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Letters in Drug Design & Discovery


ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Review Article

Progress in Synthesis and Bioactivity Evaluation of Pyrazoloquinazolines

Author(s): Hui Zhao, Xiaoxia Hu, Yue Zhang, Chunlei Tang* and Bainian Feng*

Volume 17, Issue 2, 2020

Page: [104 - 113] Pages: 10

DOI: 10.2174/1570180815666181017120100

Price: $65


Background: This paper reviews the research progress of pyrazoloquinazolines which widely used in the field of medicine and pesticide in recent years. Five types of pyrazoloquinazolines are introduced: pyrazolo [4,3-h]quinazolines, pyrazolo[1,5-c]quinazolines, pyrazolo[4,3-f]quinazolines, pyrazolo[1,5-a] quinazolines , pyrazolo[1,5-b]quinazolines, and their new progress in the synthesis methods and treatment of diseases.

Methodology: The derivatives of pyrazoloquinazolines exhibit a wide range of pharmacological properties such as antibacterial, anticancer, antioxidants, anti-inflammatory, anti-diabetic, antiviral activities. Consequently, their syntheses have attracted significant interest. Various methodologies have been developed for the synthesis and functionalization of these class of compounds.

Conclusion: In the present article, the relevant and recent advances in the field will be briefly covered.

Keywords: Pyrazoloquinazolines, synthesis, bioactivity, diseases, anti-inflammatory, anti-diabetic.

