

Keywords:

Microwave irradiation, Acridine, Pyrazoles, Chalcones, Aurora kinase

Abstract

Objective: A series of novel synthesis of 5-Substituted-3-phenyl-4,5-dihydro-pyrazole-1-carbothioic acid [4-(9, 10-dihydro-acridin-9-yl)-phenyl]- amide (IV) were synthesized using standard procedures and evaluated for cytotoxic studies.

Methods: 9-(4-Chloro-phenyl)-9 and 10-dihydro-acridine (I) were formed by cyclization of diphenylamine with substituted acids in the prescience of zinc chloride and synthesis of 5-substituted-3-phenyl-4, 5-dihydro-pyrazole-1-carbothioic acid amide (3) by the cyclization of different chalcones (II) and final compounds were synthesized by fusion of 5-substituted-3-phenyl-4, 5-dihydro-pyrazole-1-carbothioic acid amide (III) with 9-(4-Chloro-phenyl)-9, 10-dihydro-acridine (I) by microwave irradiation method. Characterization of synthesized compounds by infrared, 1H nuclear magnetic resonance (NMR), 13C NMR, and mass spectroscopic methods. Obtained compounds were evaluated for their cytotoxicity against human breast cancer cell lines (MCF/wt) by sulforhodamine-B assay. Docking studies with Aurora kinase protein were performed to elucidate the possible mechanistic insights of these novel acridine tagged pyrazole derivatives.

Results: Moderate to good in vitro cytotoxic potentials of the newly synthesized molecules was reported against selected human breast cancer cell lines. Among the tested molecules, compound C6 showed good cytotoxic activity against MCF/wt (08.2±0.4 μM). The dock scores of the tested compounds were ranged between −8.926 and −5.139. Compound C6 which has been reported as the most effective cytotoxic agent among the series also reported the highest dock score of -8.926 and showed hydrogen bond interaction with GLU-211, LYS-162, and LYS-143. Ligand binding energy with protein suggested compound C6 has shown the highest binding energy of −86.32133 kcal/mol.

Conclusion: The in vitro studies of the newly synthesized acridine tagged pyrazole derivatives reported considerable cytotoxic potentials against human breast cancer cell lines and structure-activity relationship studies to suggest that acridine tagged pyrazole derivatives with hydroxy group present on phenyl ring at fifth position of pyrazole ring could probably increase the cytotoxic potentials. With the reported bioactivities of these derivatives, further studies on the derivatization could elucidate the broader cytotoxic potentials.

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Author Biography

HARATHI PERKA, Department of Pharmaceutical Chemistry, Teegala Krishna Reddy College of Pharmacy, Hyderabad, Telangana, India.

Pharmaceutical chemistry

References

Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin 2017;67:7-30.

Katayama H, Subrata S. Aurora kinase inhibitors as anticancer molecules. Biochim Biophys Acta 1799;2010:829-39.

Albert A. The Acridines. New York: St. Martin’s Press; 1966. p. 403-504.

Greenwood D. Conflicts of Interest: The genesis of synthetic antimalarial agents in peace and war. J Antimicrob Chemother 1995;36:857-72.

Grove WR. Review of amsacrine, an investigational antineoplastic agent. Clin Pharm 1982;1:320-6.

Van Mouwerik TJ, Caines PM, Ballentine R. Amsacrine evaluation. Drug Intell Clin Pharm 1987;21:330-4

Jehn U. Stem cell transplantation in chronic lymphocytic leukemia. Biol Blood Bone Marrow Transplant 1989;3:53-8.

Harousseau JL. New therapies for acute myeloid leukaemia. Blood 1997;90:2978-86.

Prasad VV, Reddy GD, Kathmann I, Amareswararao M, Peters GJ. Nitric oxide releasing acridonecarboxamide derivatives as reverters of doxorubicin resistance in MCF7/Dx cancer cells. Bioorg Chem 2016;64:51-8.

