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Current Topics in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Review Article

2,4,5-Trisubstituted Thiazole: A Privileged Scaffold in Drug Design and Activity Improvement

Author(s): Zhen Zhang, Bing Shu, Yaodong Zhang*, Girdhar Singh Deora * and Qing-Shan Li*

Volume 20, Issue 28, 2020

Page: [2535 - 2577] Pages: 43

DOI: 10.2174/1568026620999200917153856

Price: $65

Abstract

Thiazole is an important 5-membered heterocyclic compound containing nitrogen and sulfur atoms with various pharmaceutical applications including anti-inflammatory, anti-cancer, anti-viral, hypoglycemic, anti-bacterial and anti-fungal activities. Until now, the FDA-approved drugs containing thiazole moiety have achieved great success such as dasatinib and dabrafenib. In recent years, considerable research has been focused on thiazole derivatives, especially 2,4,5-trisubstituted thiazole derivatives, due to their multiple medicinal applications. This review covers related literature in the past 20 years, which reported the 2,4,5-trisubstituted thiazole as a privileged scaffold in drug design and activity improvement. Moreover, this review aimed to provide greater insights into the rational design of more potent pharmaceutical molecules based on 2,4,5-trisubstituted thiazole in the future.

Keywords: 2, 4, 5-trisubstituted thiazole, Biological activity, Structure activity relationships, Supplementary drug design, Antiinflammatory, Anti-cancer.

Graphical Abstract

[1]
Rouf, A.; Tanyeli, C. Bioactive thiazole and benzothiazole derivatives. Eur. J. Med. Chem., 2015, 97, 911-927.
[http://dx.doi.org/10.1016/j.ejmech.2014.10.058] [PMID: 25455640]
[2]
Kashyap, S.J.; Garg, V.K.; Sharma, P.K.; Kumar, N.; Dudhe, R.; Gupta, J.K. Thiazoles: having diverse biological activities. Med. Chem. Res., 2011, 21(8), 2123-2132.
[http://dx.doi.org/10.1007/s00044-011-9685-2]
[3]
Eicher, T.; Hauptmann, S.; Speicher, A. The chemistry of heterocycles, Wiley Online Library: Haboken, 2012
[4]
Abele, E.; Abele, R.; Arsenyan, P.; Belyakov, S.; Veveris, M.; Lukevics, E. Phase-transfer catalytic synthesis and hypocholesterolemic activity of thiazino[3,2-a]benzimidazole and its silicon analogue. ChemInform, 2007, 38(47)
[http://dx.doi.org/10.1002/chin.200747128]
[5]
Mishra, R.; Sharma, P.K.; Verma, P.K.; Tomer, I.; Mathur, G.; Dhakad, P.K. Biological potential of thiazole derivatives of synthetic origin. J. Heterocycl. Chem., 2017, 54(4), 2103-2116.
[http://dx.doi.org/10.1002/jhet.2827]
[6]
Singh, I.P.; Gupta, S.; Kumar, S. Thiazole compounds as antiviral agents: an update. Med. Chem., 2020, 16(1), 4-23.
[http://dx.doi.org/10.2174/1573406415666190614101253] [PMID: 31203807]
[7]
Lombardo, L.J.; Lee, F.Y.; Chen, P.; Norris, D.; Barrish, J.C.; Behnia, K.; Castaneda, S.; Cornelius, L.A.; Das, J.; Doweyko, A.M.; Fairchild, C.; Hunt, J.T.; Inigo, I.; Johnston, K.; Kamath, A.; Kan, D.; Klei, H.; Marathe, P.; Pang, S.; Peterson, R.; Pitt, S.; Schieven, G.L.; Schmidt, R.J.; Tokarski, J.; Wen, M.L.; Wityak, J.; Borzilleri, R.M. Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J. Med. Chem., 2004, 47(27), 6658-6661.
[http://dx.doi.org/10.1021/jm049486a] [PMID: 15615512]
[8]
Lindauer, M.; Hochhaus, A. Dasatinib. Recent Results Cancer Res., 2010, 201, 27-65.
[9]
Karaman, M.W.; Herrgard, S.; Treiber, D.K.; Gallant, P.; Atteridge, C.E.; Campbell, B.T.; Chan, K.W.; Ciceri, P.; Davis, M.I.; Edeen, P.T.; Faraoni, R.; Floyd, M.; Hunt, J.P.; Lockhart, D.J.; Milanov, Z.V.; Morrison, M.J.; Pallares, G.; Patel, H.K.; Pritchard, S.; Wodicka, L.M.; Zarrinkar, P.P. A quantitative analysis of kinase inhibitor selectivity. Nat. Biotechnol., 2008, 26(1), 127-132.
[http://dx.doi.org/10.1038/nbt1358] [PMID: 18183025]
[10]
Montero, J.C.; Seoane, S.; Ocaña, A.; Pandiella, A. Inhibition of SRC family kinases and receptor tyrosine kinases by dasatinib: possible combinations in solid tumors. Clin. Cancer Res., 2011, 17(17), 5546-5552.
[http://dx.doi.org/10.1158/1078-0432.CCR-10-2616] [PMID: 21670084]
[11]
Shah, N.P.; Tran, C.; Lee, F.Y.; Chen, P.; Norris, D.; Sawyers, C.L. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science, 2004, 305(5682), 399-401.
[http://dx.doi.org/10.1126/science.1099480] [PMID: 15256671]
[12]
Burgess, M.R.; Skaggs, B.J.; Shah, N.P.; Lee, F.Y.; Sawyers, C.L. Comparative analysis of two clinically active BCR-ABL kinase inhibitors reveals the role of conformation-specific binding in resistance. Proc. Natl. Acad. Sci. USA, 2005, 102(9), 3395-3400.
[http://dx.doi.org/10.1073/pnas.0409770102] [PMID: 15705718]
[13]
Tokarski, J.S.; Newitt, J.A.; Chang, C.Y.J.; Cheng, J.D.; Wittekind, M.; Kiefer, S.E.; Kish, K.; Lee, F.Y.; Borzillerri, R.; Lombardo, L.J.; Xie, D.; Zhang, Y.; Klei, H.E. The structure of Dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. Cancer Res., 2006, 66(11), 5790-5797.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-4187] [PMID: 16740718]
[14]
Talpaz, M.; Shah, N.P.; Kantarjian, H.; Donato, N.; Nicoll, J.; Paquette, R.; Cortes, J.; O’Brien, S.; Nicaise, C.; Bleickardt, E.; Blackwood-Chirchir, M.A.; Iyer, V.; Chen, T.T.; Huang, F.; Decillis, A.P.; Sawyers, C.L. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N. Engl. J. Med., 2006, 354(24), 2531-2541.
[http://dx.doi.org/10.1056/NEJMoa055229] [PMID: 16775234]
[15]
Hochhaus, A.; Kantarjian, H.M.; Baccarani, M.; Lipton, J.H.; Apperley, J.F.; Druker, B.J.; Facon, T.; Goldberg, S.L.; Cervantes, F.; Niederwieser, D.; Silver, R.T.; Stone, R.M.; Hughes, T.P.; Muller, M.C.; Ezzeddine, R.; Countouriotis, A.M.; Shah, N.P. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood, 2007, 109(6), 2303-2309.
[http://dx.doi.org/10.1182/blood-2006-09-047266] [PMID: 17138817]
[16]
Hochhaus, A.; Baccarani, M.; Deininger, M.; Apperley, J.F.; Lipton, J.H.; Goldberg, S.L.; Corm, S.; Shah, N.P.; Cervantes, F.; Silver, R.T.; Niederwieser, D.; Stone, R.M.; Dombret, H.; Larson, R.A.; Roy, L.; Hughes, T.; Müller, M.C.; Ezzeddine, R.; Countouriotis, A.M.; Kantarjian, H.M. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia, 2008, 22(6), 1200-1206.
[http://dx.doi.org/10.1038/leu.2008.84] [PMID: 18401416]
[17]
Shah, N.P.; Kantarjian, H.M.; Kim, D.W.; Réa, D.; Dorlhiac-Llacer, P.E.; Milone, J.H.; Vela-Ojeda, J.; Silver, R.T.; Khoury, H.J.; Charbonnier, A.; Khoroshko, N.; Paquette, R.L.; Deininger, M.; Collins, R.H.; Otero, I.; Hughes, T.; Bleickardt, E.; Strauss, L.; Francis, S.; Hochhaus, A. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. J. Clin. Oncol., 2008, 26(19), 3204-3212.
[http://dx.doi.org/10.1200/JCO.2007.14.9260] [PMID: 18541900]
[18]
Kantarjian, H.; Pasquini, R.; Hamerschlak, N.; Rousselot, P.; Holowiecki, J.; Jootar, S.; Robak, T.; Khoroshko, N.; Masszi, T.; Skotnicki, A.; Hellmann, A.; Zaritsky, A.; Golenkov, A.; Radich, J.; Hughes, T.; Countouriotis, A.; Shah, N. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood, 2007, 109(12), 5143-5150.
[http://dx.doi.org/10.1182/blood-2006-11-056028] [PMID: 17317857]
[19]
Hauschild, A.; Grob, J-J.; Demidov, L.V.; Jouary, T.; Gutzmer, R.; Millward, M.; Rutkowski, P.; Blank, C.U.; Miller, W.H., Jr; Kaempgen, E.; Martín-Algarra, S.; Karaszewska, B.; Mauch, C.; Chiarion-Sileni, V.; Martin, A.M.; Swann, S.; Haney, P.; Mirakhur, B.; Guckert, M.E.; Goodman, V.; Chapman, P.B. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet, 2012, 380(9839), 358-365.
[http://dx.doi.org/10.1016/S0140-6736(12)60868-X] [PMID: 22735384]
[20]
Laquerre, S.; Arnone, M.; Moss, K.; Yang, J.; King, A.J. Abstract B88: A selective Raf kinase inhibitor induces cell death and tumor regression of human cancer cell lines encoding B-RafV600E mutation. Mol. Cancer Ther., 2009, 8(Suppl. 1), B88-B88.
[21]
Murali, R. Menzies; Long, G., Dabrafenib and its potential for the treatment of metastatic melanoma. Drug Des. Devel. Ther., 2012, 6, 391.
[http://dx.doi.org/10.2147/DDDT.S38998]
[22]
Falchook, G.S.; Long, G.V.; Kurzrock, R.; Kim, K.B.; Arkenau, T.H.; Brown, M.P.; Hamid, O.; Infante, J.R.; Millward, M.; Pavlick, A.C.; O’Day, S.J.; Blackman, S.C.; Curtis, C.M.; Lebowitz, P.; Ma, B.; Ouellet, D.; Kefford, R.F. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet, 2012, 379(9829), 1893-1901.
