Chiral Pyrazolo[4,3-e][1,2,4]triazine Sulfonamides—Their Biological Activity, Lipophilicity, Protein Affinity, and Metabolic Transformations
Source abstract
Abstract
Referring to our previous laboratory results related to the tyrosinase and urease inhibition by pyrazolo[4,3-e][1,2,4]triazine sulfonamides, we examined here in silico the mechanism of action at the molecular level of the investigated pyrazolotriazine sulfonamides by the molecular docking method. The studied compounds being evaluated for their cytotoxic effect against cancer cell lines (MCF-7, K-562) and for recombinant Abl and CDK2/E kinase inhibitory potency turned out to be inactive in these tests. The pyrazolotriazines were also investigated with respect to their lipophilicity and plasma protein binding using HPLC chromatography in isocratic conditions. The observed small affinity for plasma proteins could be advantageous in the potential in vivo studies. Moreover, the compounds were sensitive to metabolic transformations with phase I enzymes, which led to the hydroxylation and dealkylation products, whereas phase II transformations did not occur.
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Research context
OpenAlex topics: Synthesis and Characterization of Heterocyclic Compounds · Synthesis and biological activity · Enzyme function and inhibition
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
Department of Chemistry, Siedlce University of Natural Sciences and Humanities, 3-go Maja 54, 08-110 Siedlce, Poland
Department of Pharmaceutical Technology and Biochemistry, Gdansk University of Technology, 80-233 Gdańsk, Poland
Department of Chemistry, University of Life Sciences, Akademicka 15, 20-950 Lublin, Poland
Department of Histology, Embriology and Cytophysiology, Medical University of Lublin, Radziwiłłowska 11, (Collegium Medicum), 20-080 Lublin, Poland
References (57)
Show source-provided references
1. [Pyrazolo 4.3-e] as triazine, a new heterocyclic system from Pseudomonas fluorescens Var. Pseudoiodinum10.1002/cber.19721050619 ↗
2. Novel violet pigment, Nostocine A, an extracelluar metabolite from cyanobacterium Nostoc spongiaeforme10.3987/COM-96-7494 ↗
3. Fluviols, bicyclic nitrogen- rich antibiotics produced by Pseudomonas fluorescens10.1111/j.1574-6968.1997.tb12596.x ↗
4. Protease inhibitors of the sulfonamide type: Anticancer, antiinflammatory, and antiviral agents10.1002/med.10047 ↗
5. Anticancer and antiviral sulfonamides10.2174/0929867033457647 ↗
6. Kleeman, A., Engel, J., Kutscher, B., and Reichert, D. (1999). Pharmaceutical Substances, Syntheses, Patents, Applications, Thieme.
7. Sildenafil (VIAGRATM), a potent and selective inhibitor of type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction10.1016/0960-894X(96)00323-X ↗
8. Interfering with pH regulation in tumours as a therapeutic strategy10.1038/nrd3554 ↗
9. Carbonic anhydrases: Novel therapeutic applications for inhibitors and activators10.1038/nrd2467 ↗
10. Synthesis of methyl ether analogues of sildenafil (Viagra®) possessing tyrosinase inhibitory potential10.1002/cbdv.200590027 ↗
11. A facile and improved synthesis of sildenafil (Viagra®) analogs through solid support microwave irradiation possessing tyrosinase inhibitory potential, their conformational analysis and molecular dynamics simulation studies10.1007/s11030-005-1299-5 ↗
12. Imidazolo[1,2-a]pyridines. Part 2: SAR and optimization of a potent and selective class of cyclin-dependent kinase inhibitors10.1016/j.bmcl.2004.02.008 ↗
13. Recent advances in medicinal chemistry of sulfonamides. Rational design as anti-tumoral, anti-bacterial and anti-inflammatory agents10.2174/138955713804484749 ↗
14. Carbonic anhydrase inhibitors10.1002/med.10025 ↗
15. Supuran, C.T. (2004). Carbonic anhydrases: Catalytic and inhibition mechanisms, distribution and physiological roles. Carbonic Anhydrase: Its Inhibitors and Activators, CRC Press.10.1201/9780203475300.ch1 ↗
16. Carbonic anhydrases as targets for medicinal chemistry10.1016/j.bmc.2007.04.020 ↗
17. Inhibition of carbonic anhydrase IX: A new strategy against cancer10.2174/187152009788680028 ↗
18. Carbonic Anhydrase IX: A new druggable target for the design of antitumor agents10.1002/med.20112 ↗
19. Supuran, C.T., Scozzafava, A., and Conway, J. (2004). Cancer-related carbonic anhydrase isozymes and their inhibition. Carbonic Anhydrase. Its Inhibitors and Activators, CRC Press.10.1201/9780203475300 ↗
20. Synthesis of chiral pyrazolo [4, 3-e][1, 2, 4] triazine sulfonamides with tyrosinase and urease inhibitory activity10.1080/14756366.2016.1238362 ↗
21. Lipophilicity and pKa estimates from gradient high-performance liquid chromatography10.1016/S0021-9673(02)00114-0 ↗
22. Estimation of volume of distribution in humans from high throughput HPLC-based measurements of human serum albumin binding and immobilized artificial membrane partitioning10.1021/jm050957i ↗
23. Reaction of 1, 2, 4-triazines with nitronate anions, direct nucleophilic acylation of 1, 2, 4-triazines10.1016/S0040-4039(01)81522-7 ↗
