Login Register Cart 0
Generic placeholder image

Current Computer-Aided Drug Design

Editor-in-Chief

ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Design and Biological Evaluation of 3-Aryl-4-alkylpyrazol-5-amines Based on the Target Fishing

Author(s): Shuchao Ma, Ben Ouyang, Linan Wang and Lei Yao*

Volume 16, Issue 5, 2020

Page: [564 - 570] Pages: 7

DOI: 10.2174/1573409915666191003123900

Price: $65

Abstract

Background: Pyrazol-5-amine derivatives are an important class of heterocyclic compounds. However, there are less 4-alkyl substituted pyrazoles reported.

Objective: Here reported are the design, synthesis and biological evaluation of 3-aryl-4- alkylpyrazol-5-amines derivatives.

Methods: A serials of 3-aryl-4-alkylpyrazol-5-amines were designed and the biological action targets were screened by target fishing function of Discovery Studio software. The synthesis route involved 3-oxo-3-arylpropanenitrile formation, alkylation, pyrazole formation, and amides formation. The antitumor activities of these compounds were carried out by thiazolyl blue tetrazolium bromide (MTT) method using U-2 OS (osteosarcoma) and A549 (lung cancer) tumor cells.

Results: Eight 3-aryl-4-alkylpyrazol-5-amines were synthesized, and their structures were verified by 1H NMR, 13C NMR, and HRMS. Thirteen pharmacophores were mapped out by target fishing. Compound 5h showed anti-proliferation activities against U-2 OS and A549 tumor cell with IC50 value of 0.9 μM and 1.2 μM, respectively.

Conclusion: Compound 5h might represent a promising scaffold for the further development of novel antitumor drugs.

Keywords: Target fishing, 3-aryl-4-alkylpyrazol-5-amines, design, synthesis, antitumor, P53.

