DESIGN, SYNTHESIS, MOLECULAR DOCKING, ADMET STUDIES AND BIOLOGICAL EVALUATION OF PYRAZOLINE INCORPORATED 1, 2, 3-TRIAZOLE BENZENE SULPHONAMIDES
DOI:
https://doi.org/10.22159/ijpps.2019v11i6.32684Keywords:
ADMET, Cancer, Docking, Malignant, Nil, ProliferationAbstract
Objective: The main objective of this work was to design, synthesize and evaluate the novel pyrazoline incorporated 1,2,3-triazole benzene sulphonamides for cytotoxic and anti-gout activities also to perform Insilco molecular docking studies.
Methods: Designed compounds were synthesized by condensation of different substituted chalcones (3a-i) with hydrazine hydrate and substituted phenylhydrazines. All the synthesized compounds were characterized on the basis of physical and spectral data. To predict the affinity and activity of the ligand molecule Libdock program was employed to generate different bioactive binding poses of designing molecules at the active site of protein Phosphatidylinositol 3-kinase (PI3Kα). Title compounds were evaluated for cytotoxic activity by using 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and anti-gout activity by potassium oxonate induced assay.
Results: All the synthesized compounds showed characteristic peaks in FTIR, 1H, 13C NMR and MASS spectral analysis. In molecular docking studies, compound 3i has shown good binding affinity to the active site of PI3Kα with a docking score of 145.031 and 4 hydrogen bonding interactions with least hepatotoxicity and good bioavailability when compared with that of reference ligand KKR exhibited a Libdock score of 88.35. Remaining compounds also have a good binding affinity with a minimum of 2 bonding interactions and having better absorption, distribution, metabolism, elimination and toxicity (ADMET) profile. The same compound (3i) exhibited the highest cytotoxic activity with an IC50 value of 4.54µg/ml. Compound 4d was evaluated for anti-inflammatory activity and it has significantly ameliorated against potassium oxonate induced gout in mice when compared with that of standard drug allopurinol due to its anti-inflammatory property.
Conclusion: We designed and synthesized a novel series of title compounds in quantitative yields and performed docking studies. New derivatives have a good binding affinity towards PI3Kα enzyme, good bioavailability, least hepatotoxicity and significant cytotoxic activity.
Downloads
References
Vander Heiden MG, Cantley LC, Thompson CB. Understanding the warburg effect: the metabolic requirements of cell proliferation. Science 2009;324:1029-33.
Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT. The PI3Kα pathway in human disease. Cell 2017;170:605-35.
De Sousa Mesquita AP, de Araujo Lopes S, Pernambuco Filho PC, Nader HB, Lopes CC. Acquisition of anoikis resistance promotes alterations in the Ras/ERK and PI3K/Akt signaling pathways and matrix remodeling in endothelial cells. Apoptosis 2017;22:1116-37.
Akinleye A, Avvaru P, Furqan M, Song Y, Liu D. Phosphatidylinositol 3-kinase (PI3K) inhibitors as cancer therapeutics. J Hem Onc 2013;6:88.
Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002;296:1655-7.
Yamaguchi H, Yoshida S, Muroi E, Yoshida N, Kawamura M, Kouchi Z, et al. Phosphoinositide 3-kinase signaling pathway mediated by p110α regulates invadopodia formation. J Cell Biol 2011;193:1275-88.
Rao Jyothi N, Sujith KV, Kalluraya B. An efficient microwave-assisted the synthesis of some novel pyrazoles and their biological activity. Saudi Chem Soc 2008;12:347-52.
Rai NS, Kalluraya B, Lingappa B, Shenoy S, Puranic VG. Convenient access to 1, 3, 4-trisubstituted pyrazoles carrying 5-nitrothiophene moiety via 1, 3-dipolar cycloaddition of sydnones with acetylenic ketones and their antimicrobial evaluation. Eur J Med Chem 2008;43:1715-20.
Sahu SK, Banerjee M, Samantray A, Behera C, Azam MA. Synthesis, analgesic, anti-inflammatory and antimicrobial activities of some novel pyrazoline derivatives. Trop J Pharm Res 2008;7:961-8.
Argade ND, Kalrale BK, Gill CH. Microwave assisted improved method for the synthesis of pyrazole containing 2, 4,-disubstituted oxazole-5-one and their antimicrobial activity. J Chem 2008;5:120-9.
Chovatia PT, Akabari JD, Kachhadia PK, Zalavadia PD, Joshi HS. Synthesis and selective antitubercular and antimicrobial inhibitory activity of 1-acetyl-3, 5-diphenyl-4, 5-dihydro-(1H)-pyrazole derivatives. J Serb Chem Soc 2006;71:713-20.
Manna K, Agrawal YK. Microwave assisted synthesis of new indophenazine 1, 3, 5-trisubstruted pyrazoline derivatives of benzofuran and their antimicrobial activity. Bioorg Med Chem Lett 2009;19:2688-92.
