Pyrrolо[1,2-a]azolo-(azino-)[c]quinazolines and their derivatives as 15-LOX inhibitors: Design, in vitro studies and QSAR-analysis
Pyrrolо[1,2-a]azolo-(azino-)[c]quinazolines and their derivatives as 15-LOX inhibitors: Design, in vitro studies and QSAR-analysis
Present manuscript is devoted to the search of 15-LOX inhibiting agents among pyrrolo[1,2-a]azolo-(azino- )[c]quinazolines using in silico and in vitro methods. Molecular docking method was used for calculation of affinity and evaluation of protein ligand interactions features. Colorimetric in vitro assay was used for estimation of LOX-15- inhibiting activity of synthesized compounds. QSAR-analysis was used for formation of the models applicable for prediction of properties of not yet synthesized inhibitors of 15-LOX. It was shown that some of the studied compounds reveal LOX-inhibiting activity that was comparable or higher than activity of the reference compound – Nordihydroguaiaretic acid. The conducted molecular docking study allowed to elucidate the affinity towards the enzyme. The visualization of docking study results allowed to establish and to discuss the features of ligand – 15-LOX interactions. The correlations between structure, LOX-inhibiting activity, calculated affinity and lipophilicity were considered as well. The performed QSAR-analysis resulted the five parametric linear model that like docking study results are valuable for further search of promising 15-LOX-inhibitors. Pyrrolo[1,2-a]azolo-(azino-)[c]quinazolines were identified as 15-LOX inhibitors. The reliable correlation between 15-LOX inhibiting activity of the synthesized compounds, their lipophilicity and calculated affinity was not observed. Visualization of molecular docking results and formed QSAR-models may be used as theoretical basis for novel LOX-inhibitors design.
___
- [1] Funk C. The molecular biology of mammalian lipoxygenases and the quest for eicosanoid functions using lipoxygenase-deficient mice. Biochim Biophys Acta. 1996; 1304(1): 65-84.
- [2] Brash A. Lipoxygenases: occurrence, functions, catalysis, and acquisition of substrate. J Biol Chem. 1999; 274(34): 23679-23682.
- [3] Bürger F, Krieg P, Marks F, Fürstenberger G. Positionaland stereo-selectivity of fatty acid oxygenation catalysed by mouse (12S)-lipoxygenase isoenzymes. Biochem J. 2000; 348: 329-335.
- [4] Israel E, Rubin P, Kemp JP, Grossman J, Pierson W, Siegel SC, Tinkelman D, Murray JJ, Busse W, Segal AT, Fish J, Kaiser HB, Ledford D, Wenzel S, Rosenthal R, Cohn J, Lanni C, Pearlman H, Karahalios P. The effect of inhibition of 5-lipoxygenase by zileuton in mild-to-moderate asthma. Ann Intern Med. 1993; 119(11): 1059-1066.
- [5] Nelson H, Kemp J, Berger W, Corren J, Casale T, Dube L, Walton-Bowen K, LaVallee N, Stepanians M. Efficacy of zileuton controlled-release tablets administered twice daily in the treatment of moderate persistent asthma: a 3- month randomized controlled study. Ann Allerg Asthma Im. 2007; 99(2): 178-84.
- [6] Hofmann B, Steinhilber D. 5-Lipoxygenase inhibitors: a review of recent patents (2010-2012). Expert Opin Ther Pat. 2013; 23(7): 895-909.
- [7] Yoshimoto T, Takahashi Y. Arachidonate 12-lipoxygenases. Prostag Oth Lipid M. 2002; 68-69: 245-262.
- [8] Mashima R, Okuyama T. The role of lipoxygenases in pathophysiology; new insights and future perspectives. Redox Biol. 2015; 6: 297-310.
- [9] Karatas H, Cakir-Aktas C. 12/15 Lipoxygenase as a therapeutic target in brain disorders. Noro Psikiyatr Ars. 2019; 56(4): 288-291.
- [10] Orafaie A, Matin MM, Sadeghian H. The importance of 15-lipoxygenase inhibitors in cancer treatment. Cancer Metastasis Rev. 2018; 37: 397-408.
- [11] Orafaie A, Mousavian M, Orafai H, Sadeghian H. An overview of lipoxygenase inhibitors with approach of in vivo studies. Prostag Oth Lipid M. 2020; 146; 106411.