« Previous Next »
Graphical Abstract

[1]
Raju, H.; Nagamani, T.S.; Chandrappa, S.; Ananda, H.; Vinaya, K.; Thimmegowda, N.R.; Byregowda, S.M.; Rangappa, K.S. Synthesis of 1-(4-methoxybenzyl)-3-cyclopropyl-1H-pyrazol-5-amine derivatives as antimicrobial agents. J. Enzyme Inhib. Med. Chem., 2010, 25(4), 537-543.
[http://dx.doi.org/10.3109/14756360903357601] [PMID: 20235748]
[2]
Karrouchi, K.; Radi, S.; Ramli, Y.; Taoufik, J.; Mabkhot, Y.N.; Al-Aizari, F.A.; Ansar, M. Synthesis and pharmacological activities of pyrazole derivatives: A review. Molecules, 2018, 23(1), 134.
[http://dx.doi.org/10.3390/molecules23010134] [PMID: 29329257]
[3]
Kane, J.L., Jr; Hirth, B.H.; Liang, B.; Gourlie, B.B.; Nahill, S.; Barsomian, G. Ureas of 5-aminopyrazole and 2-aminothiazole inhibit growth of gram-positive bacteria. Bioorg. Med. Chem. Lett., 2003, 13(24), 4463-4466.
[http://dx.doi.org/10.1016/j.bmcl.2003.09.013] [PMID: 14643347]
[4]
Bekhit, A.A.; Hymete, A.; Asfaw, H. Bekhit, Ael-D. Synthesis and biological evaluation of some pyrazole derivatives as anti-malarial agents. Arch. Pharm. (Weinheim), 2012, 345(2), 147-154.
[http://dx.doi.org/10.1002/ardp.201100078] [PMID: 21989651]
[5]
Liu, X.R.; Wu, H.; He, Z.Y.; Ma, Z.Q.; Feng, J.T.; Zhang, X. Design, synthesis and fungicidal activities of some novel pyrazole derivatives. Molecules, 2014, 19(9), 14036-14051.
[http://dx.doi.org/10.3390/molecules190914036] [PMID: 25203055]
[6]
Bondock, S.; Fadaly, W.; Metwally, M.A. Synthesis and antimicrobial activity of some new thiazole, thiophene and pyrazole derivatives containing benzothiazole moiety. Eur. J. Med. Chem., 2010, 45(9), 3692-3701.
[http://dx.doi.org/10.1016/j.ejmech.2010.05.018]
[7]
Raju, H.; Chandrappa, S.; Prasanna, D.S.; Ananda, H.; Nagamani, T.S.; Byregowda, S.M.; Rangappa, K.S. Synthesis, characterization and in-vitro antiproliferative effects of novel 5-amino pyrazole derivatives against breast cancer cell lines. Recent Patents Anticancer Drug Discov., 2011, 6(2), 186-195.
[http://dx.doi.org/10.2174/157489211795328459] [PMID: 21247401]
[8]
Vujasinović, I.; Paravić-Radičević, A.; Mlinarić-Majerski, K.; Brajša, K.; Bertoša, B. Synthesis and biological validation of novel pyrazole derivatives with anticancer activity guided by 3D-QSAR analysis. Bioorg. Med. Chem., 2012, 20(6), 2101-2110.
[http://dx.doi.org/10.1016/j.bmc.2012.01.032] [PMID: 22341245]
[9]
Nitulescu, G.M.; Draghici, C.; Missir, A.V. Synthesis of new pyrazole derivatives and their anticancer evaluation. Eur. J. Med. Chem., 2010, 45(11), 4914-4919.
[http://dx.doi.org/10.1016/j.ejmech.2010.07.064] [PMID: 20728965]
[10]
Balbi, A.; Anzaldi, M.; Macciò, C.; Aiello, C.; Mazzei, M.; Gangemi, R.; Castagnola, P.; Miele, M.; Rosano, C.; Viale, M. Synthesis and biological evaluation of novel pyrazole derivatives with anticancer activity. Eur. J. Med. Chem., 2011, 46(11), 5293-5309.
[http://dx.doi.org/10.1016/j.ejmech.2011.08.014] [PMID: 21920636]
[11]
Bajaj, S.; Sambi, S.S.; Madan, A.K. Topochemical models for prediction of anti-tumor activity of 3-aminopyrazoles. Chem. Pharm. Bull. (Tokyo), 2005, 53(6), 611-615.
[http://dx.doi.org/10.1248/cpb.53.611] [PMID: 15930768]
[12]
Wang, Y.; Zhi, Y.; Jin, Q.; Lu, S.; Lin, G.; Yuan, H.; Yang, T.; Wang, Z.; Yao, C.; Ling, J.; Guo, H.; Li, T.; Jin, J.; Li, B.; Zhang, L.; Chen, Y.; Lu, T. Discovery of 4-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazole-3-carboxamide (FN-1501), an FLT3- and CDK-Kinase Inhibitor with Potentially High Efficiency against Acute Myelocytic Leukemia. J. Med. Chem., 2018, 61(4), 1499-1518.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01261] [PMID: 29357250]
[13]
Christodoulou, M.S.; Fokialakis, N.; Nam, S.; Jove, R.; Skaltsounis, A.L.; Haroutounian, S.A. Synthesis and in vitro biological evaluation of novel pyrazole derivatives as potential antitumor agents. Med. Chem., 2012, 8(5), 779-788.
[http://dx.doi.org/10.2174/157340612802084252] [PMID: 22741785]