Graphical Abstract
Salat, K.; Moniczewski, A.; Librowski, T. Nitrogen, oxygen or sulfur containing heterocyclic compounds as analgesic drugs used as modulators of the nitroxidative stress. Mini Rev. Med. Chem., 2013, 13(3), 335-352.
[PMID: 22876956]
Mistry, M.H.; Parmar, S.J.; Desai, G.C. Synthesis of some heterocyclic compounds and studies of their antimicrobial efficacy. J. Chem. Pharm. Res., 2011, 3(4), 831-837.
Veres, Z.; Takacs, D.; Riedl, Z. Heterocyclic Compounds as MDR Modulators. Lett. Drug Des. Discov., 2015, 8(2)
Rout, S.K.; Kar, D.M. Biological importance of heterocyclic compounds with special attention to isatin and indole derivatives a brief review; Inventi Journals Ltd, 2013.
Souza, M.V.N.D. Synthesis and Biological Activity of Natural Thiazoles: An Important Class of Heterocyclic Compounds. ChemInform, 2005, 26(4-5), 429-449.
Nabil, S. The use of pyridazine thione derivative in the preparation of some new heterocyclic compounds with expected antitumor activity. J. Chem. Pharm. Res., 2012, 4(10), 4562-4569.
Garg, M.; Chauhan, M.; Singh, P.K.; Alex, J.M.; Kumar, R. Pyrazoloquinazolines: Synthetic strategies and bioactivities. Eur. J. Med. Chem., 2015, 97(32), 444-461.
[] [PMID: 25438709]
Jorda, R.; Schütznerová, E.; Cankař, P.; Brychtová, V.; Navrátilová, J.; Kryštof, V. Novel arylazopyrazole inhibitors of cyclin-dependent kinases. Bioorg. Med. Chem., 2015, 23(9), 1975-1981.
[] [PMID: 25835357]
Gnanasekaran, K.K.; Muddala, N.P.; Bunce, R.A. ChemInform Abstract: Pyrazoloquinazolinones and Pyrazolopyrido-pyrimidinones by a Sequential N‐Acylation-SNAr Reaction. ChemInform, 2015, 56(11), 1367-1369.
Degrassi, A.; Russo, M.; Nanni, C.; Patton, V.; Alzani, R.; Giusti, A.M.; Fanti, S.; Ciomei, M.; Pesenti, E.; Texido, G. Efficacy of PHA-848125, a cyclin-dependent kinase inhibitor, on the K-Ras(G12D)LA2 lung adenocarcinoma transgenic mouse model: evaluation by multimodality imaging. Mol. Cancer Ther., 2010, 9(3), 673-681.
[] [PMID: 20197397]
Premnath, P.N.; Liu, S.; Perkins, T.; Abbott, J.; Anderson, E.; McInnes, C. Fragment based discovery of arginine isosteres through REPLACE: towards non-ATP competitive CDK inhibitors. Bioorg. Med. Chem., 2014, 22(1), 616-622.
[] [PMID: 24286762]
Sánchez-Martínez, C.; Gelbert, L.M.; Lallena, M.J.; de Dios, A. Cyclin dependent kinase (CDK) inhibitors as anticancer drugs. Bioorg. Med. Chem. Lett., 2015, 25(17), 3420-3435.
[] [PMID: 26115571]
Ai, Y.; Wang, S.T.; Sun, P.H.; Song, F.J. Molecular modeling studies of 4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline derivatives as potent CDK2/Cyclin a inhibitors using 3D-QSAR and docking. Int. J. Mol. Sci., 2010, 11(10), 3705-3724.
[] [PMID: 21152296]
Cicenas, J.; Kalyan, K.; Sorokinas, A.; Jatulyte, A.; Valiunas, D.; Kaupinis, A.; Valius, M. Highlights of the latest advances in research on CDK inhibitors. Cancers (Basel), 2014, 6(4), 2224-2242.
[] [PMID: 25349887]
Brasca, M.G.; Amboldi, N.; Ballinari, D.; Cameron, A.; Casale, E.; Cervi, G. Identification of N,1,4,4-Tetramethyl-8-[4-(4-methylpiperazin-1-yl)phenyl]amino-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (PHA-848125), a Potent, Orally Available Cyclin Dependent Kinase Inhibitor. J. Med. Chem., 2009, 52(16), 5152-5163.
[] [PMID: 19603809]
Traquandi, G.; Brasca, M.G.; D'Alessio, R.; Polucci, P.; Roletto, F.; Vulpetti, A.; Pevarello, P.; Panzeri, A.; Quartieri, F.; Ferguson, R.; Vianello, P.; Fancelli, D. Pyrazolo-quinazoline derivatives, process for their preparation and their use as kinase inhibitors: US, 20080262933[P] 2016, 10-11.
