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QSAR and pharmacophore models for screening antiinflammatory activity among substituted (pyrrolо[1,2- a][1,2,4]triazino[2,3-c]quinazoline-5a-yl)carboxylic acids

Yıl 2022, Cilt: 26 Sayı: 5, 1420 - 1431, 28.06.2025

Viktor Stavytskyi Oleksii Voskoboinik , Oleg Devinyak Oleksii Voskoboinik , Sergiy Kovalenko

Öz

This study is devoted to the development of QSAR and pharmacophore models for screening of antiinflammatory
activity among substituted (pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazoline-5a-yl)carboxylic acids,
obtained in earlier research of our scientist group. Genetic algorithm–multiple linear regression allowed to calculate
two three-parameter QSAR equations for each model of experimental inflammation. It was found that the antiinflammatory
activity in the "carrageenan" model depends on the descriptors GATS5m and B10[C-O] and the presence
in the structure nROH functional group. Whereas, in the "formalin" model, pharmacological effect is determined by the
descriptors E2p, R2e+, F09[N-F], that reveal positive contribution to the anti-inflammatory activity. The obtained
equations are characterized by significant predictive power and are determined by both internal and external validation.
The parameters of prognostic ability, namely the values of the cross-validation Q2LOO coefficient, are 0.8509 and 0.7653
respectively. Using pharmacophore modeling, it was found that substituted (pyrrolo[1,2-a][1,2,4]triazino[2,3-
c]quinazoline-5a-yl)carboxylic acids bind with potential biotargets through the carboxyl moiety at the 5a position
(potential participant in the formation of hydrogen bonds), regardless of the model of experimental inflammation.
Additional factors influencing activity are electron withdrawing substituents, namely aromatic (fluorophenyl) cycle at
the certain distance and oxygen at the second position in the molecule. The aforesaid shows the prospects for further
structural modification of the molecule by replacing the triazole ring with azole one or by removing it while retaining
the noted pharmacophore fragments. It is important that the developed models complement each other and can later
be used for virtual screening of anti-inflammatory activity among quinazolines and its condensed analogues.

Anahtar Kelimeler

Pyrrolo[1-2-a][1-2-4]triazino[2-3-c]quinazolines anti-inflammatory activity QSAR- and pharmacophoric models screening