[http://dx.doi.org/10.1016/S0140-6736(12)60398-5] [PMID: 22608338]
[23]
Kefford, R.A.; Arkenau, H.; Brown, M.P. Phase I/II study of GSK2118436, a selective inhibitor of oncogenic mutant BRAF kinase, in patients with metastatic melanoma and other solid tumors. J. Clin. Oncol., 2010, 28(15), 8503-8503.
[http://dx.doi.org/10.1200/jco.2010.28.15_suppl.8503]
[24]
Therasse, P.; Arbuck, S.G.; Eisenhauer, E.A.; Wanders, J.; Kaplan, R.S.; Rubinstein, L.; Verweij, J.; Van Glabbeke, M.; van Oosterom, A.T.; Christian, M.C.; Gwyther, S.G. New guidelines to evaluate the response to treatment in solid tumors. European organization for research and treatment of cancer, national cancer institute of the United States, National Cancer Institute of Canada. J. Natl. Cancer Inst., 2000, 92(3), 205-216.
[http://dx.doi.org/10.1093/jnci/92.3.205] [PMID: 10655437]
[25]
Ascierto, P.A.; Minor, D.; Ribas, A.; Lebbe, C.; O’Hagan, A.; Arya, N.; Guckert, M.; Schadendorf, D.; Kefford, R.F.; Grob, J.J.; Hamid, O.; Amaravadi, R.; Simeone, E.; Wilhelm, T.; Kim, K.B.; Long, G.V.; Martin, A.M.; Mazumdar, J.; Goodman, V.L.; Trefzer, U. Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma. J. Clin. Oncol., 2013, 31(26), 3205-3211.
[http://dx.doi.org/10.1200/JCO.2013.49.8691] [PMID: 23918947]
[26]
Eisenhauer, E. A.; Therasse, P.; Bogaerts, J.; Schwartz, L. H.; Sargent, D.; Ford, R.; Dancey, J.; Arbuck, S.; Gwyther, S.; Mooney, M. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1) Eur. J. Cancer, 2009, 45(2), 0-247.
[27]
Das, D.; Sikdar, P.; Bairagi, M. Recent developments of 2-aminothiazoles in medicinal chemistry. Eur. J. Med. Chem., 2016, 109, 89-98.
[http://dx.doi.org/10.1016/j.ejmech.2015.12.022] [PMID: 26771245]
[28]
Wu, Y.; Chen, C.; Sun, X.; Shi, X.; Jin, B.; Ding, K.; Yeung, S-C.J.; Pan, J. Cyclin-dependent kinase 7/9 inhibitor SNS-032 abrogates FIP1-like-1 platelet-derived growth factor receptor α and bcr-abl oncogene addiction in malignant hematologic cells. Clin. Cancer Res., 2012, 18(7), 1966-1978.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-1971] [PMID: 22447844]
[29]
Liaras, K.; Fesatidou, M.; Geronikaki, A. Thiazoles and thiazolidinones as COX/LOX inhibitors. Molecules, 2018, 23(3)E685
[http://dx.doi.org/10.3390/molecules23030685] [PMID: 29562646]
[30]
Jimonet, P.; Audiau, F.; Barreau, M.; Blanchard, J-C.; Boireau, A.; Bour, Y.; Coléno, M-A.; Doble, A.; Doerflinger, G.; Huu, C.D.; Donat, M.H.; Duchesne, J.M.; Ganil, P.; Guérémy, C.; Honor, E.; Just, B.; Kerphirique, R.; Gontier, S.; Hubert, P.; Laduron, P.M.; Le Blevec, J.; Meunier, M.; Miquet, J.M.; Nemecek, C.; Mignani, S. Riluzole series. Synthesis and in vivo “antiglutamate” activity of 6-substituted-2-benzothiazolamines and 3-substituted-2-imino-benzothiazolines. J. Med. Chem., 1999, 42(15), 2828-2843.
[http://dx.doi.org/10.1021/jm980202u] [PMID: 10425092]
[31]
Laczkowski, K.Z.; Biernasiuk, A.; Baranowska-Laczkowska, A.; Misiura, K.; Malm, A.; Plech, T.; Paneth, A.K.; Biernasiuk, A.; Baranowska-Laczkowska, A.; Misiura, K.; Malm, A.; Plech, T.; Paneth, A. Synthesis, antibacterial activity, interaction with nucleobase and molecular docking studies of 4-formylbenzoic acid based thiazoles. Med. Chem., 2016, 12(6), 553-562.
[http://dx.doi.org/10.2174/1573406412666160201121310] [PMID: 26833073]
[32]
Mishra, C.B.; Kumari, S.; Tiwari, M. Thiazole: a promising heterocycle for the development of potent CNS active agents. Eur. J. Med. Chem., 2015, 92, 1-34.
[http://dx.doi.org/10.1016/j.ejmech.2014.12.031] [PMID: 25544146]
[33]
Ayati, A.; Emami, S.; Moghimi, S.; Foroumadi, A. Thiazole in the targeted anticancer drug discovery. Future Med. Chem., 2019, 11(15), 1929-1952.
[http://dx.doi.org/10.4155/fmc-2018-0416] [PMID: 31313595]
[34]
Sharma, P.C.; Bansal, K.K.; Sharma, A.; Sharma, D.; Deep, A. Thiazole-containing compounds as therapeutic targets for cancer therapy. Eur. J. Med. Chem., 2020, 188112016
[http://dx.doi.org/10.1016/j.ejmech.2019.112016] [PMID: 31926469]
[35]
Tripathi, A.C.; Gupta, S.J.; Fatima, G.N.; Sonar, P.K.; Verma, A.; Saraf, S.K. 4-Thiazolidinones: the advances continue…. Eur. J. Med. Chem., 2014, 72, 52-77.
[http://dx.doi.org/10.1016/j.ejmech.2013.11.017] [PMID: 24355348]
[36]
Vengurlekar, S.; Prachand, S.; Jain, S.; Gupta, R. Synthesis and Evaluation of some Thiazole derivatives as an Antifungal agent. Int. J. Pharm. Life Sci., 2014, 5(5), 3526-3530.
[37]
Kaur, H.; Kumar, S.; Vishwakarma, P.; Sharma, M.; Saxena, K.K.; Kumar, A. Synthesis and antipsychotic and anticonvulsant activity of some new substituted oxa/thiadiazolylazetidinonyl/thiazoli-dinonylcarbazoles. Eur. J. Med. Chem., 2010, 45(7), 2777-2783.
[http://dx.doi.org/10.1016/j.ejmech.2010.02.060] [PMID: 20392546]
[38]
Ulusoy Güzeldemirci, N.; Karaman, B. Antibacterial, antitubercular and antiviral activity evaluations of some arylidenehydrazide derivatives bearing imidazo [2, 1-b] thiazole moiety Turk. J. Pharm. Sci, 2017, 14(2)
[39]
Dawood, K.M.; Abdel-Gawad, H.; Rageb, E.A.; Ellithey, M.; Mohamed, H.A. Synthesis, anticonvulsant, and anti-inflammatory evaluation of some new benzotriazole and benzofuran-based heterocycles. Bioorg. Med. Chem., 2006, 14(11), 3672-3680.
[http://dx.doi.org/10.1016/j.bmc.2006.01.033] [PMID: 16464601]
[40]
Bondock, S.; Fouda, A.M. Synthesis and evaluation of some new 5-(hetaryl) thiazoles as potential antimicrobial agents. Synth. Commun., 2018, 48(5), 561-573.
[http://dx.doi.org/10.1080/00397911.2017.1412465]
[41]
Iravani, N.; Keshavarz, M.; Allah-Karampour, M. One-pot three-component synthesis of some novel ethyl 3-alkyl-2-thioxo-2, 3-dihydrothiazole-4-carboxylates under solvent-and catalyst-free conditions at room temperature. J. Sulfur Chem., 2018, 39(4), 414-421.
[http://dx.doi.org/10.1080/17415993.2018.1441841]
[42]
Ouf, S.A.; Gomha, S.M.; Ewies, M.M.; Sharawy, I.A. Synthesis, characterization, and anifungal activity evaluation of some novel arylazothiazoles. J. Heterocycl. Chem., 2018, 55(1), 258-264.
[http://dx.doi.org/10.1002/jhet.3040]
[43]
Ouf, S.A.; Gomha, S.M.; Eweis, M.; Ouf, A.S.; Sharawy, I.A. Efficiency of newly prepared thiazole derivatives against some cutaneous fungi. Bioorg. Med. Chem., 2018, 26(12), 3287-3295.
[http://dx.doi.org/10.1016/j.bmc.2018.04.056] [PMID: 29729988]
[44]
Khalil, A.; Elsayed, G.A.; Mohamed, H.A.; Raafat, A. Utility of chloroacetonitrile in construction of some hitherto novel pyrazole and thiazole derivatives. J. Iran. Chem. Soc., 2018, 15(1), 191-199.
[http://dx.doi.org/10.1007/s13738-017-1223-9]
[45]
Ueda, S.; Terauchi, H.; Kawasaki, M.; Yano, A.; Ido, M. Structure-activity relationships of 2-aminothiazole derivatives as inducible nitric oxide synthase inhibitor. Chem. Pharm. Bull. (Tokyo), 2004, 52(5), 634-637.
[http://dx.doi.org/10.1248/cpb.52.634] [PMID: 15133224]
[46]
Tiperciuc, B.; Pârvu, A.; Tamaian, R.; Nastasă, C.; Ionuţ, I.; Oniga, O. New anti-inflammatory thiazolyl-carbonyl-thiosemicarbazides and thiazolyl-azoles with antioxidant properties as potential iNOS inhibitors. Arch. Pharm. Res., 2013, 36(6), 702-714.
[http://dx.doi.org/10.1007/s12272-013-0083-9] [PMID: 23504664]
[47]
Zia-ur-Rehman, M.; Choudary, J.A.; Ahmad, S. An efficient synthesis of 2-alkyl-4-hydroxy-2H-1, 2-benzothiazine-3-carboxamide-1, 1-dioxides. Bull. Korean Chem. Soc., 2005, 26(11), 1771.
