Abstract
Background: 1,3-Diones are versatile reagents used for many heterocyclic transformations. Among such groups of compounds, cyclohexane-1,3-dione is widely used in organic synthesis to produce biologically active compounds.
Objective: In this work, target molecules were synthesized from tetrahydrobenzo[b]thiophen-3- carboxamide derivative with different substituents, and their structure-activity relationships were discussed in detail.
Methods: Cyclohexane-1,3-dione underwent different multi-component reactions to produce fused thiophene, thiazole, coumarin, pyran, and pyridine derivatives. The anti-proliferative activity of the newly synthesized compounds toward the six cancer cell lines, namely A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721 was studied. In addition, inhibitions of the most active compounds toward cancer cell lines classified according to the disease were also studied. Furthermore, Pan Assay Interference compounds (PAINS) of the selected compounds were analyzed, along with the c- Met inhibitions.
Results: Anti-proliferative evaluations were performed for all of the synthesized compounds, in which the varieties of substituents through the aryl ring and the heterocyclic ring afforded compounds with high activities. Inhibition activity against the cancer cell lines classified according to the disease, c-Met, and PAINS of the synthesized compounds were measured.
Conclusion: Compounds 3, 13a, 13b, 14a, 16f, 17a, 28, 30a, and 31were the most cytotoxic compounds toward the six cancer cell lines. Inhibition toward cancer cell lines classified according to the disease showed that, in most cases, the presence of the electronegative CN and or Cl groups within the molecule was responsible for its high activity.
Keywords: Cyclohexane-1, 3-dione, thiazole, coumarin, pyran, pyridine, anti-proliferative.
Graphical Abstract
[http://dx.doi.org/10.1182/blood-2009-03-212852] [PMID: 19734450]
[http://dx.doi.org/10.1016/j.tet.2009.06.122]
[http://dx.doi.org/10.1016/j.tet.2012.01.075]
[http://dx.doi.org/10.1016/S0040-4020(01)01173-5]
[http://dx.doi.org/10.1016/j.tet.2011.04.092]
[http://dx.doi.org/10.1016/j.ultsonch.2012.11.002] [PMID: 23218731]
[http://dx.doi.org/10.1016/j.tetasy.2013.01.004]
[http://dx.doi.org/10.1016/j.carres.2007.01.013] [PMID: 17306239]
[http://dx.doi.org/10.1016/j.tetlet.2008.04.160]
[http://dx.doi.org/10.1016/j.molcata.2006.12.039]
[http://dx.doi.org/10.1016/j.apcata.2006.06.035]
[http://dx.doi.org/10.1007/s12039-010-0049-0]
[http://dx.doi.org/10.5155/eurjchem.2.2.272-275.359]
[http://dx.doi.org/10.1016/j.bmcl.2009.03.040] [PMID: 19328691]
[http://dx.doi.org/10.1016/j.tetlet.2009.10.032]
[http://dx.doi.org/10.1016/j.tet.2011.03.078]
[http://dx.doi.org/10.2174/1871520619666190402153429] [PMID: 30947678]
[http://dx.doi.org/10.1016/j.tetlet.2010.07.009]
[http://dx.doi.org/10.1007/s10593-013-1259-4]
[http://dx.doi.org/10.1016/j.steroids.2012.09.007] [PMID: 23064008]
[http://dx.doi.org/10.1093/jnci/83.11.757] [PMID: 2041050]
[http://dx.doi.org/10.1002/ddr.430340203]
[http://dx.doi.org/10.1007/978-1-4615-8152-9_2]
[http://dx.doi.org/10.1038/nrc1951] [PMID: 16990858]
[http://dx.doi.org/10.1021/jm020427b] [PMID: 12672248]
[http://dx.doi.org/10.1038/nchembio718] [PMID: 16408018]
[http://dx.doi.org/10.1021/jm060029z] [PMID: 16570910]
[http://dx.doi.org/10.1007/s10822-007-9109-z] [PMID: 17340041]
[http://dx.doi.org/10.1021/tx700319t] [PMID: 18001056]
[http://dx.doi.org/10.1038/513481a] [PMID: 25254460]
[http://dx.doi.org/10.4155/fmc.14.60] [PMID: 25163000]
[http://dx.doi.org/10.1021/acs.jmedchem.5b00361] [PMID: 26313340]
[http://dx.doi.org/10.1016/j.bmc.2013.04.013] [PMID: 23628470]
[http://dx.doi.org/10.4103/0975-7406.129170] [PMID: 24741273]
[http://dx.doi.org/10.3390/12081910] [PMID: 17960096]
[http://dx.doi.org/10.3390/molecules171214126] [PMID: 23192189]
[http://dx.doi.org/10.1016/j.ejmech.2009.04.048] [PMID: 19535179]
[http://dx.doi.org/10.4314/bcse.v32i2.9]
[http://dx.doi.org/10.1016/j.steroids.2013.08.007] [PMID: 24012739]
[http://dx.doi.org/10.1016/j.tetlet.2014.01.043]
[http://dx.doi.org/10.1016/j.micromeso.2016.05.025]
[http://dx.doi.org/10.1016/j.dyepig.2007.02.007]
[http://dx.doi.org/10.1016/j.molcata.2012.11.011]
[http://dx.doi.org/10.1016/j.tetlet.2015.07.090]
[http://dx.doi.org/10.1016/j.apcatb.2018.03.058]
[http://dx.doi.org/10.1016/j.molstruc.2019.03.006]
[http://dx.doi.org/10.1016/j.tetlet.2016.12.050]
[http://dx.doi.org/10.1016/j.tetlet.2016.03.032]
[http://dx.doi.org/10.1016/j.tet.2014.01.037]
[http://dx.doi.org/10.1016/j.tetlet.2019.151408]
[http://dx.doi.org/10.1016/j.tet.2020.131231]
[http://dx.doi.org/10.1016/j.cis.2020.102138] [PMID: 32387754]
[http://dx.doi.org/10.1016/j.molstruc.2019.127553]
[http://dx.doi.org/10.1016/j.tetlet.2019.01.035]
[http://dx.doi.org/10.1016/j.tetlet.2016.02.068]
[http://dx.doi.org/10.1016/j.bmcl.2012.04.109] [PMID: 22632935]
[http://dx.doi.org/10.1007/s11164-015-2048-8]
[http://dx.doi.org/10.2174/1570180816666190618105907]
[http://dx.doi.org/10.1002/jhet.3865]
[http://dx.doi.org/10.1016/j.apsb.2019.03.001] [PMID: 31193822]
[http://dx.doi.org/10.1016/S0165-0270(00)00280-6] [PMID: 11000412]