Kaynakça

  • [1] Ajani OO, Audu OY, Aderohunmu DV, Owolabi FE, Olomieja AO. Undeniable pharmacological potentials of quinazoline motifs in therapeutic medicine. Am J Drug Discov Dev. 2017; 7: 1-24. [CrossRef]
  • [2] Reddy AG, Babu VH, Prakash RYJ. A review on quinazolines as anticancer agents. J Chem Pharm Sci. 2017; 10(3): 1492-1504. [CrossRef]
  • [3] Shagufta IA. An insight into the therapeutic potential of quinazoline derivatives as anticancer agents. Меd Chem Commun. 2017; 8: 871-885. [CrossRef]
  • [4] Hameed A, al-Rashida M, Uroos M, Ali SA, Ishtiaq AM, Khan KM. Quinazoline and quinazolinone as important medicinal scaffoldes: a comparative patent review (2011-2016). Expert Opin Ther Pat. 2018; 4: 281-297. [CrossRef]
  • [5] Auti PS, George G, Paul AT. Recent advances in the pharmacological diversification of quinazoline/quinazolinone hybrids. RSC Adv. 2020; 10(68): 41353-41392. [CrossRef]
  • [6] Hameed A, Al-Rashida M, Uroos M, Ali SA, Arshia IM, Khan KM. Quinazoline and quinazolinone as important medicinal scaffolds: a comparative patent review (2011-2016). Expert Opin Ther Pat. 2018; 28(4): 281-297. [CrossRef]
  • [7] Ravez S, Castillo-Aguilera O, Depreux P, Goossens L. Quinazoline derivatives as anticancer drugs: a patent review (2011 - present). Expert Opin Ther Pat. 2015; 25(7): 1-16. [CrossRef]
  • [8] Li SN, Li HQ. Epidermal growth factor receptor inhibitors: a patent review (2010 - present). Expert Opin Ther Pat. 2014; 24(3): 309-21. [CrossRef]
  • [9] Marzaro G, Guiotto A, Chilin A. Quinazoline derivatives as potential anticancer agents: a patent review (2007 - 2010). Expert Opin Ther Pat. 2012; 22(3): 223-252. [CrossRef]
  • [10] Ismail RSM, Ismail NSM, Abuserii S, Abou El EDA. Recent advances in 4-aminoquinazoline based scaffold derivatives targeting EGFR kinases as anticancer agents. Future J Pharm Sci. 2016; 2(1): 9-19. [CrossRef]
  • [11] Alam J, Alam О, Naim MJ, Alam P. A review: recent investigations on quinazoline scaffold. Int J Adv Res. 2015; 3(12): 1656-1664. [CrossRef]
  • [12] Selvam TP, Kumar PV. Quinazoline marketed drugs – a review. Res Pharm. 2011; 1(1): 1-21. [CrossRef]
  • [13] Jafari E, Khajouei MR, Hassanzadeh F, Hakimelahi GH, Khodarahmi GA. Quinazolinone and quinazoline derivatives: recent structures with potent antimicrobial and cytotoxic activities. Res Pharm Sci. 2016; 11(1): 1-14. [CrossRef]
  • [14] Drugbank Online. https://go.drugbank.com/ (accessed 17 January 2022)
  • [15] Paul D, Sanap G, Shenoy S, Kalyane D, Kiran K, Tekade RK. Artificial intelligence in drug discovery and development. Drug Discov Today. 2021; 26(1): 80-93. [CrossRef]
  • [16] Talha B. A new paradigm for drug development. The Lancet Digit Health. 2020; 2(5): e226-e227. [CrossRef]
  • [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. Antiinflamm Antiallergy Agents Med Chem. 2021; 20(1): 75-88. [CrossRef]
  • [18] Stavitsky VV, Voskoboinik OY, 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. [CrossRef]
  • [19] Sidhu RS, Lee JY, Yuan C, Smith WL. Comparison of cyclooxygenase-1 crystal structures: cross-talk between monomers comprising cyclooxygenase-1 homodimers. Biochemistry. 2010; 49: 7069-7079. [CrossRef]
  • [20] Rowlinson SW, Kiefer JR, Prusakiewicz JJ, Pawlitz JL, Kozak KR, Kalgutkar AS, Stallings WC, Kurumbail RG, Marnett LJ. A novel mechanism of cyclooxygenase-2 inhibition involving interactions with Ser-530 and Tyr-385. J Biol Chem, 2003; 278(46): 45763-45769. [CrossRef]
  • [21] Auffinger P, Hays FA, Westhof E, Ho PS. Halogen bonds in biological molecules. Proc Natl Acad Sci. 2004; 101(48): 16789-16794. [CrossRef]
  • [22] Stavytskyi V, Voskoboinik O, Antypenko O, Krasovska N, Shabelnyk K, Konovalova I, Shishkyna S, Kholodniak S, Kovalenko S. Tandem heterocyclization of 2-(azolyl-(azinyl-))anilines as an efficient method for preparation of substituted pyrrolo[1,2-a]azolo-(azino-)[c]quinazolines. J Heterocyclic Chem. 2020; 57(3): 1249-1260. [CrossRef]
  • [23] Todeschini R, Consonni V, Handbook of Molecular Descriptors Wiley-VCH: Weinheim and New York, USA 2000.
  • [24] Talete srl DRAGON for Windows. (Software for Molecular Descriptor Calculations). Version 5.5–2007. http://www.talete.mi.it/ (accessed 17 January 2022).
  • [25] MOPAC2012. http://openmopac.net/MOPAC2012.html (accessed 17 January 2022)
  • [26] 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. [CrossRef]
  • [27] 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. [CrossRef]
  • [28] 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. [CrossRef]
  • [29] Krasovska NI, Stavytskyi VV, Nosulenko I, Kholodniak OV, Antypenko OM, Voskoboinik ОYu, Kovalenko SI. Pyrrolо[1,2-a]azolo-(azino-)[c]quinazolines and their derivatives as 15-LOX inhibitors: design, in vitro studies and QSAR-analysis. J Res Pharm. 2021; 25(5): 1-9. [CrossRef]
  • [30] Yang SY. Pharmacophore modeling and applications in drug discovery: challenges and recent advances. Drug Discov Today. 2010; 15(11-12): 444-450. [CrossRef]
  • [31] Gao Q, Yang L, Zhu Y. Pharmacophore based drug design approach as a practical process in drug discovery. Curr Comput-Aid Drug. 2010; 6(1): 37-49. [CrossRef]
  • [32] Horvath D. Pharmacophore-based virtual screening. Methods in Molecular Biology. 2010, pp. 261-298. [CrossRef]

