Substituted pyrrolo[1,2-a][1,2,4]triazolo-(triazino-)[c]quinazolines - a promising class of lipoxygenase inhibitors
DOI:
https://doi.org/10.14739/2409-2932.2020.1.198109Keywords:
drug discovery, pyrrolo[1, 2-a][1, 2, 4]triazolo-(triazino-)[c]quinazolines, molecular docking, lipoxygenase activityAbstract
The modern strategy of potential biologically active molecules search (“drug-design”) is based on several innovation approaches. The method of high thrоughрut biological screening and method of molecular modeling deserves the most attention among such approaches. Lipoxygenase (LOX) is one owf the most perspective biological target for the substituted pyrrolo[1,2-a][1,2,4]triazolo-(triazino-)[c]quinazolines. So, molecular docking towards LOX and enzyme activating activity was investigated.
The aim: Directed search of potential inhibitors of lipoxygenases among the unknown pyrrolo[1,2-a][1,2,4]triazolo-(triazino-)[c]quinazolines with the use of molecular docking and in vitro high throughput screening.
Materials and methods. The research of lipoxygenase activity has been conducted for a number of original pyrrolo[1,2-a][1,2,4]triazolo-(triazino-)[c]quinazolines. Standard software was used for molecular docking and “drug-like” criteria research. Sodium letinate was used as a substrate to study soybean LOX enzyme activating activity.
Results. The results of molecular docking have shown, that substituted pyrrolo[1,2-a][1,2,4]triazolo[1,5-c]quinazolines reveal a strong affinity toward LOX. The main types of interactions with aminoacid residues of mentioned the enzyme were identified. The conducted researches showed, that the substituted pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazolines had the highest soybean LOX inhibition activity. Compounds with a fluorine atom and a 2-thienyl moiety in the structure revealed the highest activity inhibiting lipoxygenase by 36.33 % and 39.83 % respectively. The increased lipophilicity of triazine derivatives promotes a higher ability to inhibit soybean LOX, whereas, for triazole derivatives, which have lower molecular weight, an inverse relation is observed.
Conclusions. The research of the substituted pyrrolo[1,2-a][1,2,4]triazolo-(triazino-)[c]quinazolines inhibition ability of soybean LOX as one of the possible mechanisms of their activity is proved and conducted. It is shown, that their lipoxygenase activity depends on lipophilicity and is defined by the availability of donor-acceptor fragments in the molecule, that is capable to form hydrogen and other types of interaction. The specified results are strong arguments for their further study as promising anti-inflammatory agents.
References
Krogsgaard-Larsen, P., Liljefors, T., & Madsen, U. (2002). Textbook of Drug Design and Discovery (3rd ed.). Washington, DC: Taylor & Francis.
Keseru, G. M., & Makara, G. M. (2009, Mar). The influence of lead discovery strategies on the properties of drug candidates. Nature Reviews Drug Discovery, 8(3), 203-212. https://doi.org/10.1038/nrd2796
Hajduk, P. J., & Greer, J. (2007). A decade of fragment-based drug design: strategic advances and lessons learned. Nature Reviews Drug Discovery, 6(3), 211-219. https://doi.org/10.1038/nrd2220
Landry, Y., & Gies, J. P. (2008). Drugs and their molecular targets: an updated overview. Fundamental & Clinical Pharmacology, 22(1), 1-18. https://doi.org/10.1111/j.1472-8206.2007.00548.x