[http://dx.doi.org/10.5012/bkcs.2005.26.11.1771]
[48]
Potewar, T.M.; Ingale, S.A.; Srinivasan, K.V. Efficient synthesis of 2, 4-disubstituted thiazoles using ionic liquid under ambient conditions: a practical approach towards the synthesis of Fanetizole. Tetrahedron, 2007, 63(45), 11066-11069.
[http://dx.doi.org/10.1016/j.tet.2007.08.036]
[49]
Thore, S.; Gupta, S.V.; Baheti, K.G. Synthesis and pharmacological evaluation of 5-methyl-2-phenylthiazole-4-substituted heteroazoles as a potential anti-inflammatory and analgesic agents. J. Saudi Chem. Soc., 2016, 20, S46-S52.
[http://dx.doi.org/10.1016/j.jscs.2012.09.002]
[50]
Khillare, L.D.; Bhosle, M.R.; Deshmukh, A.R.; Mane, R.A. Synthesis and anti-inflammatory evaluation of new pyrazoles bearing biodynamic thiazole and thiazolidinone scaffolds. Med. Chem. Res., 2015, 24(4), 1380-1386.
[http://dx.doi.org/10.1007/s00044-014-1222-7]
[51]
Zhu, J.; Han, L.; Diao, Y.; Ren, X.; Xu, M.; Xu, L.; Li, S.; Li, Q.; Dong, D.; Huang, J.; Liu, X.; Zhao, Z.; Wang, R.; Zhu, L.; Xu, Y.; Qian, X.; Li, H. Design, synthesis, X-ray crystallographic analysis, and biological evaluation of thiazole derivatives as potent and selective inhibitors of human dihydroorotate dehydrogenase. J. Med. Chem., 2015, 58(3), 1123-1139.
[http://dx.doi.org/10.1021/jm501127s] [PMID: 25580811]
[52]
Miwatashi, S.; Arikawa, Y.; Matsumoto, T.; Uga, K.; Kanzaki, N.; Imai, Y.N.; Ohkawa, S. Synthesis and biological activities of 4-phenyl-5-pyridyl-1,3-thiazole derivatives as selective adenosine A3 antagonists. Chem. Pharm. Bull. (Tokyo), 2008, 56(8), 1126-1137.
[http://dx.doi.org/10.1248/cpb.56.1126] [PMID: 18670113]
[53]
Lagoja, I.; Pannecouque, C.; Griffioen, G.; Wera, S.; Rojasdelaparra, V.M.; Van Aerschot, A. Substituted 2-aminothiazoles are exceptional inhibitors of neuronal degeneration in tau-driven models of Alzheimer’s disease. Eur. J. Pharm. Sci., 2011, 43(5), 386-392.
[http://dx.doi.org/10.1016/j.ejps.2011.05.014] [PMID: 21664968]
[54]
Lee, Y.S.; Kim, H.; Kim, Y-H.; Roh, E.J.; Han, H.; Shin, K.J. Synthesis and structure-activity relationships of tri-substituted thiazoles as RAGE antagonists for the treatment of Alzheimer’s disease. Bioorg. Med. Chem. Lett., 2012, 22(24), 7555-7561.
[http://dx.doi.org/10.1016/j.bmcl.2012.10.022] [PMID: 23140885]
[55]
Shidore, M.; Machhi, J.; Shingala, K.; Murumkar, P.; Sharma, M.K.; Agrawal, N.; Tripathi, A.; Parikh, Z.; Pillai, P.; Yadav, M.R. Benzylpiperidine-linked diarylthiazoles as potential anti-Alzheimer’s agents: synthesis and biological evaluation. J. Med. Chem., 2016, 59(12), 5823-5846.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00426] [PMID: 27253679]
[56]
Dos Santos, T.A.R.; da Silva, A.C.; Silva, E.B.; Gomes, P.A.; Espíndola, J.W.P.; Cardoso, M.V.; Moreira, D.R.M.; Leite, A.C.L.; Pereira, V.R. Antitumor and immunomodulatory activities of thiosemicarbazones and 1,3-Thiazoles in Jurkat and HT-29 cells. Biomed. Pharmacother., 2016, 82, 555-560.
[http://dx.doi.org/10.1016/j.biopha.2016.05.038] [PMID: 27470396]
[57]
Duan, Y.; Zhu, H. The Advance in important target proteins. Curr. Top. Med. Chem., 2019, 19(15), 1275-1275.
[http://dx.doi.org/10.2174/156802661915190827162456] [PMID: 31526338]
[58]
Liu, W.; Wang, X.; Zhu, H.; Duan, Y. Precision tumor medicine and drug targets. Curr. Top. Med. Chem., 2019, 19(17), 1488-1489.
[http://dx.doi.org/10.2174/156802661917190828111130] [PMID: 31592750]
[59]
Duan, Y.; Liu, W.; Tian, L.; Mao, Y.; Song, C. Targeting tubulin-colchicine site for cancer therapy: inhibitors, antibody- drug conjugates and degradation agents. Curr. Top. Med. Chem., 2019, 19(15), 1289-1304.
[http://dx.doi.org/10.2174/1568026619666190618130008] [PMID: 31210108]
[60]
Duan, Y.T.; Sangani, C.B.; Liu, W.; Soni, K.V.; Yao, Y. New promises to cure cancer and other genetic diseases/disorders: epi-drugs through epigenetics. Curr. Top. Med. Chem., 2019, 19(12), 972-994.
[http://dx.doi.org/10.2174/1568026619666190603094439] [PMID: 31161992]
[61]
Romagnoli, R.; Baraldi, P.G.; Brancale, A.; Ricci, A.; Hamel, E.; Bortolozzi, R.; Basso, G.; Viola, G. Convergent synthesis and biological evaluation of 2-amino-4-(3′,4′,5′-trimethoxyphenyl)-5-aryl thiazoles as microtubule targeting agents. J. Med. Chem., 2011, 54(14), 5144-5153.
[http://dx.doi.org/10.1021/jm200392p] [PMID: 21663319]
[62]
Romagnoli, R.; Baraldi, P.G.; Salvador, M.K.; Camacho, M.E.; Preti, D.; Tabrizi, M.A.; Bassetto, M.; Brancale, A.; Hamel, E.; Bortolozzi, R.; Basso, G.; Viola, G. Synthesis and biological evaluation of 2-substituted-4-(3′,4′,5′-trimethoxyphenyl)-5-aryl thiazoles as anticancer agents. Bioorg. Med. Chem., 2012, 20(24), 7083-7094.
[http://dx.doi.org/10.1016/j.bmc.2012.10.001] [PMID: 23117171]
[63]
Wang, F.; Yang, Z.; Liu, Y.; Ma, L.; Wu, Y.; He, L.; Shao, M.; Yu, K.; Wu, W.; Pu, Y.; Nie, C.; Chen, L. Synthesis and biological evaluation of diarylthiazole derivatives as antimitotic and antivascular agents with potent antitumor activity. Bioorg. Med. Chem., 2015, 23(13), 3337-3350.
[http://dx.doi.org/10.1016/j.bmc.2015.04.055] [PMID: 25937236]
[64]
Giri, R.S.; Thaker, H.M.; Giordano, T.; Chen, B.; Nuthalapaty, S.; Vasu, K.K.; Sudarsanam, V. Synthesis and evaluation of quinazolinone derivatives as inhibitors of NF-kappaB, AP-1 mediated transcription and eIF-4E mediated translational activation: inhibitors of multi-pathways involve in cancer. Eur. J. Med. Chem., 2010, 45(9), 3558-3563.
[http://dx.doi.org/10.1016/j.ejmech.2010.04.038] [PMID: 20557982]
[65]
Wu, Z.; Fang, Y.; Tang, Y.; Xiao, M.; Ye, J.; Li, G.; Hu, A. Synthesis and antitumor evaluation of 5-(benzo [d][1, 3] dioxol-5-ylmethyl)-4-(tert-butyl)-N-arylthiazol-2-amines. MedChemComm, 2016, 7(9), 1768-1774.
[http://dx.doi.org/10.1039/C6MD00234J]
[66]
Wu, Z.; Ding, N.; Tang, Y.; Ye, J.; Peng, J.; Hu, A. Synthesis and antitumor activity of novel N-(5-benzyl-4-(tert-butyl) thiazol-2-yl)-2-(piperazin-1-yl) acetamides. Res. Chem. Intermed., 2017, 43(8), 4833-4850.
[http://dx.doi.org/10.1007/s11164-017-2915-6]
[67]
Gomha, S.M.; Ahmed, S.A.; Abdelhamid, A.O. Synthesis and cytotoxicity evaluation of some novel thiazoles, thiadiazoles, and pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-ones incorporating triazole moiety. Molecules, 2015, 20(1), 1357-1376.
[http://dx.doi.org/10.3390/molecules20011357] [PMID: 25594346]
[68]
Gomha, S.M.; Zaki, Y.H.; Abdelhamid, A.O. Utility of 3-Acetyl-6-bromo-2H-chromen-2-one for the synthesis of new heterocycles as potential antiproliferative agents. Molecules, 2015, 20(12), 21826-21839.
[http://dx.doi.org/10.3390/molecules201219803] [PMID: 26690106]
[69]
Gomha, S.M.; Salaheldin, T.A.; Hassaneen, H.M.; Abdel-Aziz, H.M.; Khedr, M.A. Synthesis, characterization and molecular docking of novel bioactive thiazolyl-thiazole derivatives as promising cytotoxic antitumor drug. Molecules, 2015, 21(1)E3.
[http://dx.doi.org/10.3390/molecules21010003] [PMID: 26703554]
[70]
Gomha, S.M.; Abdelhamid, A.O.; Abdelrehem, N.A.; Kandeel, S.M. Efficient synthesis of new benzofuran-based thiazoles and investigation of their cytotoxic activity against human breast carcinoma cell lines. J. Heterocycl. Chem., 2018, 55(4), 995-1001.
[http://dx.doi.org/10.1002/jhet.3131]
[71]
Napolitano, G.; Majello, B.; Lania, L. Role of cyclinT/Cdk9 complex in basal and regulated transcription (review). Int. J. Oncol., 2002, 21(1), 171-177.
[http://dx.doi.org/10.3892/ijo.21.1.171] [PMID: 12063565]
[72]
Shao, H.; Shi, S.; Foley, D.W.; Lam, F.; Abbas, A.Y.; Liu, X.; Huang, S.; Jiang, X.; Baharin, N.; Fischer, P.M.; Wang, S. Synthesis, structure-activity relationship and biological evaluation of 2,4,5-trisubstituted pyrimidine CDK inhibitors as potential anti-tumour agents. Eur. J. Med. Chem., 2013, 70, 447-455.