Yıl 2022, Cilt: 26 Sayı: 5, 1420 - 1431, 28.06.2025

Viktor Stavytskyi Oleksii Voskoboinik , Oleg Devinyak Oleksii Voskoboinik , Sergiy Kovalenko

Öz

Kaynakça

  • [1] Ajani OO, Audu OY, Aderohunmu DV, Owolabi FE, Olomieja AO. Undeniable pharmacological potentials of quinazoline motifs in therapeutic medicine. Am J Drug Discov Dev. 2017; 7: 1-24. [CrossRef]
  • [2] Reddy AG, Babu VH, Prakash RYJ. A review on quinazolines as anticancer agents. J Chem Pharm Sci. 2017; 10(3): 1492-1504. [CrossRef]
  • [3] Shagufta IA. An insight into the therapeutic potential of quinazoline derivatives as anticancer agents. Меd Chem Commun. 2017; 8: 871-885. [CrossRef]
  • [4] Hameed A, al-Rashida M, Uroos M, Ali SA, Ishtiaq AM, Khan KM. Quinazoline and quinazolinone as important medicinal scaffoldes: a comparative patent review (2011-2016). Expert Opin Ther Pat. 2018; 4: 281-297. [CrossRef]
  • [5] Auti PS, George G, Paul AT. Recent advances in the pharmacological diversification of quinazoline/quinazolinone hybrids. RSC Adv. 2020; 10(68): 41353-41392. [CrossRef]
  • [6] Hameed A, Al-Rashida M, Uroos M, Ali SA, Arshia IM, Khan KM. Quinazoline and quinazolinone as important medicinal scaffolds: a comparative patent review (2011-2016). Expert Opin Ther Pat. 2018; 28(4): 281-297. [CrossRef]
  • [7] Ravez S, Castillo-Aguilera O, Depreux P, Goossens L. Quinazoline derivatives as anticancer drugs: a patent review (2011 - present). Expert Opin Ther Pat. 2015; 25(7): 1-16. [CrossRef]
  • [8] Li SN, Li HQ. Epidermal growth factor receptor inhibitors: a patent review (2010 - present). Expert Opin Ther Pat. 2014; 24(3): 309-21. [CrossRef]
  • [9] Marzaro G, Guiotto A, Chilin A. Quinazoline derivatives as potential anticancer agents: a patent review (2007 - 2010). Expert Opin Ther Pat. 2012; 22(3): 223-252. [CrossRef]
  • [10] Ismail RSM, Ismail NSM, Abuserii S, Abou El EDA. Recent advances in 4-aminoquinazoline based scaffold derivatives targeting EGFR kinases as anticancer agents. Future J Pharm Sci. 2016; 2(1): 9-19. [CrossRef]
  • [11] Alam J, Alam О, Naim MJ, Alam P. A review: recent investigations on quinazoline scaffold. Int J Adv Res. 2015; 3(12): 1656-1664. [CrossRef]
  • [12] Selvam TP, Kumar PV. Quinazoline marketed drugs – a review. Res Pharm. 2011; 1(1): 1-21. [CrossRef]
  • [13] Jafari E, Khajouei MR, Hassanzadeh F, Hakimelahi GH, Khodarahmi GA. Quinazolinone and quinazoline derivatives: recent structures with potent antimicrobial and cytotoxic activities. Res Pharm Sci. 2016; 11(1): 1-14. [CrossRef]
  • [14] Drugbank Online. https://go.drugbank.com/ (accessed 17 January 2022)
  • [15] Paul D, Sanap G, Shenoy S, Kalyane D, Kiran K, Tekade RK. Artificial intelligence in drug discovery and development. Drug Discov Today. 2021; 26(1): 80-93. [CrossRef]