Caporali, S.; Alvino, E.; Starace, G.; Ciomei, M.; Brasca, M.G.; Levati, L.; Garbin, A.; Castiglia, D.; Covaciu, C.; Bonmassar, E.; D’Atri, S. The cyclin-dependent kinase inhibitor PHA-848125 suppresses the in vitro growth of human melanomas sensitive or resistant to temozolomide, and shows synergistic effects in combination with this triazene compound. Pharmacol. Res., 2010, 61(5), 437-448.
[] [PMID: 20026273]
Mayer, E.L. Targeting breast cancer with CDK inhibitors. Curr. Oncol. Rep., 2015, 17(5), 443-445.
[] [PMID: 25716100]
Asghar, U.; Witkiewicz, A.K.; Turner, N.C.; Knudsen, E.S. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat. Rev. Drug Discov., 2015, 14(2), 130-146.
[] [PMID: 25633797]
Weiss, G.J.; Hidalgo, M.; Borad, M.J.; Laheru, D.; Tibes, R.; Ramanathan, R.K.; Blaydorn, L.; Jameson, G.; Jimeno, A.; Isaacs, J.D.; Scaburri, A.; Pacciarini, M.A.; Fiorentini, F.; Ciomei, M.; Von Hoff, D.D. Phase I study of the safety, tolerability and pharmacokinetics of PHA-848125AC, a dual tropomyosin receptor kinase A and cyclin-dependent kinase inhibitor, in patients with advanced solid malignancies. Invest. New Drugs, 2012, 30(6), 2334-2343.
[] [PMID: 22160853]
Albanese, C.; Alzani, R.; Amboldi, N.; Degrassi, A.; Festuccia, C.; Fiorentini, F.; Gravina, G.; Mercurio, C.; Pastori, W.; Brasca, M.; Pesenti, E.; Galvani, A.; Ciomei, M. Anti-tumour efficacy on glioma models of PHA-848125, a multi-kinase inhibitor able to cross the blood-brain barrier. Br. J. Pharmacol., 2013, 169(1), 156-166.
[] [PMID: 23347136]
Albanese, C.; Alzani, R.; Amboldi, N.; Avanzi, N.; Ballinari, D.; Brasca, M.G.; Festuccia, C.; Fiorentini, F.; Locatelli, G.; Pastori, W.; Patton, V.; Roletto, F.; Colotta, F.; Galvani, A.; Isacchi, A.; Moll, J.; Pesenti, E.; Mercurio, C.; Ciomei, M. Dual targeting of CDK and tropomyosin receptor kinase families by the oral inhibitor PHA-848125, an agent with broad-spectrum antitumor efficacy. Mol. Cancer Ther., 2010, 9(8), 2243-2254.
[] [PMID: 20682657]
Beria, I.; Bossi, R.T.; Brasca, M.G.; Caruso, M.; Ceccarelli, W.; Fachin, G.; Fasolini, M.; Forte, B.; Fiorentini, F.; Pesenti, E.; Pezzetta, D.; Posteri, H.; Scolaro, A.; Re Depaolini, S.; Valsasina, B. NMS-P937, a 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivative as potent and selective Polo-like kinase 1 inhibitor. Bioorg. Med. Chem. Lett., 2011, 21(10), 2969-2974.
[] [PMID: 21470862]
Caldarelli, M.; Angiolini, M.; Disingrini, T.; Donati, D.; Guanci, M.; Nuvoloni, S.; Posteri, H.; Quartieri, F.; Silvagni, M.; Colombo, R. Synthesis and SAR of new pyrazolo[4,3-h]quinazoline-3-carboxamide derivatives as potent and selective MPS1 kinase inhibitors. Bioorg. Med. Chem. Lett., 2011, 21(15), 4507-4511.
[] [PMID: 21723120]
Lan, P.; Chen, W.N.; Xiao, G.K.; Sun, P.H.; Chen, W.M. 3D-QSAR and docking studies on pyrazolo[4,3-h]qinazoline-3-carboxamides as cyclin-dependent kinase 2 (CDK2) inhibitors. Bioorg. Med. Chem. Lett., 2010, 20(22), 6764-6772.
[] [PMID: 20869873]
Beria, I.; Ballinari, D.; Bertrand, J.A.; Borghi, D.; Bossi, R.T.; Brasca, M.G.; Cappella, P.; Caruso, M.; Ceccarelli, W.; Ciavolella, A.; Cristiani, C.; Croci, V.; De Ponti, A.; Fachin, G.; Ferguson, R.D.; Lansen, J.; Moll, J.K.; Pesenti, E.; Posteri, H.; Perego, R.; Rocchetti, M.; Storici, P.; Volpi, D.; Valsasina, B. Identification of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as a new class of orally and selective Polo-like kinase 1 inhibitors. J. Med. Chem., 2010, 53(9), 3532-3551.
[] [PMID: 20397705]