Karthikeyan MS, Holla BS, Kumari NS. Synthesis and antimicrobial studies on novel chloro-fluorine containing hydroxy pyrazolines. Eur J Med Chem 2007;42:30-6.
Ragavan RV, Vijayakumar V, Kumari NS. Synthesis and antimicrobial activities of novel 1, 5-diaryl pyrazoles. Eur J Med Chem 2010;45:1173-80.
Menozzi G, Merello L, Fossa P, Schenone S, Ranise A, Mosti L, et al. Synthesis, antimicrobial activity and molecular modeling studies of halogenated 4-[1H-imidazol-1-yl (phenyl) methyl]-1, 5-diphenyl-1H-pyrazoles. Bioorg Med Chem 2004;12:5465-83.
Lee YT, Chung YK. Silver (I)-catalyzed facile synthesis of pyrazoles from propargyl N-sulfonylhydrazones. J Org Chem 2008;73:4698-701.
Ezawa M, Garvey DS, Janero DR, Khanapure SP, Letts LG, Martino, et al. Design of a heteroaryl modified 1, 5-disubstituted pyrazole cyclooxygenase-2 (COX-2) selective inhibitors. Lett Drug Design Dis 2005;2:40-3.
Dmytro Коrоbkо, Dimitra J Hadjipavlou Litina, Liliya Logoyda. Antioxidant and anti-inflammatory properties of a series of new 7,8-disubstituted theophylline containing a pyrazole ring. Asian J Pharm Clin Res 2018;11:448-50.
Cocconcelli G, Diodato E, Caricasole A, Gaviraghi G, Genesio E, Ghiron C, et al. Aryl azoles with neuroprotective activity Parallel synthesis and attempts at target identification. Bioorg Med Chem 2008;16:2043-52.
Naoum F, Kasiotis KM, Magiatis P, Haroutounian SA. Synthesis of novel nitro-substituted triaryl pyrazole derivatives as potential estrogen receptor ligands. Molecules 2007;12:1259-73.
Manojkumar P, Ravi TK, Gopalakrishnan S. Antioxidant and antibacterial studies of arylazopyrazoles and arylhydrazonopyrazolones containing coumarin moiety. Eur J Med Chem 2009;44:4690-4.
Singh MS, Chowdhury S, Koley S. Advances of azide-alkyne cycloaddition-click chemistry over the recent decade. Tetrahedron 2016;72:5257-83.
Whiting M, Tripp JC, Lin YC, Lindstrom W, Olson AJ, Elder JH, et al. Rapid discovery and structure-activity profiling of novel inhibitors of human immunodeficiency virus type 1 protease enabled by the copper (I)-catalyzed synthesis of 1, 2, 3-triazoles and their further functionalization. J Med Chem 2006;49:7697-710.
Kumar BS, Lakshmi PA. Synthesis and molecular docking studies of novel 1, 2, 3-triazole ring-containing 4-(1, 4, 5-triphenyl-1H-imidazol-2-yl) phenol derivatives as COX inhibitors. Res Chem Int 2018;44:455-67.
Kumar BS, Veena BS, Lakshmi PA, Kamala L, Sujatha E. Synthesis and antimicrobial activity of novel 1, 4, 5-triphenyl-1H-imidazol-[1, 2, 3]-triazole derivatives. Russ J Bioorg Chem 2017;43:589-94.
Giffin MJ, Heaslet H, Brik A, Lin YC, Cauvi G, Wong CH, et al. A copper (I)-catalyzed 1, 2, 3-triazole azide-alkyne click compound is a potent inhibitor of a multidrug-resistant HIV-1 protease variant. J Med Chem 2008;51:6263-70.
Aher NG, Pore VS, Mishra NN, Kumar A, Shukla PK, Sharma A, et al. Synthesis and antifungal activity of 1, 2, 3-triazole containing fluconazole analogues. Bioorg Med Chem Lett 2009;19:759-63.
Kumar R, Sharma V, Bua S, Supuran CT, Sharma PK. Synthesis and biological evaluation of benzenesulphonamide-bearing 1,4,5-trisubstituted-1,2,3-triazoles possessing human carbonic anhydrase I, II, IV, and IX inhibitory activity. J Enz Inhi Med Chem 2017;32:1187-94.
Prabhu C Jalihala, Vaibhav Rajoriya, Varsha Kashaw. Design, synthesis, and evaluation of a new derivative of 1,2,4-triazoles for antimicrobial and anti-inflammatory activity. Int J Curr Pharm Res 2018;10:29-35.
Mousumi Das, Bhaskar Das, Arnab De, Subhasis Banerjee, Amalesh Samanta. Antimicrobial investigation and binding mode analysis of some newly synthesized 4-amino-5-((aryl substituted)-4h-1, 2, 4-triazole-3-yl)-thio linked hydroxamic acid derivatives. Asian J Pharm Clin Res 2019;12:404-6.
Mossman T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Meth 1983;65:55-63.
Published
How to Cite
Issue
Section