[14]
Gawad, A.E.; Hassan, G.S.; Georgey, H.H. Design and synthesis of some pyrazole derivatives of expected anti-inflammatory and analgesic activities. Med. Chem. Res., 2012, 21(7), 983-994.
[http://dx.doi.org/10.1007/s00044-011-9606-4]
[15]
Bekhit, A.A.; Abdel-Aziem, T. Design, synthesis and biological evaluation of some pyrazole derivatives as anti-inflammatory-antimicrobial agents. Bioorg. Med. Chem., 2004, 12(8), 1935-1945.
[http://dx.doi.org/10.1016/j.bmc.2004.01.037] [PMID: 15051061]
[16]
Rai, G.; Brimacombe, K.R.; Mott, B.T.; Urban, D.J.; Hu, X.; Yang, S.M.; Lee, T.D.; Cheff, D.M.; Kouznetsova, J.; Benavides, G.A.; Pohida, K.; Kuenstner, E.J.; Luci, D.K.; Lukacs, C.M.; Davies, D.R.; Dranow, D.M.; Zhu, H.; Sulikowski, G.; Moore, W.J.; Stott, G.M.; Flint, A.J.; Hall, M.D.; Darley-Usmar, V.M.; Neckers, L.M.; Dang, C.V.; Waterson, A.G.; Simeonov, A.; Jadhav, A.; Maloney, D.J. Discovery and optimization of potent, cell-active pyrazole-based inhibitors of lactate dehydrogenase (LDH). J. Med. Chem., 2017, 60(22), 9184-9204.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00941] [PMID: 29120638]
[17]
Sidique, S.; Ardecky, R.; Su, Y.; Narisawa, S.; Brown, B.; Millán, J.L.; Sergienko, E.; Cosford, N.D. Design and synthesis of pyrazole derivatives as potent and selective inhibitors of tissue-nonspecific alkaline phosphatase (TNAP). Bioorg. Med. Chem. Lett., 2009, 19(1), 222-225.
[http://dx.doi.org/10.1016/j.bmcl.2008.10.107] [PMID: 19038545]
[18]
Cho, S.Y.; Lee, B.H.; Jung, H.; Yun, C.S.; Ha, J.D.; Kim, H.R.; Chae, C.H.; Lee, J.H.; Seo, H.W.; Oh, K.S. Design and synthesis of novel 3-(benzo[d]oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine derivatives as selective G-protein-coupled receptor kinase-2 and -5 inhibitors. Bioorg. Med. Chem. Lett., 2013, 23(24), 6711-6716.
[http://dx.doi.org/10.1016/j.bmcl.2013.10.036] [PMID: 24210504]
[19]
Deng, X.L.; Zhang, L.; Hu, X.P.; Yin, B.; Liang, P.; Yang, X.L. Target-based design, synthesis and biological activity of new pyrazole amide derivatives. Chin. Chem. Lett., 2016, 27(2), 251-255.
[http://dx.doi.org/10.1016/j.cclet.2015.10.006]
[20]
Tanitame, A.; Oyamada, Y.; Ofuji, K.; Fujimoto, M.; Iwai, N.; Hiyama, Y.; Suzuki, K.; Ito, H.; Terauchi, H.; Kawasaki, M.; Nagai, K.; Wachi, M.; Yamagishi, J. Synthesis and antibacterial activity of a novel series of potent DNA gyrase inhibitors. Pyrazole derivatives. J. Med. Chem., 2004, 47(14), 3693-3696.
[http://dx.doi.org/10.1021/jm030394f] [PMID: 15214796]
[21]
Foote, K.M.; Mortlock, A.A.; Heron, N.M.; Jung, F.H.; Hill, G.B.; Pasquet, G.; Brady, M.C.; Green, S.; Heaton, S.P.; Kearney, S.; Keen, N.J.; Odedra, R.; Wedge, S.R.; Wilkinson, R.W. Synthesis and SAR of 1-acetanilide-4-aminopyrazole-substituted quinazolines: selective inhibitors of Aurora B kinase with potent anti-tumor activity. Bioorg. Med. Chem. Lett., 2008, 18(6), 1904-1909.
[http://dx.doi.org/10.1016/j.bmcl.2008.02.002] [PMID: 18294849]
[22]
Kasiotis, K.M.; Tzanetou, E.N.; Haroutounian, S.A. Pyrazoles as potential anti-angiogenesis agents: a contemporary overview. Front Chem., 2014, 2, 78.
[http://dx.doi.org/10.3389/fchem.2014.00078] [PMID: 25250310]
[23]
Abdel-Aziz, M. Abuo-Rahma, Gel-D.; Hassan, A.A. Synthesis of novel pyrazole derivatives and evaluation of their antidepressant and anticonvulsant activities. Eur. J. Med. Chem., 2009, 44(9), 3480-3487.
[http://dx.doi.org/10.1016/j.ejmech.2009.01.032] [PMID: 19268406]
[24]
Kumar, G.G.; Vikas, K.; Vinod, K. Pyrazoles as potential antiobesity agents. Res. J. Chem. Environ., 2011, 15(3), 90-103.
[25]
Ouyang, G.; Cai, X.J.; Chen, Z.; Song, B.A.; Bhadury, P.S.; Yang, S.; Jin, L.H.; Xue, W.; Hu, D.Y.; Zeng, S. Synthesis and antiviral activities of pyrazole derivatives containing an oxime moiety. J. Agric. Food Chem., 2008, 56(21), 10160-10167.
[http://dx.doi.org/10.1021/jf802489e] [PMID: 18939848]
[26]