Beria, I.; Valsasina, B.; Brasca, M.G.; Ceccarelli, W.; Colombo, M.; Cribioli, S.; Fachin, G.; Ferguson, R.D.; Fiorentini, F.; Gianellini, L.M.; Giorgini, M.L.; Moll, J.K.; Posteri, H.; Pezzetta, D.; Roletto, F.; Sola, F.; Tesei, D.; Caruso, M. 4,5-Dihydro-1H-pyrazolo[4,3-h]quinazolines as potent and selective Polo-like kinase 1 (PLK1) inhibitors. Bioorg. Med. Chem. Lett., 2010, 20(22), 6489-6494.
[] [PMID: 20932759]
Quiroga, J.; Gálvez, J.; Cobo, J.; Glidewell, C. (5RS)-6H-Spiro[pyrazolo[1,5-c]quinazoline-5,4′-thiochroman]: efficient synthesis under mild conditions, molecular structure and supramolecular assembly. Acta Crystallogr. C Struct. Chem., 2015, 71(Pt 11), 1028-1032.
[] [PMID: 26524179]
Kumar, D.; Kumar, R. Microwave-assisted synthesis of pyrazolo[1,5- c ]quinazolines and their derivatives. Tetrahedron Lett., 2014, 55(16), 2679-2683.
Varano, F.; Catarzi, D.; Colotta, V.; Lenzi, O.; Filacchioni, G.; Galli, A.; Costagli, C. Novel AMPA and kainate receptor antagonists containing the pyrazolo[1,5-c]quinazoline ring system: Synthesis and structure-activity relationships. Bioorg. Med. Chem., 2008, 16(5), 2617-2626.
[] [PMID: 18063372]
Guo, S.; Wang, J.; Fan, X.; Zhang, X.; Guo, D. Synthesis of pyrazolo[1,5-c]quinazoline derivatives through copper-catalyzed tandem reaction of 5-(2-bromoaryl)-1H-pyrazoles with carbonyl compounds and aqueous ammonia. J. Org. Chem., 2013, 78(7), 3262-3270.
[] [PMID: 23485094]
Catarzi, D.; Colotta, V.; Varano, F.; Poli, D.; Squarcialupi, L.; Filacchioni, G.; Varani, K.; Vincenzi, F.; Borea, P.A.; Dal Ben, D.; Lambertucci, C.; Cristalli, G. Pyrazolo[1,5-c]quinazoline derivatives and their simplified analogues as adenosine receptor antagonists: synthesis, structure-affinity relationships and molecular modeling studies. Bioorg. Med. Chem., 2013, 21(1), 283-294.
[] [PMID: 23171656]
Kumar, D.; Kaur, G.; Negi, A.; Kumar, S.; Singh, S.; Kumar, R. Synthesis and study of the electronic properties of pyrazolo[1,5- c]pyrrolo[1,2-a]quinazoline and pyrazolo[1,5-c]pyrido[1,2- a]quinazoline derivatives Monatshefte für Chemie - Chemical Monthly 2017, 148(2), 1-8.
[] [PMID: 182 25222504]
Acosta, P.; Ortiz, A.; Insuasty, B.; Abonia, R.; Quiroga, R. Synthesis and xanthine oxidase inhibitory activity of 5,6-dihydropyrazolo/pyrazolo[1,5-c]quinazoline derivatives. Bioorg. Chem., 2017.
Wang, T.; Shao, A.; Feng, H.; Yang, S.; Gao, M.; Tian, J.; Lei, A. An efficient [3+2] cycloaddition for the synthesis of substituted pyrazolo[1,5- c ]quinazolines. Tetrahedron, 2015, 71(26), 4473-4477.
Varano, F.; Catarzi, D.; Colotta, V.; Calabri, F.R.; Lenzi, O.; Filacchioni, G.; Galli, A.; Costagli, C.; Deflorian, F.; Moro, S. 1-Substituted pyrazolo[1,5-c]quinazolines as novel Gly/NMDA receptor antagonists: synthesis, biological evaluation, and molecular modeling study. Bioorg. Med. Chem., 2005, 13(19), 5536-5549.
[] [PMID: 16087341]
Colotta, V.; Catarzi, D.; Varano, F.; Filacchioni, G.; Cecchi, L.; Galli, A.; Costagli, C. Synthesis and binding activity of some pyrazolo[1,5-c]quinazolines as tools to verify an optional binding site of a benzodiazepine receptor ligand. J. Med. Chem., 1996, 39(15), 2915-2921.
[] [PMID: 8709126]
Varano, F.; Catarzi, D.; Colotta, V.; Poli, D.; Filacchioni, G.; Galli, A.; Costagli, C. Synthesis and biological evaluation of a new set of pyrazolo[1,5-c]quinazolines as glycine/N-methyl-D-aspartic acid receptor antagonists. Chem. Pharm. Bull. (Tokyo), 2009, 57(8), 826-829.
[] [PMID: 19652407]