  • [16] Talha B. A new paradigm for drug development. The Lancet Digit Health. 2020; 2(5): e226-e227. [CrossRef]
  • [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. Antiinflamm Antiallergy Agents Med Chem. 2021; 20(1): 75-88. [CrossRef]
  • [18] Stavitsky VV, Voskoboinik OY, 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. [CrossRef]
  • [19] Sidhu RS, Lee JY, Yuan C, Smith WL. Comparison of cyclooxygenase-1 crystal structures: cross-talk between monomers comprising cyclooxygenase-1 homodimers. Biochemistry. 2010; 49: 7069-7079. [CrossRef]
  • [20] Rowlinson SW, Kiefer JR, Prusakiewicz JJ, Pawlitz JL, Kozak KR, Kalgutkar AS, Stallings WC, Kurumbail RG, Marnett LJ. A novel mechanism of cyclooxygenase-2 inhibition involving interactions with Ser-530 and Tyr-385. J Biol Chem, 2003; 278(46): 45763-45769. [CrossRef]
  • [21] Auffinger P, Hays FA, Westhof E, Ho PS. Halogen bonds in biological molecules. Proc Natl Acad Sci. 2004; 101(48): 16789-16794. [CrossRef]
  • [22] Stavytskyi V, Voskoboinik O, Antypenko O, Krasovska N, Shabelnyk K, Konovalova I, Shishkyna S, Kholodniak S, Kovalenko S. Tandem heterocyclization of 2-(azolyl-(azinyl-))anilines as an efficient method for preparation of substituted pyrrolo[1,2-a]azolo-(azino-)[c]quinazolines. J Heterocyclic Chem. 2020; 57(3): 1249-1260. [CrossRef]
  • [23] Todeschini R, Consonni V, Handbook of Molecular Descriptors Wiley-VCH: Weinheim and New York, USA 2000.
  • [24] Talete srl DRAGON for Windows. (Software for Molecular Descriptor Calculations). Version 5.5–2007. http://www.talete.mi.it/ (accessed 17 January 2022).
  • [25] MOPAC2012. http://openmopac.net/MOPAC2012.html (accessed 17 January 2022)
  • [26] 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. [CrossRef]
  • [27] 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. [CrossRef]
  • [28] 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. [CrossRef]
  • [29] Krasovska NI, Stavytskyi VV, Nosulenko I, Kholodniak OV, Antypenko OM, Voskoboinik ОYu, Kovalenko SI. Pyrrolо[1,2-a]azolo-(azino-)[c]quinazolines and their derivatives as 15-LOX inhibitors: design, in vitro studies and QSAR-analysis. J Res Pharm. 2021; 25(5): 1-9. [CrossRef]
  • [30] Yang SY. Pharmacophore modeling and applications in drug discovery: challenges and recent advances. Drug Discov Today. 2010; 15(11-12): 444-450. [CrossRef]
  • [31] Gao Q, Yang L, Zhu Y. Pharmacophore based drug design approach as a practical process in drug discovery. Curr Comput-Aid Drug. 2010; 6(1): 37-49. [CrossRef]
  • [32] Horvath D. Pharmacophore-based virtual screening. Methods in Molecular Biology. 2010, pp. 261-298. [CrossRef]
Toplam 32 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Eczacılık Bilimleri
Bölüm Articles
Yazarlar