[http://dx.doi.org/10.1016/j.ejmech.2013.08.052] [PMID: 24185375]
[73]
Wang, S.; Griffiths, G.; Midgley, C.A.; Barnett, A.L.; Cooper, M.; Grabarek, J.; Ingram, L.; Jackson, W.; Kontopidis, G.; McClue, S.J.; McInnes, C.; McLachlan, J.; Meades, C.; Mezna, M.; Stuart, I.; Thomas, M.P.; Zheleva, D.I.; Lane, D.P.; Jackson, R.C.; Glover, D.M.; Blake, D.G.; Fischer, P.M. Discovery and characterization of 2-anilino-4- (thiazol-5-yl)pyrimidine transcriptional CDK inhibitors as anticancer agents. Chem. Biol., 2010, 17(10), 1111-1121.
[http://dx.doi.org/10.1016/j.chembiol.2010.07.016] [PMID: 21035734]
[74]
Wang, S.; Meades, C.; Wood, G.; Osnowski, A.; Anderson, S.; Yuill, R.; Thomas, M.; Mezna, M.; Jackson, W.; Midgley, C.; Griffiths, G.; Fleming, I.; Green, S.; McNae, I.; Wu, S.Y.; McInnes, C.; Zheleva, D.; Walkinshaw, M.D.; Fischer, P.M. 2-Anilino-4-(thiazol-5-yl)pyrimidine CDK inhibitors: synthesis, SAR analysis, X-ray crystallography, and biological activity. J. Med. Chem., 2004, 47(7), 1662-1675.
[http://dx.doi.org/10.1021/jm0309957] [PMID: 15027857]
[75]
Rostom, S.A.; Faidallah, H.M.; Radwan, M.F.; Badr, M.H. Bifunctional ethyl 2-amino-4-methylthiazole-5-carboxylate derivatives: synthesis and in vitro biological evaluation as antimicrobial and anticancer agents. Eur. J. Med. Chem., 2014, 76, 170-181.
[http://dx.doi.org/10.1016/j.ejmech.2014.02.027] [PMID: 24583356]
[76]
Zaharia, V.; Ignat, A.; Palibroda, N.; Ngameni, B.; Kuete, V.; Fokunang, C.N.; Moungang, M.L.; Ngadjui, B.T. Synthesis of some p-toluenesulfonyl-hydrazinothiazoles and hydrazino-bis-thiazoles and their anticancer activity. Eur. J. Med. Chem., 2010, 45(11), 5080-5085.
[http://dx.doi.org/10.1016/j.ejmech.2010.08.017] [PMID: 20810194]
[77]
He, H.; Wang, X.; Shi, L.; Yin, W.; Yang, Z.; He, H.; Liang, Y. Synthesis, antitumor activity and mechanism of action of novel 1,3-thiazole derivatives containing hydrazide-hydrazone and carboxamide moiety. Bioorg. Med. Chem. Lett., 2016, 26(14), 3263-3270.
[http://dx.doi.org/10.1016/j.bmcl.2016.05.059] [PMID: 27262600]
[78]
Shi, H-B.; Zhang, S-J.; Ge, Q-F.; Guo, D-W.; Cai, C-M.; Hu, W-X. Synthesis and anticancer evaluation of thiazolyl-chalcones. Bioorg. Med. Chem. Lett., 2010, 20(22), 6555-6559.
[http://dx.doi.org/10.1016/j.bmcl.2010.09.041] [PMID: 20888764]
[79]
Abou-Seri, S.M.; Eldehna, W.M.; Ali, M.M.; Abou El Ella, D.A. 1-Piperazinylphthalazines as potential VEGFR-2 inhibitors and anticancer agents: Synthesis and in vitro biological evaluation. Eur. J. Med. Chem., 2016, 107, 165-179.
[http://dx.doi.org/10.1016/j.ejmech.2015.10.053] [PMID: 26590508]
[80]
Cai, W-X.; Liu, A-L.; Li, Z-M.; Dong, W-L.; Liu, X-H.; Sun, N-B. Synthesis and anticancer activity of novel thiazole-5-carboxamide derivatives. Appl. Sci. (Basel), 2016, 6(1), 8.
[http://dx.doi.org/10.3390/app6010008]
[81]
Gomha, S.M.; Kheder, N.A.; Abdelaziz, M.R.; Mabkhot, Y.N.; Alhajoj, A.M. A facile synthesis and anticancer activity of some novel thiazoles carrying 1,3,4-thiadiazole moiety. Chem. Cent. J., 2017, 11(1), 25.
[http://dx.doi.org/10.1186/s13065-017-0255-7] [PMID: 29086817]
[82]
Gomha, S.M.; Abdelaziz, M.R.; Kheder, N.A.; Abdel-Aziz, H.M.; Alterary, S.; Mabkhot, Y.N. A facile access and evaluation of some novel thiazole and 1,3,4-thiadiazole derivatives incorporating thiazole moiety as potent anticancer agents. Chem. Cent. J., 2017, 11(1), 105.
[http://dx.doi.org/10.1186/s13065-017-0335-8] [PMID: 29086869]
[83]
Amin, H.K.; El-Araby, A.M.; Eid, S.; Nasr, T.; Bondock, S.; Leheta, O.; Dawoud, M.E. A thiazole analogue exhibits an anti-proliferative effect in different human carcinoma cell lines and its mechanism based on molecular modeling. Adv. Biol. Chem., 2017, 7(1), 76-87.
[http://dx.doi.org/10.4236/abc.2017.71005]
[84]
Luo, Y.; Xiao, F.; Qian, S.; Lu, W.; Yang, B. Synthesis and in vitro cytotoxic evaluation of some thiazolylbenzimidazole derivatives. Eur. J. Med. Chem., 2011, 46(1), 417-422.
[http://dx.doi.org/10.1016/j.ejmech.2010.11.014] [PMID: 21115212]
[85]
Romagnoli, R.; Baraldi, P.G.; Lopez Cara, C.; Kimatrai Salvador, M.; Bortolozzi, R.; Basso, G.; Viola, G.; Balzarini, J.; Brancale, A.; Fu, X-H.; Li, J.; Zhang, S.Z.; Hamel, E. One-pot synthesis and biological evaluation of 2-pyrrolidinyl-4-amino-5-(3′,4′,5′-trimethoxybenzoyl)thiazole: a unique, highly active antimicrotubule agent. Eur. J. Med. Chem., 2011, 46(12), 6015-6024.
[http://dx.doi.org/10.1016/j.ejmech.2011.10.013] [PMID: 22027100]
[86]
Romagnoli, R.; Baraldi, P.G.; Carrion, M.D.; Cruz-Lopez, O.; Cara, C.L.; Basso, G.; Viola, G.; Khedr, M.; Balzarini, J.; Mahboobi, S.; Sellmer, A.; Brancale, A.; Hamel, E. 2-Arylamino-4-amino-5-aroylthiazoles. “One-pot” synthesis and biological evaluation of a new class of inhibitors of tubulin polymerization. J. Med. Chem., 2009, 52(17), 5551-5555.
[http://dx.doi.org/10.1021/jm9001692] [PMID: 19663386]
[87]
Johnson, L.N. Protein kinase inhibitors: contributions from structure to clinical compounds. Q. Rev. Biophys., 2009, 42(1), 1-40.
[http://dx.doi.org/10.1017/S0033583508004745] [PMID: 19296866]
[88]
Hall, M.; Peters, G. Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer. Adv. Cancer Res., 1996, Vol. 68, pp. 67-108.
[http://dx.doi.org/10.1016/S0065-230X(08)60352-8]
[89]
Schonbrunn, E.; Betzi, S.; Alam, R.; Martin, M.P.; Becker, A.; Han, H.; Francis, R.; Chakrasali, R.; Jakkaraj, S.; Kazi, A.; Sebti, S.M.; Cubitt, C.L.; Gebhard, A.W.; Hazlehurst, L.A.; Tash, J.S.; Georg, G.I. Development of highly potent and selective diaminothiazole inhibitors of cyclin-dependent kinases. J. Med. Chem., 2013, 56(10), 3768-3782.
[http://dx.doi.org/10.1021/jm301234k] [PMID: 23600925]
[90]
Ayati, A.; Oghabi Bakhshaiesh, T.; Moghimi, S.; Esmaeili, R.; Majidzadeh-A, K.; Safavi, M.; Firoozpour, L.; Emami, S.; Foroumadi, A. Synthesis and biological evaluation of new coumarins bearing 2,4-diaminothiazole-5-carbonyl moiety. Eur. J. Med. Chem., 2018, 155, 483-491.
[http://dx.doi.org/10.1016/j.ejmech.2018.06.015] [PMID: 29908441]
[91]
Romagnoli, R.; Baraldi, P.G.; Salvador, M.K.; Preti, D.; Aghazadeh Tabrizi, M.; Brancale, A.; Fu, X-H.; Li, J.; Zhang, S-Z.; Hamel, E.; Bortolozzi, R.; Porcù, E.; Basso, G.; Viola, G. Discovery and optimization of a series of 2-aryl-4-amino-5-(3′,4′,5′-trimethoxybenzoyl)thiazoles as novel anticancer agents. J. Med. Chem., 2012, 55(11), 5433-5445.
[http://dx.doi.org/10.1021/jm300388h] [PMID: 22578111]
[92]
Ayati, A.; Esmaeili, R.; Moghimi, S.; Oghabi Bakhshaiesh, T.; Eslami-S, Z.; Majidzadeh-A, K.; Safavi, M.; Emami, S.; Foroumadi, A. Synthesis and biological evaluation of 4-amino-5-cinnamoylthiazoles as chalcone-like anticancer agents. Eur. J. Med. Chem., 2018, 145, 404-412.
[http://dx.doi.org/10.1016/j.ejmech.2018.01.015] [PMID: 29335206]
[93]
Lu, K.P.; Hanes, S.D.; Hunter, T. A human peptidyl-prolyl isomerase essential for regulation of mitosis. Nature, 1996, 380(6574), 544-547.
[http://dx.doi.org/10.1038/380544a0] [PMID: 8606777]
[94]
Winkler, K.E.; Swenson, K.I.; Kornbluth, S.; Means, A.R. Requirement of the prolyl isomerase Pin1 for the replication checkpoint. Science, 2000, 287(5458), 1644-1647.
[http://dx.doi.org/10.1126/science.287.5458.1644] [PMID: 10698738]
[95]
Xu, G.G.; Etzkorn, F.A. Pin1 as an anticancer drug target. Drug News Perspect., 2009, 22(7), 399-407.