Asproni, B.; Murineddu, G.; Pau, A.; Pinna, G.A.; Langgård, M.; Christoffersen, C.T.; Nielsen, J.; Kehler, J. Synthesis and SAR study of new phenylimidazole-pyrazolo[1,5-c]quinazolines as potent phosphodiesterase 10A inhibitors. Bioorg. Med. Chem., 2011, 19(1), 642-649.
[] [PMID: 21087867]
Varano, F.; Catarzi, D.; Colotta, V.; Filacchioni, G.; Galli, A.; Costagli, C.; Carlà, V. Synthesis and biological evaluation of a new set of pyrazolo[1,5-c]quinazoline-2-carboxylates as novel excitatory amino acid antagonists. J. Med. Chem., 2002, 45(5), 1035-1044.
[] [PMID: 11855983]
Tonkikh, N.N.; Ryzhanova, K.V.; Petrova, M.V.; Strakovs, A. 4,5-Dihydropyrazolo[3,4- f ]quinazolines. Chem. Heterocycl. Compd., 2004, 35(8), 651-653.
Debray, J.; Bonte, S.; Lozach, O.; Meijer, L.; Demeunynck, M. Catalyst-free synthesis of quinazolin-4-ones from (hetero)aryl-guanidines: application to the synthesis of pyrazolo[4,3-f]quinazolin-9-ones, a new family of DYRK1A inhibitors. Mol. Divers., 2012, 16(4), 659-667.
[] [PMID: 22991074]
Ragab, E.A.; Metwally, N.H.; Mohamed, M.S. Synthesis of some novel pyrazolo[1,5-a] quinazolines and their fused derivatives. Synth. Commun., 2017, 47(2), 148-158.
Hussein, G. M. Characterization and Application of 2-Amino-3-(4- bromophenylazo)-8, 9-Dihydro-7H-Pyrazolo [1,5-a]Quinazolin-6- One in Solvent Extraction of Uranium (VI). International Journal of Nuclear Energy Science and Engineering,, 2017, (7), 6-20.
Taliani, S.; Pugliesi, I.; Barresi, E.; Salerno, S.; Marchand, C.; Agama, K.; Simorini, F.; La Motta, C.; Marini, A.M.; Di Leva, F.S.; Marinelli, L.; Cosconati, S.; Novellino, E.; Pommier, Y.; Di Santo, R.; Da Settimo, F. Phenylpyrazolo[1,5-a]quinazolin-5(4H)-one: a suitable scaffold for the development of noncamptothecin topoisomerase I (Top1) inhibitors. J. Med. Chem., 2013, 56(18), 7458-7462.
[] [PMID: 23987476]
Wenthur, C.J.; Morrison, R.D.J.; Daniels, J.S.; Conn, P.J.; Lindsley, C.W. Synthesis and SAR of substituted pyrazolo[1,5-a]quinazolines as dual mGlu(2)/mGlu(3) NAMs. Bioorg. Med. Chem. Lett., 2014, 24(12), 2693-2698.
[] [PMID: 24794112]
Sircar, J. C.; Capiris, T.; Kesten, S. J. Reactions of 2H-3,l- Benzoxazine-2,4-(1H)dione (Isatoic Anhydride) (1) with Anions of 1,4-Dihydro-5N-Pyrazol-5-ones: Synthesis of Pyrazolo[5,1 - b]quinazolin-9-ones. I. Heterocyclic Chem 1981, (18), 117.
Orlov, V.D.; Sidorenko, D.Yu. Carbo[3+3] Cyclocondensation Reactions. A New Method for the Synthesis of Tetrahydropyrazolo[1,5‐b]quinazolines and Tetrahydropyrazolo[4,5-b]quinazolines. Chem. Heterocycl. Compd., 2012, 48(4), 650-657.
Mohareb, R.M.; Abdo, N.Y.M.; Wardakhan, W.W. Synthesis and evaluation of pyrazolo[5,1-b]quinazoline-2-carboxylate, and its thiazole derivatives as potential antiproliferative agents and Pim-1 kinase inhibitors. Med. Chem. Res., 2017, 1-18.
Ammar, Y.A.; Bondock, S. AL-SEHEMI, A. G.; El-Gaby, M. S. A.; Fouda, A. M.; Thabe, H. Facile and convenient synthesis of pyrimidine, 4H-3,1-benzoxazin-4-one, pyrazolo[5,1-b]quinazoline, pyrido[1,2-a]quinazoline, and chromeno[3,4:4,5]pyrido[1,2-a]quinazoline derivatives. Turk. J. Chem., 2011, 35(6), 893-903.
Ibrahim, Y.R.; Hassan, A.A.; Mohamed, N.K.; Mourad, A.F.E. 3‐Amino‐4‐arylazopyrazoles: CT Complexation and a Novel Synthesis of Pyrazolo[2,3-a]quinazolines. Arch. Pharm. (Weinheim), 1992, 325(7), 389-392.
Strakova, I.A.; Strakov, A.Y.; Petrova, M.V. Pyrazolo[5,4- h]quinazolines. Chem. Heterocycl. Compd., 2000, 36(7), 847-850.
Khamry, A.A.; Shiba, S.A.; Shalaby, A.A. Abd alaha, A. A. Synthesis of Some New Pyrazoloquinazolinone and Quinazolinone Derivatives. J. Heterocycl. Chem., 2006, 43(5), 1189-1193.

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