Viktor Stavytskyi 0000-0001-5897-5845

Oleksii Voskoboinik 0000-0002-8048-445X

Oleg Devinyak 0000-0001-5696-7614

Oleksii Voskoboinik 0000-0002-5790-3564

Sergiy Kovalenko 0000-0001-8017-9108

Yayımlanma Tarihi 28 Haziran 2025
Yayımlandığı Sayı Yıl 2022 Cilt: 26 Sayı: 5

Kaynak Göster

APA Stavytskyi, V., Voskoboinik, O., Devinyak, O., Voskoboinik, O., vd. (2025). QSAR and pharmacophore models for screening antiinflammatory activity among substituted (pyrrolо[1,2- a][1,2,4]triazino[2,3-c]quinazoline-5a-yl)carboxylic acids. Journal of Research in Pharmacy, 26(5), 1420-1431.
AMA Stavytskyi V, Voskoboinik O, Devinyak O, Voskoboinik O, Kovalenko S. QSAR and pharmacophore models for screening antiinflammatory activity among substituted (pyrrolо[1,2- a][1,2,4]triazino[2,3-c]quinazoline-5a-yl)carboxylic acids. J. Res. Pharm. Haziran 2025;26(5):1420-1431.
Chicago Stavytskyi, Viktor, Oleksii Voskoboinik, Oleg Devinyak, Oleksii Voskoboinik, ve Sergiy Kovalenko. “QSAR and Pharmacophore Models for Screening Antiinflammatory Activity Among Substituted (pyrrolо[1,2- a][1,2,4]triazino[2,3-c]quinazoline-5a-yl)carboxylic Acids”. Journal of Research in Pharmacy 26, sy. 5 (Haziran 2025): 1420-31.
EndNote Stavytskyi V, Voskoboinik O, Devinyak O, Voskoboinik O, Kovalenko S (01 Haziran 2025) QSAR and pharmacophore models for screening antiinflammatory activity among substituted (pyrrolо[1,2- a][1,2,4]triazino[2,3-c]quinazoline-5a-yl)carboxylic acids. Journal of Research in Pharmacy 26 5 1420–1431.
IEEE V. Stavytskyi, O. Voskoboinik, O. Devinyak, O. Voskoboinik, ve S. Kovalenko, “QSAR and pharmacophore models for screening antiinflammatory activity among substituted (pyrrolо[1,2- a][1,2,4]triazino[2,3-c]quinazoline-5a-yl)carboxylic acids”, J. Res. Pharm., c. 26, sy. 5, ss. 1420–1431, 2025.
ISNAD Stavytskyi, Viktor vd. “QSAR and Pharmacophore Models for Screening Antiinflammatory Activity Among Substituted (pyrrolо[1,2- a][1,2,4]triazino[2,3-c]quinazoline-5a-yl)carboxylic Acids”. Journal of Research in Pharmacy 26/5 (Haziran 2025), 1420-1431.
JAMA Stavytskyi V, Voskoboinik O, Devinyak O, Voskoboinik O, Kovalenko S. QSAR and pharmacophore models for screening antiinflammatory activity among substituted (pyrrolо[1,2- a][1,2,4]triazino[2,3-c]quinazoline-5a-yl)carboxylic acids. J. Res. Pharm. 2025;26:1420–1431.
MLA Stavytskyi, Viktor vd. “QSAR and Pharmacophore Models for Screening Antiinflammatory Activity Among Substituted (pyrrolо[1,2- a][1,2,4]triazino[2,3-c]quinazoline-5a-yl)carboxylic Acids”. Journal of Research in Pharmacy, c. 26, sy. 5, 2025, ss. 1420-31.
Vancouver Stavytskyi V, Voskoboinik O, Devinyak O, Voskoboinik O, Kovalenko S. QSAR and pharmacophore models for screening antiinflammatory activity among substituted (pyrrolо[1,2- a][1,2,4]triazino[2,3-c]quinazoline-5a-yl)carboxylic acids. J. Res. Pharm. 2025;26(5):1420-31.