[http://dx.doi.org/10.1358/dnp.2009.22.7.1414594] [PMID: 19890497]
[96]
Zhao, H.; Cui, G.; Jin, J.; Chen, X.; Xu, B. Synthesis and Pin1 inhibitory activity of thiazole derivatives. Bioorg. Med. Chem., 2016, 24(22), 5911-5920.
[http://dx.doi.org/10.1016/j.bmc.2016.09.049] [PMID: 27692510]
[97]
Chauhan, D.; Tian, Z.; Nicholson, B.; Kumar, K.G.; Zhou, B.; Carrasco, R.; McDermott, J.L.; Leach, C.A.; Fulcinniti, M.; Kodrasov, M.P.; Weinstock, J.; Kingsbury, W.D.; Hideshima, T.; Shah, P.K.; Minvielle, S.; Altun, M.; Kessler, B.M.; Orlowski, R.; Richardson, P.; Munshi, N.; Anderson, K.C. A small molecule inhibitor of ubiquitin-specific protease-7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance. Cancer Cell, 2012, 22(3), 345-358.
[http://dx.doi.org/10.1016/j.ccr.2012.08.007] [PMID: 22975377]
[98]
Chen, C.; Song, J.; Wang, J.; Xu, C.; Chen, C.; Gu, W.; Sun, H.; Wen, X. Synthesis and biological evaluation of thiazole derivatives as novel USP7 inhibitors. Bioorg. Med. Chem. Lett., 2017, 27(4), 845-849.
[http://dx.doi.org/10.1016/j.bmcl.2017.01.018] [PMID: 28108249]
[99]
Zhou, W.; Huang, A.; Zhang, Y.; Lin, Q.; Guo, W.; You, Z.; Yi, Z.; Liu, M.; Chen, Y. Design and optimization of hybrid of 2,4-diaminopyrimidine and arylthiazole scaffold as anticancer cell proliferation and migration agents. Eur. J. Med. Chem., 2015, 96, 269-280.
[http://dx.doi.org/10.1016/j.ejmech.2015.04.027] [PMID: 25899332]
[100]
Salehi, M.; Amini, M.; Ostad, S.N.; Riazi, G.H.; Assadieskandar, A.; Shafiei, B.; Shafiee, A. Synthesis, cytotoxic evaluation and molecular docking study of 2-alkylthio-4-(2,3,4-trimethoxyphenyl)-5-aryl-thiazoles as tubulin polymerization inhibitors. Bioorg. Med. Chem., 2013, 21(24), 7648-7654.
[http://dx.doi.org/10.1016/j.bmc.2013.10.030] [PMID: 24238904]
[101]
Hayden, M.S.; Ghosh, S. NF-κB, the first quarter-century: remarkable progress and outstanding questions. Genes Dev., 2012, 26(3), 203-234.
[http://dx.doi.org/10.1101/gad.183434.111] [PMID: 22302935]
[102]
Brown, K.D.; Claudio, E.; Siebenlist, U. The roles of the classical and alternative nuclear factor-kappaB pathways: potential implications for autoimmunity and rheumatoid arthritis. Arthritis Res. Ther., 2008, 10(4), 212.
[http://dx.doi.org/10.1186/ar2457] [PMID: 18771589]
[103]
Vasu, K.K.; Digwal, C.S.; Pandya, A.N.; Pandya, D.H.; Sharma, J.A.; Patel, S.; Agarwal, M. Imidazo[1,2-a]pyridines linked with thiazoles/thiophene motif through keto spacer as potential cytotoxic agents and NF-κB inhibitors. Bioorg. Med. Chem. Lett., 2017, 27(24), 5463-5466.
[http://dx.doi.org/10.1016/j.bmcl.2017.10.060] [PMID: 29138027]
[104]
Lefranc, F.; Xu, Z.; Burth, P.; Mathieu, V.; Revelant, G.; de Castro Faria, M.V.; Noyon, C.; Garcia, D.G.; Dufour, D.; Bruyère, C.; Gonçalves-de-Albuquerque, C.F.; Van Antwerpen, P.; Rogister, B.; Hesse, S.; Kirsch, G.; Kiss, R. 4-Bromo-2-(piperidin-1-yl)thiazol-5-yl-phenyl methanone (12b) inhibits Na+/K(+)-ATPase and Ras oncogene activity in cancer cells. Eur. J. Med. Chem., 2013, 63, 213-223.
[http://dx.doi.org/10.1016/j.ejmech.2013.01.046] [PMID: 23474907]
[105]
Reichelt, A.; Bailis, J.M.; Bartberger, M.D.; Yao, G.; Shu, H.; Kaller, M.R.; Allen, J.G.; Weidner, M.F.; Keegan, K.S.; Dao, J.H. Synthesis and structure-activity relationship of trisubstituted thiazoles as Cdc7 kinase inhibitors. Eur. J. Med. Chem., 2014, 80, 364-382.
[http://dx.doi.org/10.1016/j.ejmech.2014.04.013] [PMID: 24793884]
[106]
Vanotti, E.; Amici, R.; Bargiotti, A.; Berthelsen, J.; Bosotti, R.; Ciavolella, A.; Cirla, A.; Cristiani, C.; D’Alessio, R.; Forte, B.; Isacchi, A.; Martina, K.; Menichincheri, M.; Molinari, A.; Montagnoli, A.; Orsini, P.; Pillan, A.; Roletto, F.; Scolaro, A.; Tibolla, M.; Valsasina, B.; Varasi, M.; Volpi, D.; Santocanale, C. Cdc7 kinase inhibitors: pyrrolopyridinones as potential antitumor agents. 1. Synthesis and structure-activity relationships. J. Med. Chem., 2008, 51(3), 487-501.
[http://dx.doi.org/10.1021/jm700956r] [PMID: 18201066]
[107]
Menichincheri, M.; Bargiotti, A.; Berthelsen, J.; Bertrand, J.A.; Bossi, R.; Ciavolella, A.; Cirla, A.; Cristiani, C.; Croci, V.; D’Alessio, R.; Fasolini, M.; Fiorentini, F.; Forte, B.; Isacchi, A.; Martina, K.; Molinari, A.; Montagnoli, A.; Orsini, P.; Orzi, F.; Pesenti, E.; Pezzetta, D.; Pillan, A.; Poggesi, I.; Roletto, F.; Scolaro, A.; Tatò, M.; Tibolla, M.; Valsasina, B.; Varasi, M.; Volpi, D.; Santocanale, C.; Vanotti, E. First Cdc7 kinase inhibitors: pyrrolopyridinones as potent and orally active antitumor agents. 2. Lead discovery. J. Med. Chem., 2009, 52(2), 293-307.
[http://dx.doi.org/10.1021/jm800977q] [PMID: 19115845]
[108]
Ramírez, J.; Svetaz, L.; Quiroga, J.; Abonia, R.; Raimondi, M.; Zacchino, S.; Insuasty, B. Synthesis of novel thiazole-based 8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepines as potential antitumor and antifungal agents. Eur. J. Med. Chem., 2015, 92, 866-875.
[http://dx.doi.org/10.1016/j.ejmech.2015.01.053] [PMID: 25638570]
[109]
Jeong, K.W.; Lee, J.H.; Park, S.M.; Choi, J-H.; Jeong, D-Y.; Choi, D-H.; Nam, Y.; Park, J-H.; Lee, K-N.; Kim, S-M.; Ku, J.M. Synthesis and in-vitro evaluation of 2-amino-4-arylthiazole as inhibitor of 3D polymerase against foot-and-mouth disease (FMD). Eur. J. Med. Chem., 2015, 102, 387-397.
[http://dx.doi.org/10.1016/j.ejmech.2015.08.020] [PMID: 26301555]
[110]
Xu, Z.; Ba, M.; Zhou, H.; Cao, Y.; Tang, C.; Yang, Y.; He, R.; Liang, Y.; Zhang, X.; Li, Z.; Zhu, L.; Guo, Y.; Guo, C. 2,4,5-Trisubstituted thiazole derivatives: a novel and potent class of non-nucleoside inhibitors of wild type and mutant HIV-1 reverse transcriptase. Eur. J. Med. Chem., 2014, 85, 27-42.
[http://dx.doi.org/10.1016/j.ejmech.2014.07.072] [PMID: 25072874]
[111]
Rawal, R.K.; Tripathi, R.; Katti, S.B.; Pannecouque, C.; De Clercq, E. Design, synthesis, and evaluation of 2-aryl-3-heteroaryl-1,3-thiazolidin-4-ones as anti-HIV agents. Bioorg. Med. Chem., 2007, 15(4), 1725-1731.
[http://dx.doi.org/10.1016/j.bmc.2006.12.003] [PMID: 17178227]
[112]
Mayhoub, A.S.; Khaliq, M.; Kuhn, R.J.; Cushman, M. Design, synthesis, and biological evaluation of thiazoles targeting flavivirus envelope proteins. J. Med. Chem., 2011, 54(6), 1704-1714.
[http://dx.doi.org/10.1021/jm1013538] [PMID: 21355607]
[113]
Zhan, P.; Wang, L.; Liu, H.; Chen, X.; Li, X.; Jiang, X.; Zhang, Q.; Liu, X.; Pannecouque, C.; Naesens, L.; De Clercq, E.; Liu, A.; Du, G. Arylazolyl(azinyl)thioacetanilide. Part 9: Synthesis and biological investigation of thiazolylthioacetamides derivatives as a novel class of potential antiviral agents. Arch. Pharm. Res., 2012, 35(6), 975-986.
[http://dx.doi.org/10.1007/s12272-012-0604-y] [PMID: 22870806]
[114]
Li, Z.; Khaliq, M.; Zhou, Z.; Post, C.B.; Kuhn, R.J.; Cushman, M. Design, synthesis, and biological evaluation of antiviral agents targeting flavivirus envelope proteins. J. Med. Chem., 2008, 51(15), 4660-4671.
[http://dx.doi.org/10.1021/jm800412d] [PMID: 18610998]
[115]
Stoddart, L.A.; Smith, N.J.; Milligan, G. International Union of Pharmacology. LXXI. Free fatty acid receptors FFA1, -2, and -3: pharmacology and pathophysiological functions. Pharmacol. Rev., 2008, 60(4), 405-417.
[http://dx.doi.org/10.1124/pr.108.00802] [PMID: 19047536]
[116]
Wellendorph, P.; Johansen, L.D.; Bräuner-Osborne, H. Molecular pharmacology of promiscuous seven transmembrane receptors sensing organic nutrients. Mol. Pharmacol., 2009, 76(3), 453-465.