- [12] Sadeghian H, Jabbari A. 15-Lipoxygenase inhibitors: a patent review. Expert Opin Ther Pat. 2015; 26(1): 1-24.
- [13] Guo H, Verhoek IC, Prins GGH, van der Vlag R, van der Wouden PE, van Merkerk R, Quax WJ, Olinga P, Hirsch AKH, Dekker FJ. Novel 15-lipoxygenase-1 inhibitor protects macrophages from lipopolysaccharide-induced cytotoxicity. J Med Chem. 2019; 62(9): 4624-4637.
- [14] Shintoku R, Takigawa Y, Yamada K, Kubota C, Yoshimoto Y, Takeuchi T, Torii S. Lipoxygenase-mediated generation of lipid peroxides enhances ferroptosis induced by erastin and RSL3. Cancer Sci. 2017; 108(11): 2187-2194.
- [15] Stavytskyi VV, Nosulenko IS, Kandybey KI, Voskoboinik OYu, Kovalenko SI. Esters and amides of 3-R-2,8-dioxo7,8-dihydro-2H-pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazolin-5a(6H)-carboxylic (propanoic) acids: synthesis and biological activity. J Org Pharm Chem. 2020; 18(69): 14-21.
- [16] Stavytskyi VV, Nosulenko IS, Portna OO, Shvets VM, Voskoboynik OYu, Kovalenko SI. Substituted pyrrolo[1,2- a][1,2,4]triazolo-(triazino-)[c]quinazolines - a promising class of lipoxygenase inhibitors. Curr Issues Pharm Med Sci Pract. 2020; 13(1): 4-10.
- [17] Stavytskyi V, Antypenko O, Nosylenko I, Berest G, Voskoboinik O, Kovalenko S. Substituted 3-R-2,8-Dioxo-7,8- dihydro-2H-pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazoline-5a(6H)-carboxylic acids and their salts – a promising class of anti-inflammatory agents. Anti-Inflammatory Anti-Allergy Agents Med Chem. 2021; 20(1): 75-88.
- [18] Stavitsky VV, Voskoboinik OYu, Kazunin MS, Nosylenko IS, Shishkina SV, Kovalenko SI. Substituted pyrrolo[1,2- a][1,2,4]triazolo-([1,2,4]triazino-)[c]quinazoline-4a(5a)-propanoic acids: synthesis, spectral characteristics and antiinflammatory activity. Voprosy khimii i khimicheskoi tekhnologii. 2020; 1: 61-70.
- [19] The Protein Data Bank. http://www.rcsb.org/pdb/home/home.do (accessed 16 February 2021).
- [20] Jeremy IL, Stefan L, Anti-Inflammatory Drug Discovery, first ed., RSC Publishing, Cambridge, ENG 2012.
- [21] ChemAxon - Software Solutions and Services for Chemistry & Biology. http://www.chemaxon.com (accessed 16 February 2021).
- [22] Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J Comput Chem. 2010; 31: 455-461.
- [23] BIOVIA Discovery Studio - BIOVIA - Dassault Systèmes® https://www.3ds.com/productsservices/biovia/products/molecular-modeling-simulation/biovia-discovery-studio (accessed 16 February 2021).
- [24] Molinspiration Cheminformatics https://www.molinspiration.com/ (accessed 16 February 2021).
- [25] Todeschini R, Consonni V, Handbook of Molecular Descriptors Wiley-VCH: Weinheim and New York, USA 2000.
- [26] Talete srl DRAGON for Windows (Software for Molecular Descriptor Calculations). Version 5.5 – 2007 - http://www.talete.mi.it/ (accessed 16 February 2021).
- [27] MOPAC2012 http://openmopac.net/MOPAC2012.html (accessed 16 February 2021).
- [28] Gramatica P, Chirico N, Papa E, Cassani S, Kovarich S. QSARINS: A new software for the development, analysis, and validation of QSAR MLR models. J Comput Chem. 2013; 34: 2121-2132.
- [29] Antypenko OM, Kovalenko SI, Karpenko OV, Nikitin VO, Antypenko LM. 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. Helv Chim Acta. 2016; 99(8): 621-631.