24. A Concise Route to a Key Intermediate in the Total Synthesis of Sempervirine110.1080/00397919608003843 ↗
25. A new synthesis of pyrazolo [4, 3-e][1, 2, 4] triazines via acid promoted ring closure of the phenylhydrazones of 5-acyl-1, 2, 4-triazines10.3987/COM-00-8972 ↗
26. Transformations of phenylhydrazones of 5-acyl-1, 2, 4-triazines to pyrazolo [4, 3-e][1, 2, 4] triazines or 4-cyanopyrazole10.1002/jhet.5570440504 ↗
27. Palladium-catalyzed 3-thiomethyltriazine-boronic acid cross coupling: Easy access to 3-substituted-1, 2, 4-triazines10.1055/s-2002-20462 ↗
28. Relaxant effects of selected sildenafil analogues in the rat aorta
29. New approaches to the synthesis of sildenafil analogues and their enzyme inhibitory activity10.1016/j.bmc.2015.02.026 ↗
30. New pyrazolo [4, 3-e][1, 2, 4] triazine sulfonamides as carbonic anhydrase inhibitors10.1016/j.bmc.2015.04.011 ↗
31. Pyrazolo [4, 3-e][1, 2, 4] triazine sulfonamides as carbonic anhydrase inhibitors with antitumor activity10.1016/j.bmc.2014.03.029 ↗
32. The relation between the composition of certain ternary two-phase solvent systems and RM values10.1016/S0021-9673(01)86422-0 ↗
33. A new method for estimating log kw values and solute biological activity
34. Influence of modifier and molecular structure of some dihydroxythiobenzanilides on retention in reversed-phase high-performance thin-layer chromatography10.1016/S0021-9673(97)00828-5 ↗
35. Application of high-performance liquid chromatography based measurements of lipophilicity to model biological distribution10.1016/j.chroma.2003.10.084 ↗
36. Thermodynamics of solute partitioning into immobilized artificial membranes10.1021/ac00109a034 ↗
37. Mojzych, M., Bernat, Z., Karczmarzyk, Z., Matysiak, J., and Fruziński, A. (2020). Synthesis, Structural Characterization, and Biological Activity of New Pyrazolo [4, 3-e][1, 2, 4] triazine Acyclonucleosides. Molecules, 25.10.3390/molecules25010221 ↗
38. Atomic physicochemical parameters for three-dimensional-structure-directed quantitative structure-activity relationships. 2. Modeling dispersive and hydrophobic interactions10.1021/ci00053a005 ↗
39. ACD/Log P method description10.1023/A:1008719622770 ↗
40. Reversed-phase liquid chromatography with octadecylsilyl, immobilized artificial membrane and cholesterol columns in correlation studies with in silico biological descriptors of newly synthesized antiproliferative and analgesic active compounds10.1016/j.chroma.2013.09.060 ↗
41. A comparison of theoretical methods of calculation of partition coefficients for selected drugs
42. Comparison between immobilized artificial membrane (IAM) HPLC data and lipophilicity in n-octanol for quinolone antibacterial agents10.1016/j.ejps.2007.04.003 ↗
43. Molecular properties that influence the oral bioavailability of drug candidates10.1021/jm020017n ↗
44. Fast gradient HPLC method to determine compounds binding to human serum albumin. Relationships with octanol/water and immobilized artificial membrane lipophilicity10.1002/jps.10494 ↗
45. The discovery of in vivo active mitochondrial branched-chain aminotransferase (BCATm) inhibitors by hybridizing fragment and HTS hits10.1021/acs.jmedchem.5b00313 ↗
46. Use of a human serum albumin-based stationary phase for high-performance liquid chromatography as a tool for the rapid determination of drug-plasma protein binding10.1002/jps.2600820629 ↗
47. Crystal structure of Agaricus bisporus mushroom tyrosinase: Identity of the tetramer subunits and interaction with tropolone10.1021/bi200395t ↗
48. Begum, A., Choudhary, M.I., and Betzel, C. (2009, March 20). The First Jack Bean Urease (Canavalia Ensiformis) Complex Obtained at 1.52 Resolution. Available online: https://dx.doi.org/10.2210/pdb4h9m/pdb.10.2210/pdb4h9m/pdb ↗
49. Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Montgomery, J.A., Vreven, T., Kudin, K.N., and Burant, J.C. (2004). Pople, Gaussian 03, Revision E.01, Gaussian, Inc.
50. HyperChem (2011). Release 8.0.10 for Windows Molecular Modeling System, Hypercube Inc.
51. Frisch, A., Dennington, R.D., Keith, T.A., Millam, J., Nielsen, A.B., Holder, A.J., and Hiscocks, J. (2007). Gauss View Reference, Gaussian Inc.. Version 4.
52. Development and validation of a genetic algorithm for flexible docking10.1006/jmbi.1996.0897 ↗
53. Empirical scoring functions for advanced protein−Ligand docking with PLANTS10.1021/ci800298z ↗
54. Evaluation of a tetrazolium-based semiautomated colorimetric assay: Assessment of chemosensitivity testing
55. Synthesis and kinase inhibitory activity of new sulfonamide derivatives of pyrazolo[4,3-e][1,2,4]triazines10.1016/j.ejmech.2014.03.054 ↗
56. Synthesis and in vitro biological evaluation of 2, 6, 9-trisubstituted purines targeting multiple cyclin-dependent kinases10.1016/j.ejmech.2012.06.036 ↗
57. Pyrazolo [4, 3-d] pyrimidine bioisostere of roscovitine: Evaluation of a novel selective inhibitor of cyclin-dependent kinases with antiproliferative activity10.1021/jm200064p ↗