[http://dx.doi.org/10.1124/mol.109.055244] [PMID: 19487246]
[117]
Shapiro, H.; Shachar, S.; Sekler, I.; Hershfinkel, M.; Walker, M.D. Role of GPR40 in fatty acid action on the beta cell line INS-1E. Biochem. Biophys. Res. Commun., 2005, 335(1), 97-104.
[http://dx.doi.org/10.1016/j.bbrc.2005.07.042] [PMID: 16081037]
[118]
Li; Zheng; Xu; Xue; Hou; Jie; Wang; Shaohong; Jiang; Hongwei, Structure-based optimization of free fatty acid receptor 1 agonists bearing thiazole scaffold. Bioorg. Chem., 2018, 77(9), 402-410.
[119]
Artis, D.R.; Lin, J.J.; Zhang, C.; Wang, W.; Mehra, U.; Perreault, M.; Erbe, D.; Krupka, H.I.; England, B.P.; Arnold, J.; Plotnikov, A.N.; Marimuthu, A.; Nguyen, H.; Will, S.; Signaevsky, M.; Kral, J.; Cantwell, J.; Settachatgull, C.; Yan, D.S.; Fong, D.; Oh, A.; Shi, S.; Womack, P.; Powell, B.; Habets, G.; West, B.L.; Zhang, K.Y.; Milburn, M.V.; Vlasuk, G.P.; Hirth, K.P.; Nolop, K.; Bollag, G.; Ibrahim, P.N.; Tobin, J.F. Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent. Proc. Natl. Acad. Sci. USA, 2009, 106(1), 262-267.
[http://dx.doi.org/10.1073/pnas.0811325106] [PMID: 19116277]
[120]
Rau, O.; Zettl, H.; Popescu, L.; Steinhilber, D.; Schubert-Zsilavecz, M. ChemInform Abstract: The treatment of dyslipidemia - what′s left in the pipeline? ChemInform, 2008, 39(20)
[http://dx.doi.org/10.1002/chin.200820258]
[121]
Willson, T.M.; Brown, P.J.; Sternbach, D.D.; Henke, B.R. Cheminform abstract: the ppars: from orphan receptors to drug discovery. ChemInform, 2010, 31(22)
[http://dx.doi.org/10.1002/chin.200022291]
[122]
Makadia, P.; Shah, S.R.; Pingali, H.; Zaware, P.; Patel, D.; Pola, S.; Thube, B.; Priyadarshini, P.; Suthar, D.; Shah, M.; Giri, S.; Trivedi, C.; Jain, M.; Patel, P.; Bahekar, R. Effect of structurally constrained oxime-ether linker on PPAR subtype selectivity: Discovery of a novel and potent series of PPAR-pan agonists. Bioorg. Med. Chem., 2011, 19(2), 771-782.
[http://dx.doi.org/10.1016/j.bmc.2010.12.023] [PMID: 21215640]
[123]
Pereira, R.; Gaudon, C.; Iglesias, B.; Germain, P.; Gronemeyer, H.; de Lera, A.R. Synthesis of the PPARbeta/δ-selective agonist GW501516 and C4-thiazole-substituted analogs. Bioorg. Med. Chem. Lett., 2006, 16(1), 49-54.
[http://dx.doi.org/10.1016/j.bmcl.2005.09.060] [PMID: 16242326]
[124]
Sharma, S. B’Bhatt, Synthesis, characterization, and biological evaluation of some tri-substituted imidazole/thiazole derivatives. J. Heterocycl. Chem., 2015, 52(4), 1126-1131.
[125]
Bondock, S.; Fouda, A.M. Synthesis and evaluation of some new 5-(hetaryl)thiazoles as potential antimicrobial agents. Synth. Commun., 2018, 48(5), 561-573.
[http://dx.doi.org/10.1080/00397911.2017.1412465]
[126]
Abdel-Wahab, B.F.; Abdel-Gawad, H.; Awad, G.E.A.; Badria, F.A. Synthesis, antimicrobial, antioxidant, anti-inflammatory, and analgesic activities of some new 3-(2′-thienyl)pyrazole-based heterocycles. Med. Chem. Res., 2012, 21(7), 1418-1426.
[http://dx.doi.org/10.1007/s00044-011-9661-x]
[127]
Makam, P.; Kankanala, R.; Prakash, A.; Kannan, T. 2-(2-Hydrazinyl)thiazole derivatives: design, synthesis and in vitro antimycobacterial studies. Eur. J. Med. Chem., 2013, 69, 564-576.
[http://dx.doi.org/10.1016/j.ejmech.2013.08.054] [PMID: 24095750]
[128]
Lu, X.; Liu, X.; Wan, B.; Franzblau, S.G.; Chen, L.; Zhou, C.; You, Q. Synthesis and evaluation of anti-tubercular and antibacterial activities of new 4-(2,6-dichlorobenzyloxy)phenyl thiazole, oxazole and imidazole derivatives. Part 2. Eur. J. Med. Chem., 2012, 49(Part 2), 164-171.
[http://dx.doi.org/10.1016/j.ejmech.2012.01.007] [PMID: 22264895]
[129]
Prajapati, A.K.; Modi, V.P. Synthesis and biological evaluation of amides of aminothiazole derivatives. Asian J. Res. Chem, 2010, 2010, 240-243.
[130]
Samir; Bondock; Wesam; Khalifa; Ahmed; A.; Fadda, Synthesis and antimicrobial evaluation of some new thiazole, thiazolidinone and thiazoline derivatives starting from 1-chloro-3,4-dihydronaphthalene-2-carboxaldehyde. ChemInform, 2007, 42(7), 948-954.
[131]
Jeankumar, V.U.; Renuka, J.; Santosh, P.; Soni, V.; Sridevi, J.P.; Suryadevara, P.; Yogeeswari, P.; Sriram, D. Thiazole-aminopiperidine hybrid analogues: design and synthesis of novel Mycobacterium tuberculosis GyrB inhibitors. Eur. J. Med. Chem., 2013, 70, 143-153.
[http://dx.doi.org/10.1016/j.ejmech.2013.09.025] [PMID: 24148991]
[132]
Mohammad, H.; Mayhoub, A.S.; Ghafoor, A.; Soofi, M.; Alajlouni, R.A.; Cushman, M.; Seleem, M.N. Discovery and characterization of potent thiazoles versus methicillin- and vancomycin-resistant Staphylococcus aureus. J. Med. Chem., 2014, 57(4), 1609-1615.
[http://dx.doi.org/10.1021/jm401905m] [PMID: 24387054]
[133]
Desai, N.C.; Bhatt, N.; Somani, H.; Trivedi, A. Synthesis, antimicrobial and cytotoxic activities of some novel thiazole clubbed 1,3,4-oxadiazoles. Eur. J. Med. Chem., 2013, 67, 54-59.
[http://dx.doi.org/10.1016/j.ejmech.2013.06.029] [PMID: 23835482]
[134]
Santosh, R.; Selvam, M.K.; Kanekar, S.U.; Nagaraja, G.K.; Kumar, M. Design, synthesis, dna binding, and docking studies of thiazoles and thiazole-containing triazoles as antibacterials. ChemistrySelect, 2018, 3(14), 3892-3898.
[http://dx.doi.org/10.1002/slct.201800222]
[135]
Liaras, K.; Geronikaki, A.; Glamolija, J.; Sokovi, M. Thiazole-based aminopyrimidines and N-phenylpyrazolines as potent antimicrobial agents: synthesis and biological evaluation. MedChemComm, 2014, 5(7), 915.
[http://dx.doi.org/10.1039/C4MD00124A]
[136]
Guo, X.; Zhao, B.; Fan, Z.; Yang, D.; Zhang, N.; Wu, Q.; Yu, B.; Zhou, S.; Kalinina, T.A.; Belskaya, N.P. Discovery of novel thiazole carboxamides as antifungal succinate dehydrogenase inhibitors. J. Agric. Food Chem., 2019, 67(6), 1647-1655.
[http://dx.doi.org/10.1021/acs.jafc.8b06935] [PMID: 30669828]
[137]
Althagafi, I.; El-Metwaly, N.; Farghaly, T.A. New series of thiazole derivatives: synthesis, structural elucidation, antimicrobial activity, molecular modeling and moe docking. Molecules, 2019, 24(9), 1741.
[http://dx.doi.org/10.3390/molecules24091741] [PMID: 31060260]
[138]
Vanhaesebroeck, B.; Leevers, S.J.; Ahmadi, K.; Timms, J.; Katso, R.; Driscoll, P.C.; Woscholski, R.; Parker, P.J.; Waterfield, M.D. Synthesis and function of 3-phosphorylated inositol lipids. Annu. Rev. Biochem., 2001, 70(1), 535-602.
[http://dx.doi.org/10.1146/annurev.biochem.70.1.535] [PMID: 11395417]
[139]
Oka, Y.; Yabuuchi, T.; Oi, T.; Kuroda, S.; Fujii, Y.; Ohtake, H.; Inoue, T.; Wakahara, S.; Kimura, K.; Fujita, K. Discovery of N-5-[3-(3-hydroxypiperidin-1-yl)-1,2,4-oxadiazol-5-yl]-4-methyl-1,3-thiazol-2-ylacetamide (TASP0415914) as an orally potent phosphoinositide 3-kinase γ inhibitor for the treatment of inflammatory diseases. Bioorg. Med. Chem., 2013, 21(24), 7578-7583.
[http://dx.doi.org/10.1016/j.bmc.2013.10.042] [PMID: 24262886]
[140]
Oka, Y.; Yabuuchi, T.; Fujii, Y.; Ohtake, H.; Wakahara, S.; Matsumoto, K.; Endo, M.; Tamura, Y.; Sekiguchi, Y. Discovery and optimization of a series of 2-aminothiazole-oxazoles as potent phosphoinositide 3-kinase γ inhibitors. Bioorg. Med. Chem. Lett., 2012, 22(24), 7534-7538.
[http://dx.doi.org/10.1016/j.bmcl.2012.10.028] [PMID: 23122859]
[141]
Bruce, I.; Akhlaq, M.; Bloomfield, G.C.; Budd, E.; Cox, B.; Cuenoud, B.; Finan, P.; Gedeck, P.; Hatto, J.; Hayler, J.F.; Head, D.; Keller, T.; Kirman, L.; Leblanc, C.; Le Grand, D.; McCarthy, C.; O’Connor, D.; Owen, C.; Oza, M.S.; Pilgrim, G.; Press, N.E.; Sviridenko, L.; Whitehead, L. Development of isoform selective PI3-kinase inhibitors as pharmacological tools for elucidating the PI3K pathway. Bioorg. Med. Chem. Lett., 2012, 22(17), 5445-5450.