Jung, H. J., & Kwon, H. J. (2015). Target deconvolution of bioactive small molecules: the heart of chemical biology and drug discovery. Archives of Pharmacal Research, 38(9), 1627-1641. https://doi.org/10.1007/s12272-015-0618-3
Lee, H., & Lee, J. W. (2016). Target identification for biologically active small molecules using chemical biology approaches. Archives of Pharmacal Research, 39(9), 1193-1201. https://doi.org/10.1007/s12272-016-0791-z
Yakubovska, V. V., Seredinska, N. М., Voskoboynik, О. Yu., Stepanyuk, G. І., & Kovalenko, S. І. (2016). Spriamovanyi poshuk i kharakterystyka protyzapalnoi aktyvnosti natrii (3-R-2-okso-2H-[1,2,4]triazino[2,3-c]khinazolin-6-il)alkilkarboksylativ ta yikh halohenovmisnykh analohiv [Purposeful search and characteristic of anti-inflammatory activity of sodium (3-R-2-оxo-2Н-[1,2,4]triazino[2,3-c]quinazolin-6-yl)alkylcarboxylates and their halogen containing analogues]. Current issues in pharmacy and medicine: science and practice, (1), 60-66. [in Ukrainian]. https://doi.org/10.14739/2409-2932.2016.1.62036
Voskoboynik, O. Yu., Starosyla, S. A., Protopopov, M. V., Volynets, H. P., Shyshkina, S. V., Yarmoliuk, S. M., & Kovalenko, S. I. (2016). Synthesis, anticancer and FGFR1 inhibitory activity of isoindolo[2,1-a][1,2,4]triazino[2,3-c]quinazoline derivatives. Medychna ta klinichna khimiia, 18(1), 5-18. https://doi.org/10.11603/mcch.2410-681X.2016.v0.i1.6123
Voskoboynik O. Yu., Кovalenko S. I., & Shishkina S. V. (2016). 3-R1-8-R2-10-R3-2H-benzo[e][1,2,4]triazino[2,3-c][1,2,3]triazin-2-ones – novel high electro-deficient heterocyclic compounds with promising anticancer activity. Heterocyclic Communications, 22(3), 137-141. https://doi.org/10.1515/hc-2015-0190
Antypenko, O. M., Kovalenko, S. I., Karpenko, O. V., Nikitin, V. O., & Antypenko, L. M. (2016). Synthesis, Anticancer, and QSAR Studies of 2-Alkyl(aryl,hetaryl)quinazolin-4(3H)-thione's and 1,2,4 Triazolo 1,5-c quinazoline-2-thione's Thioderivatives. Helvetica Chimica Acta, 99(8), 621-631. https://doi.org/10.1002/hlca.201600062
Antypenko, O. M., Kovalenko, S. I., Rasulev, B. F., & Leszczynsk, J. (2016). Synthesis of 6-N-R-tetrazolo[1,5-c]quinazolin-5(6H)-ones, anticancer activity and QSAR modeling. Acta Chimica Slovenica, 63(3), 638-645. https://doi.org/10.17344/acsi.2016.2464
Kolomoets, O. S., Voskoboynik, O. Yu., Antypenko, O. M., Berest, G. G., Nosulenko, I. S., Palchikov, V. O., Karpenko, O. V., &
Kovalenko, S. I. (2017). Desing, synthesis and anti-inflammatory activity of dirivatives 10-R-3-aryl-6,7-dihydro-2H-[1,2,4]triazino[2,3-c]quinazolin-2-ones of spiro-fused cyclic frameworks. Acta Chimica Slovenica, 64(4), 902-910. https://doi.org/10.17344/acsi.2017.3575
Martynenko Yu. V., Kazunin M. S., Nosulenko I. S., Berest G. G., Kovalenko S. I., Kamyshnyi O. M., & Polishchuk N. M. (2018). 2-([1,2,4]triazolo[1,5-c]quinazoline-2-yl-)alkyl-(alkaryl-, aryl-)-amines and their derivatives. Message 2. The synthesis of (3Н-quinazoline-4-ylidene)hydrazides N-protected aminoacids, using a variety of amine-protecting approaches. Physico-chemical properties and biological activity of the synthesized compounds. Zaporozhye medical journal, 20(3), 413-420. https://doi.org/10.14739/2310-1210. 2018.3.130544