Jelic S, Nikolic-tomasevic Z, Kovcin V, Milanovic N, Tomasevic Z, Jovanovic V, et al. A two-step reevaluation of high-dose amsacrine for advanced carcinoma of the upper aerodigestive tract: A pilot phase II study. J Chemother 1997;9:364-70.

Urmila G, Sareen V, Khatri V, Chugh S. Synthesis and antifungal activity of new fluorine containing 4-(substituted phenylazo) pyrazoles and isoxazoles. Indian J Heterocycl Chem 2005;14:265-6.

Eicher T, Hauptmann S. Chemistry of Heterocycles: Structure, Reactions, Syntheses, and Applications. Weinheim, Germany: Wiley-VCH; 2003.

Talley JJ, Donald, Rogier J. Priviledged synthesis of pyrazole [1, 3, 4] thiadiazol-[1, 3, 4] oxadiazole-2-thione derivatives. Glob J Res Anal 1995;4:15-6.

Pimerova EV, Voronina EV. Antimicrobial activity of pyrazoles and pyridazines obtained by intreraction of 4-aryl-3- arylhydrazono-2, 4-dioxobutanoic acids and their esters with hydrazines. Pharm Chem J 2001;35:602-4.

Yildirim I, Ozdemir N, Akcamur Y, Dincer M, Andac O. 4-Benzoyl-1, 5-Diphenyl-1H-Pyrazole-3-Carboxylic Acid Methanol Solvate. Hoboken: Wiley; 2005.

Bailey DM, Hansen PE, Hlavac AG, Baizman ER, Pearl J, DeFelice AF, et al. 3,4-Diphenyl-1H-pyrazole-1-propanamine antidepressants. J Med Chem 1985;28:256-60.

Amr AE, Abdel-Latif NA, Abdlla MM. Synthesis of some new testosterone derivatives fused with substituted pyrazoline ring as promising 5alpha-reductase inhibitors. Acta Pharm 2006;56:203-18.

Chimichi S, Boccalini M, Hassan MM, Viola G. Dall’Acqua F, Curini M. Synthesis, structural determination and photo-antiproliferative activity of new 3-pyrazolyl or-isoxazolyl substituted 4-hydroxy-2(1H)-quinolinones. Tetrahedron 2006;62:90-6.

Li X, Lu X, Xing M, Yang XH, Zhao TT, Gong HB, et al. Synthesis, biological evaluation, and molecular docking studies of N,1,3-triphenyl-1H-pyrazole-4-carboxamide derivatives as anticancer agents. Bioorg Med Chem Lett 2012;22:3589-93.

Keepers YP, Pizao PE, Peters GJ, van Ark-Otte J, Winograd B, Pinedo HM. Comparison of the sulforhodamine B protein and tetrazolium (MTT) assays for in vitro chemosensitivity testing. Eur J Cancer 1991;27:897-900.

Harathi P, Prasad VS, Satyavati S, Subramanian S, Boya V, Gali P. Asian J Pharm Clin Res 2015;8:83-7.

LigPrep. Version 2.7. USA: Schrodinger LLC; 2016.

Gade DR, Kunala P, Raavi D, Reddy PV, Prasad RV. Structural insights of JAK2 inhibitors: Pharmacophore modeling and ligand-based 3D-QSAR studies of pyrido-indole derivatives. J Recept Signal Transduct Res 2015;35:189-201.

Reddy GD, Kumar KN, Duganath N, Divya R, Amitha K. ADMET, Docking studies and binding energy calculations of some novel ACE-inhibitors for the treatment of diabetic nephropathy. Int J Drug Dev Res 2012;4:268-82.

Chaitanya P, Reddy GD, Varun G, Srikanth LM, Prasad VV, Ravindernath A. Design and synthesis of quinazolinone derivatives as anti-inflammatory agents: Pharmacophore modeling and 3D QSAR studies. Med Chem 2014;10:711-23.