[http://dx.doi.org/10.1016/j.bmcl.2012.07.042] [PMID: 22863202]
[142]
Certal, V.; Halley, F.; Virone-Oddos, A.; Filoche-Rommé, B.; Carry, J-C.; Gruss-Leleu, F.; Bertin, L.; Guizani, H.; Pilorge, F.; Richepin, P.; Karlsson, A.; Charrier, V.; Abecassis, P-Y.; Vincent, L.; Nicolas, J-P.; Lengauer, C.; Garcia-Echeverria, C.; Schio, L. Preparation and optimization of new 4-(2-(indolin-1-yl)-2-oxoethyl)-2-morpholinothiazole-5-carboxylic acid and amide derivatives as potent and selective PI3Kβ inhibitors. Bioorg. Med. Chem. Lett., 2014, 24(6), 1506-1510.
[http://dx.doi.org/10.1016/j.bmcl.2014.02.004] [PMID: 24560540]
[143]
Agrotis, A.; Kalinina, N.; Bobik, A. Transforming growth factor-β, cell signaling and cardiovascular disorders. Curr. Vasc. Pharmacol., 2005, 3(1), 55-61.
[http://dx.doi.org/10.2174/1570161052773951] [PMID: 15638782]
[144]
Leask, A.; Abraham, D.J. TGF-β signaling and the fibrotic response. FASEB J., 2004, 18(7), 816-827.
[http://dx.doi.org/10.1096/fj.03-1273rev] [PMID: 15117886]
[145]
Kim, D.K.; Choi, J.H.; An, Y.J.; Lee, H.S. Synthesis and biological evaluation of 5-(pyridin-2-yl)thiazoles as transforming growth factor-beta type1 receptor kinase inhibitors. Bioorg. Med. Chem. Lett., 2008, 18(6), 2122-2127.
[http://dx.doi.org/10.1016/j.bmcl.2008.01.084] [PMID: 18262787]
[146]
Fredholm, B.B.; IJzerman, A.P.; Jacobson, K.A.; Linden, J.; Müller, C.E. International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors--an update. Pharmacol. Rev., 2011, 63(1), 1-34.
[http://dx.doi.org/10.1124/pr.110.003285] [PMID: 21303899]
[147]
Chen, J-F.; Eltzschig, H.K.; Fredholm, B.B. Adenosine receptors as drug targets--what are the challenges? Nat. Rev. Drug Discov., 2013, 12(4), 265-286.
[http://dx.doi.org/10.1038/nrd3955] [PMID: 23535933]
[148]
Fredholm, B.B.; IJzerman, A.P.; Jacobson, K.A.; Klotz, K.N.; Linden, J. International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol. Rev., 2001, 53(4), 527-552.
[PMID: 11734617]
[149]
Pandya, D.H.; Sharma, J.A.; Jalani, H.B.; Pandya, A.N.; Sudarsanam, V.; Kachler, S.; Klotz, K.N.; Vasu, K.K. Novel thiazole-thiophene conjugates as adenosine receptor antagonists: synthesis, biological evaluation and docking studies. Bioorg. Med. Chem. Lett., 2015, 25(6), 1306-1309.
[http://dx.doi.org/10.1016/j.bmcl.2015.01.040] [PMID: 25686851]
[150]
Sams, A.G.; Mikkelsen, G.K.e.; Larsen, M.; Torup, L.; Brennum, L.T.; Schrøder, T.J.; Bang-Andersen, B. Hit-to-lead optimization of a series of carboxamides of ethyl 2-amino-4-phenylthiazole-5-carboxylates as novel adenosine A2A receptor antagonists. Bioorg. Med. Chem. Lett., 2010, 20(17), 5241-5244.
[http://dx.doi.org/10.1016/j.bmcl.2010.06.138] [PMID: 20659802]
[151]
Scheiff, A.B.; Yerande, S.G.; El-Tayeb, A.; Li, W.; Inamdar, G.S.; Vasu, K.K.; Sudarsanam, V.; Müller, C.E. 2-Amino-5-benzoyl-4-phenylthiazoles: Development of potent and selective adenosine A1 receptor antagonists. Bioorg. Med. Chem., 2010, 18(6), 2195-2203.
[http://dx.doi.org/10.1016/j.bmc.2010.01.072] [PMID: 20188574]
[152]
Inamdar, G.S.; Pandya, A.N.; Thakar, H.M.; Sudarsanam, V.; Kachler, S.; Sabbadin, D.; Moro, S.; Klotz, K.N.; Vasu, K.K. New insight into adenosine receptors selectivity derived from a novel series of [5-substituted-4-phenyl-1,3-thiazol-2-yl] benzamides and furamides. Eur. J. Med. Chem., 2013, 63, 924-934.
[153]
Cole, A.G.; Stauffer, T.M.; Rokosz, L.L.; Metzger, A.; Dillard, L.W.; Zeng, W.; Henderson, I. Synthesis of 2-amino-5-benzoyl-4-(2-furyl)thiazoles as adenosine A(2A) receptor antagonists. Bioorg. Med. Chem. Lett., 2009, 19(2), 378-381.
[http://dx.doi.org/10.1016/j.bmcl.2008.11.066] [PMID: 19059776]
[154]
De, S.; Adhikari, S.; Tilak-Jain, J.; Menon, V.P.; Devasagayam, T.P.A. Antioxidant activity of an aminothiazole compound: possible mechanisms. Chem. Biol. Interact., 2008, 173(3), 215-223.
[http://dx.doi.org/10.1016/j.cbi.2008.03.011] [PMID: 18466888]

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      • 9. middleware::check_user_access:24
      • 10. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 11. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
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      • 11. middleware::check_user_access:24
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 14. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
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      • 11. middleware::check_user_access:27
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 14. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 15. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
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      • 10: 316870080
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      Backtrace
      • 14. app/Models/UserAccess/UserAccess.php:784
      • 15. middleware::check_user_access:114
      • 16. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 18. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
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      700μsalphaeurekaselec_live_10_06_2022Article.php#408
      Backtrace
      • 11. app/Models/Article.php:408
      • 12. app/Http/Controllers/ArticleController.php:2515
      • 13. app/Http/Controllers/ArticleController.php:2035
      • 14. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 15. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `journal` where `journal_id` = 38 limit 1
      16.6msalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 38
      Backtrace
      • 14. app/Models/Journal.php:64
      • 15. app/Http/Controllers/ArticleController.php:2516
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
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      1.29msalphaeurekaselec_live_10_06_2022Subject.php#200
      Backtrace
      • 16. app/Models/Subject.php:200
      • 17. app/Http/Controllers/ArticleController.php:2517
      • 18. app/Http/Controllers/ArticleController.php:2035
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 20. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select j.nid as journal_nid,j.flyer_link,j.title ,j.issn,j.eissn,j.keyword, j.journal_id as journal_id, j.subtitle, j.image_file_name,j.description,j.journal_insight_url,j.doi from `subject_journal` as `sj` inner join `journal` as `j` on `j`.`journal_id` = `sj`.`journal_id` where j.journal_status=1 and subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=38) and sj.journal_id!=38 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      1.02msalphaeurekaselec_live_10_06_2022Subject.php#200
      Backtrace
      • 14. app/Models/Subject.php:200
      • 15. app/Http/Controllers/ArticleController.php:2517
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select count(*) as aggregate from (select v.nid as volume_id,e.nid,e.title,v.issn,v.eissn,v.isbn,v.eisbn,e.ebook_id, v.image_file_name,v.file_path,v.flyer_link,v.ebook_volume_id, v.volume_name,v.doi,v.year_id,v.introduction from `subject_ebook` as `se` inner join `ebook` as `e` on `e`.`ebook_id` = `se`.`ebook_id` inner join `ebook_volume` as `v` on `v`.`ebook_id` = `se`.`ebook_id` inner join `year` as `y` on `y`.`id` = `v`.`year_id` where subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=38) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      3.22msalphaeurekaselec_live_10_06_2022Subject.php#220
      Backtrace
      • 16. app/Models/Subject.php:220
      • 17. app/Http/Controllers/ArticleController.php:2518
      • 18. app/Http/Controllers/ArticleController.php:2035
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 20. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select v.nid as volume_id,e.nid,e.title,v.issn,v.eissn,v.isbn,v.eisbn,e.ebook_id, v.image_file_name,v.file_path,v.flyer_link,v.ebook_volume_id, v.volume_name,v.doi,v.year_id,v.introduction from `subject_ebook` as `se` inner join `ebook` as `e` on `e`.`ebook_id` = `se`.`ebook_id` inner join `ebook_volume` as `v` on `v`.`ebook_id` = `se`.`ebook_id` inner join `year` as `y` on `y`.`id` = `v`.`year_id` where subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=38) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      2.55msalphaeurekaselec_live_10_06_2022Subject.php#220
      Backtrace
      • 14. app/Models/Subject.php:220
      • 15. app/Http/Controllers/ArticleController.php:2518
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `keywords` where `article_id` = '110036'
      990μsalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 110036
      Backtrace
      • 13. app/Models/Keywords.php:43
      • 14. app/Http/Controllers/ArticleController.php:2519
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `article_citation` where `article_id` = '110036'
      10.64msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 110036
      Backtrace
      • 13. app/Models/Article.php:1570
      • 14. app/Http/Controllers/ArticleController.php:2520
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select CONCAT_WS(' ',au.first_name, ' ', ifnull(au.initials,''), ' ', au.last_name) as authors, CONCAT(au.last_name, IFNULL(CONCAT(' ', au.initials), ''), ' ', au.first_name) AS authorsRIS, CONCAT_WS(' ',au.last_name, ' ', ifnull(au.initials,''), ' ', au.first_name) as authorsCiteAs, CONCAT_WS(' ',au.first_name, IFNULL(CONCAT(' ', au.initials), ''), IFNULL(CONCAT(' ', au.last_name), '')) as authorsmodal , `au`.*, `af`.`ror_id`, `af`.`institution`, `af`.`department`, `af`.`country`, `af`.`city`, `af`.`address`, (GROUP_CONCAT(TRIM(BOTH ', ' FROM CONCAT(ifnull(concat(af.institution,','),''), ifnull(concat(af.department,','),''), ifnull(concat(af.address,','),''), ifnull(concat(af.city,','),''), ifnull(concat(af.country,','),''), ifnull(concat(af.postal_code,','),''), ifnull(concat(af.phone,','),''), ifnull(concat(af.fax,','),''))) SEPARATOR '|')) as `author_affiliation`, (GROUP_CONCAT(TRIM(BOTH ', ' FROM CONCAT(ifnull(concat(af.web_view,','),''))) SEPARATOR '|')) as `web_view` from `author` as `au` left join `author_affiliation` as `af` on `au`.`author_id` = `af`.`author_id` where `au`.`article_id` = '110036' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      4.43msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 110036
      Backtrace
      • 13. app/Models/Author.php:86
      • 14. app/Http/Controllers/ArticleController.php:2533
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select `bo`.* from `bundle_offer` as `bo` where `bo`.`bundle_status` = 'A' order by `bo`.`bundle_id` desc
      300μsalphaeurekaselec_live_10_06_2022BundleOffer.php#57
      Bindings
      • 0: A
      Backtrace
      • 13. app/Models/BundleOffer.php:57
      • 14. app/Http/Controllers/ArticleController.php:2535
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select `subtitle` from `journal` where `continues_publication_journal` = 1
      660μsalphaeurekaselec_live_10_06_2022Article.php#1960
      Bindings
      • 0: 1
      Backtrace
      • 13. app/Models/Article.php:1960
      • 14. app/Http/Controllers/ArticleController.php:2062
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • Select j.subtitle, v.volume_id as volume_id,v.year_id,y.year as year,v.volume_name, v.total_no_of_issues, i.issue_id as issue_id,i.title as issue, i.publication_date as issue_pub_date from journal j join volume v on j.journal_id = v.journal_id join issue i on v.volume_id = i.volume_id join article a on a.issue_id = i.issue_id join year y on v.year_id = y.id where j.journal_id = 38 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      51.18msalphaeurekaselec_live_10_06_2022Issue.php#298