Voskoboynik, O. Yu., Shishkina, S. V., & Kovalenko, S. I. (2018). [1,2,4]Triazino[2,3-с]quinazolines 3. Structure and anticancer activity of products obtained from reaction of 3-(2-aminophenyl)-6-R-1,2,4-triazin-5(2H)-ones with aryl iso(thio)cyanates. Chemistry of Heterocyclic Compounds, 54(7), 717-728. https://doi.org/10.1007/s10593-018-2338-3
Martynenko, Yu. V., Antypenko, O. M., Nosulenko, I. S., Berest, G. G., & Kovalenko, S. I. (2019). Directed search of anti-inflammatory agents among (3H-quinazoline-4-ylidene)hydrazides of N-protected amino acids and their heterocyclization products. Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 18(2). 1-12. https://doi.org/10.2174/1871523018666190115092215
Stavitskiy, V. V., Voskoboinik, O. Yu., Nosulenko, I. S., Klimova, O. O., Brazhko, O. A., & Kovalenko, S. I. (2019). Zamisheni 3-R-7,8-digidro-2H-pirolo[1,2-a][1,2,4]triazino[2,3-c]hinazolin-5a(6H)-alkil-karbonovi kysloty - perspektyvnyi klas malotoksychnykh protyzapalnykh ahentiv [Substituted 3-R-7,8-dihydro-2H-pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazolin-5a-(6H)-alkyl-carboxylic acids - promising class of low-toxic anti-inflammatory agents] Farmatsevtychnyi chasopys, (3), 5-12. [in Ukrainian]. https://doi.org/10.11603/2312-0967.2019.3.10468
Mashima, R., & Okuyama, T. (2015). The role of lipoxygenases in pathophysiology; new insights and future perspectives. Redox Biology, 6, 297-310. https://doi.org/10.1016/j.redox.2015.08.006
Voskoboinyk, O. Yu., Kovalenko, S. I., Malkova, T. S., & Stavytskyi, V. V. (2018). Pirolo[1,2-a][1,2,4]tryazyno[2,3-c]khinazoliny ta izoindolo[2,1-a][1,2,4]tryazyno[2,3-c]khinazoliny [Pyrrolo [1,2-a] [1,2,4]triazino [2,3-c]quinazolines and isoindolo [2,1-a][1,2,4] triazino [2,3-c] quinazolines]. Ukraine Patent UA 118196. Retrieved from https://base.uipv.org/searchINV/search.php?action=viewdetails&IdClaim=253331 [in Ukrainian].
Worldwide Protein Data Bank. (n.d.). Protein Data Bank (PDB) [Database]. Retrieved from http://www.pdb.org
ChemAxon. (2015). MarvinSketch, Version 6.3.0. [Software]. Retrieved from http://www.chemaxon.com
Trott, O., & Olson, A. J. (2010). Software News and Update AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization, and Multithreading. Journal of Computational Chemistry, 31(2), 455-461. https://doi.org/10.1002/jcc.21334
Biovia. (2019). Discovery Studio Visualizer, v 19.1.0.18287 [Software]. Retrieved from http://www. 3dsbiovia.com/
Molinspiration Cheminformatics. (n.d.). Calculation of Molecular Properties and Bioactivity Score [Computer software]. Retrieved from http://www.molinspiration.com/cgi-bin/properties
Pontiki, E., & Hadjipavlou-Litina, D. (2007). Synthesis and pharmacochemical evaluation of novel aryl-acetic acid inhibitors of lipoxygenase, antioxidants, and anti-inflammatory agents. Bioorganic & Medicinal Chemistry, 15(17), 5819-5827. https://doi.org/10.1016/j.bmc.2007.06.001
Кorobko, D., Hadjipavlou-Litina, D. J., & Logoyda, L. (2018). Antioxidant and anti-inflammatory properties of a series of new 7,8-disubstituted theophylline containing a pyrazole ring. Asian Journal of Pharmaceutical and Clinical Research, 11(6), 448-450. http://dx.doi.org/10.22159/ajpcr.2018.v11i6.25990
Downloads
How to Cite
Issue
Section
License
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access)