Tao, C.; Wang, Q.; Asad, S.; Weingarten, P.; Ci, S. Trk inhibiton US20180346451, 2018. Dec 06
[27]
Raymond-Delpech, V.; Matsuda, K.; Sattelle, B.M.; Rauh, J.J.; Sattelle, D.B. Ion channels: molecular targets of neuroactive insecticides. Invert. Neurosci., 2005, 5(3-4), 119-133.
[http://dx.doi.org/10.1007/s10158-005-0004-9] [PMID: 16172884]
[28]
Teng, M.; Zhu, J.; Johnson, M.D.; Chen, P.; Kornmann, J.; Chen, E.; Blasina, A.; Register, J.; Anderes, K.; Rogers, C.; Deng, Y.; Ninkovic, S.; Grant, S.; Hu, Q.; Lundgren, K.; Peng, Z.; Kania, R.S. Structure-based design and synthesis of (5-arylamino-2H-pyrazol-3-yl)-biphenyl-2′,4′-diols as novel and potent human CHK1 inhibitors. J. Med. Chem., 2007, 50(22), 5253-5256.
[http://dx.doi.org/10.1021/jm0704604] [PMID: 17887663]
[29]
Abu Thaher, B.; Arnsmann, M.; Totzke, F.; Ehlert, J.E.; Kubbutat, M.H.; Schächtele, C.; Zimmermann, M.O.; Koch, P.; Boeckler, F.M.; Laufer, S.A. Tri- and tetrasubstituted pyrazole derivates: regioisomerism switches activity from p38MAP kinase to important cancer kinases. J. Med. Chem., 2012, 55(2), 961-965.
[http://dx.doi.org/10.1021/jm201391u] [PMID: 22185282]
[30]
Dietrich, J.; Hulme, C.; Hurley, L.H. The design, synthesis, and evaluation of 8 hybrid DFG-out allosteric kinase inhibitors: a structural analysis of the binding interactions of Gleevec, Nexavar, and BIRB-796. Bioorg. Med. Chem., 2010, 18(15), 5738-5748.
[http://dx.doi.org/10.1016/j.bmc.2010.05.063] [PMID: 20621496]
[31]
Kavanagh, M.E.; Coyne, A.G.; McLean, K.J.; James, G.G.; Levy, C.W.; Marino, L.B.; de Carvalho, L.P.S.; Chan, D.S.H.; Hudson, S.A.; Surade, S.; Leys, D.; Munro, A.W.; Abell, C. Fragment-based approaches to the development of mycobacterium tuberculosis CYP121 Inhibitors. J. Med. Chem., 2016, 59(7), 3272-3302.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00007] [PMID: 27002486]
[32]
Ganesan, A.; Barakat, K. Target fishing: a key to unlock the one-to-many puzzle in drug discovery. J. Pharma. Care Health Sys., 2016, 3(2)e141
[33]
Lei, Q.; Liu, H.; Peng, Y.; Xiao, P. In silico target fishing and pharmacological profiling for the isoquinoline alkaloids of Macleaya cordata (Bo Luo Hui). Chin. Med., 2015, 10(1), 37.
[http://dx.doi.org/10.1186/s13020-015-0067-4] [PMID: 26691584]
[34]
Meslamani, J.; Li, J.; Sutter, J.; Stevens, A.; Bertrand, H.O.; Rognan, D. Protein-ligand-based pharmacophores: generation and utility assessment in computational ligand profiling. J. Chem. Inf. Model., 2012, 52(4), 943-955.
[http://dx.doi.org/10.1021/ci300083r] [PMID: 22480372]
[35]
Tang, D.; McKinley, E.T.; Hight, M.R.; Uddin, M.I.; Harp, J.M.; Fu, A.; Nickels, M.L.; Buck, J.R.; Manning, H.C. Synthesis and structure-activity relationships of 5,6,7-substituted pyrazolopyrimidines: discovery of a novel TSPO PET ligand for cancer imaging. J. Med. Chem., 2013, 56(8), 3429-3433.
[http://dx.doi.org/10.1021/jm4001874] [PMID: 23521048]
[36]
Compton, D.R.; Sheng, S.; Carlson, K.E.; Rebacz, N.A.; Lee, I.Y.; Katzenellenbogen, B.S.; Katzenellenbogen, J.A. Pyrazolo[1,5-a]pyrimidines: estrogen receptor ligands possessing estrogen receptor β antagonist activity. J. Med. Chem., 2004, 47(24), 5872-5893.
[http://dx.doi.org/10.1021/jm049631k] [PMID: 15537344]
[37]
Ojima, I.; Awasthi, D.; Wei, L.; Haranahalli, K. Strategic incorporation of fluorine in the drug discovery of new-generation antitubercular agents targeting bacterial cell division protein FtsZ. J. Fluor. Chem., 2017, 196, 44-56.
[http://dx.doi.org/10.1016/j.jfluchem.2016.07.020] [PMID: 28555087]
[38]
Bhat, K.S.; Poojary, B.; Prasad, D.J.; Naik, P.; Holla, B.S. Synthesis and antitumor activity studies of some new fused 1,2,4-triazole derivatives carrying 2,4-dichloro-5-fluorophenyl moiety. Eur. J. Med. Chem., 2009, 44(12), 5066-5070.
[http://dx.doi.org/10.1016/j.ejmech.2009.09.010] [PMID: 19822384]

Rights & Permissions Print Cite
Article Metrics
17
© 2024 Bentham Science Publishers | Privacy Policy