      Backtrace
      • 11. app/Models/Issue.php:298
      • 12. app/Http/Controllers/ArticleController.php:2068
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid,a.publish_on, a.pmid,a.article_id,a.doi,j.journal_id,j.subtitle,v.volume_name,a.volume_id as volume_id, a.issue_id,a.title,first_page, last_page, page_count,abstract,ifnull(is_abstract,"y"),asec.title as article_section,at.type_name as article_type_name, a.article_id as ArticleID ,is_epub,epub_price,epub_type,a.created, y.year from `article` as `a` left join `article_section` as `asec` on `asec`.`art_sec_id` = `a`.`is_epub` left join `article_type` as `at` on `at`.`art_type_id` = `a`.`art_type` left join `journal` as `j` on `j`.`journal_id` = `a`.`journal_id` inner join `volume` as `v` on `a`.`volume_id` = `v`.`volume_id` inner join `year` as `y` on `v`.`year_id` = `y`.`id` where a.article_status != "W" and a.is_epub = 1 and a.journal_id = 38 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      43.42msalphaeurekaselec_live_10_06_2022Article.php#528
      Backtrace
      • 13. app/Models/Article.php:528
      • 14. app/Http/Controllers/ArticleController.php:2070
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid,a.publish_on, a.pmid,a.article_id,a.doi,j.journal_id,j.subtitle,v.volume_name,a.volume_id as volume_id, a.issue_id,a.title,first_page, last_page, page_count,abstract,ifnull(is_abstract,"y"),asec.title as article_section,at.type_name as article_type_name, a.article_id as ArticleID ,is_epub,epub_price,epub_type,a.created, y.year from `article` as `a` left join `article_section` as `asec` on `asec`.`art_sec_id` = `a`.`is_epub` left join `article_type` as `at` on `at`.`art_type_id` = `a`.`art_type` left join `journal` as `j` on `j`.`journal_id` = `a`.`journal_id` inner join `volume` as `v` on `a`.`volume_id` = `v`.`volume_id` inner join `year` as `y` on `v`.`year_id` = `y`.`id` where a.article_status != "W" and a.is_epub = 4 and a.journal_id = 38 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      26.88msalphaeurekaselec_live_10_06_2022Article.php#528
      Backtrace
      • 13. app/Models/Article.php:528
      • 14. app/Http/Controllers/ArticleController.php:2071
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select pdf, html, epub, prc from `article_metrics` where `article_id` = 110036 limit 1
      290μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 110036
      Backtrace
      • 14. app/Models/Article.php:744
      • 15. app/Http/Controllers/ArticleController.php:2091
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from content_by_diseases where content_id = 110036 and content_type = 'article' order by status desc limit 1
      340μsalphaeurekaselec_live_10_06_2022Article.php#751
      Backtrace
      • 11. app/Models/Article.php:751
      • 12. app/Http/Controllers/ArticleController.php:2094
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `node_meta` where `nid` = 186026 limit 1
      270μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 186026
      Backtrace
      • 14. app/Models/Meta.php:30
      • 15. app/Http/Controllers/ArticleController.php:2101
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `bo`.* from `bundle_offer` as `bo` where `bo`.`bundle_status` = 'A' order by `bo`.`bundle_id` desc
      310μsalphaeurekaselec_live_10_06_2022BundleOffer.php#57
      Bindings
      • 0: A
      Backtrace
      • 13. app/Models/BundleOffer.php:57
      • 14. app/Http/Controllers/ArticleController.php:2108
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `tbl_ht_submission` as `h` where `h`.`subtitle` = 'CTMC' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      420μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: CTMC
      Backtrace
      • 13. app/Models/Article.php:2025
      • 14. app/Http/Controllers/ArticleController.php:2112
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '110036' and content_type = 'a' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      430μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2186
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '10164' and content_type = 'i' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      370μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2207
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '2703' and content_type = 'v' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      330μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2231
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"volume" as access_level,"" as issue_id,"" as article_id from `user_access_journal_volume_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316870080 and j.to_ip >=316870080 )) and ((j.from_date <= 1740676189 and j.to_date >= 1740676189 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2703) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"volume" as access_level,"" as issue_id,"" as article_id from `user_access_journal_volume_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316870080 and j.to_ip >=316870080 )) and ((j.from_date <= 1740676189 and j.to_date >= 1740676189 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2703) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"volume" as access_level,"" as issue_id,"" as article_id from `user_access_journal_volume_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316870080 and j.to_ip >=316870080 )) and ((j.from_date <= 1740676189 and j.to_date >= 1740676189 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2703)
      60.45msalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ArticleController.php:2272
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"issue" as access_level,j.issue_id,"" as article_id from `user_access_issue_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316870080 and j.to_ip >=316870080 )) and ((j.from_date <= 1740676189 and j.to_date >= 1740676189 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 10164) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"issue" as access_level,j.issue_id,"" as article_id from `user_access_issue_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316870080 and j.to_ip >=316870080 )) and ((j.from_date <= 1740676189 and j.to_date >= 1740676189 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 10164) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"issue" as access_level,j.issue_id,"" as article_id from `user_access_issue_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316870080 and j.to_ip >=316870080 )) and ((j.from_date <= 1740676189 and j.to_date >= 1740676189 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 10164)
      910μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ArticleController.php:2297
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"article" as access_level, j.issue_id, j.article_id from `user_access_article_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316870080 and j.to_ip >=316870080 )) and ((j.from_date <= 1740676189 and j.to_date >= 1740676189 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 110036) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"article" as access_level, j.issue_id, j.article_id from `user_access_article_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316870080 and j.to_ip >=316870080 )) and ((j.from_date <= 1740676189 and j.to_date >= 1740676189 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 110036) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"article" as access_level, j.issue_id, j.article_id from `user_access_article_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316870080 and j.to_ip >=316870080 )) and ((j.from_date <= 1740676189 and j.to_date >= 1740676189 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 110036)
      830μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ArticleController.php:2329
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `article` where `first_page` < '2535' and is_uploaded = 1 and issue_id = 10164 order by cast(first_page as SIGNED) desc limit 1
      580μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 2535
      Backtrace
      • 14. app/Models/Article.php:1819
      • 15. app/Http/Controllers/ArticleController.php:2470
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `article` where `last_page` > '2577' and is_uploaded = 1 and issue_id = 10164 order by cast(first_page as SIGNED) asc limit 1
      540μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 2577
      Backtrace
      • 14. app/Models/Article.php:1831
      • 15. app/Http/Controllers/ArticleController.php:2472
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `language_id` from `multilanguage` where `short_code` = 'en'
      220μsalphaeurekaselec_live_10_06_2022ArticleController.php#2497
      Bindings
      • 0: en
      Backtrace
      • 14. app/Http/Controllers/ArticleController.php:2497
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select `source_lang_label`, `target_lang_label` from `multilanguage_labels` where `target_lang_id` = 1
      250μsalphaeurekaselec_live_10_06_2022MultiLanguage.php#23
      Bindings
      • 0: 1
      Backtrace
      • 13. app/Models/MultiLanguage.php:23
      • 14. app/Http/Controllers/ArticleController.php:2498
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `id` from `multilanguage_article` where `article_id` = 110036 limit 1
      3.84msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 110036
      Backtrace
      • 16. app/Http/Controllers/ArticleController.php:2506
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 20. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` inner join `journal` as `j` on `j`.`journal_id` = `bd`.`content_id` where `b`.`banner_journal` = 1 and `bd`.`content_type` = 'J' and `bd`.`content_id` = 38 and `b`.`banner_from_date` <= 1740676189 and `b`.`banner_to_date` >= 1740676189 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.55msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 38
      • 3: 1740676189
      • 4: 1740676189
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` inner join `journal` as `j` on `j`.`journal_id` = `bd`.`content_id` where `b`.`banner_journal` = 1 and `bd`.`content_type` = 'J' and `bd`.`content_id` = 38 and `b`.`banner_from_date` <= 1740676189 and `b`.`banner_to_date` >= 1740676189 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.12msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 38
      • 3: 1740676189
      • 4: 1740676189
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select count(*) as aggregate from `uc_cart_products` where cart_id='14b08f1268c9a2162856014a304831de'
      210μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\MultiLanguage
    1MultiLanguage.php#?
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        SV9OnuQFCwcfn0npro0l5Emq0vizoWrkd8Sux2kd
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        PHPDEBUGBAR_STACK_DATA
        []
        path_info
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        status_code
        200
        
        status_text
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        request_cookies
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        response_headers
        0 of 0
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        ClearShow all
        Date ↕MethodURLData
        #12025-02-27 17:09:49GET/article/110036314361