Esters and amides of 3-R-2,8-dioxo-7,8-dihydro2H-pyrrolo[1,2-a][1,2,4]­triazino[2,3-c]quinazolin-5a(6H)-carboxylic(-propanoic) acids: synthesis and biological activity

Authors

DOI:

https://doi.org/10.24959/ophcj.20.192826

Keywords:

pyrrolo[1, 2-а][1, 2, 4]triazino[2, 3-с]quinazolin-5а(6Н)-carboxylic(-propanoic) acid, esters, amides, synthesis, radical scavenging activity, LOX-inhibiting activity

Abstract

It is known that carboxyl groups bonded to aryl or hetaryl moieties play a role of the “pharmacophore” fragment in most NSAID molecules. It should be mentioned that the carboxyl group may cause the appearance of toxic effects and is characterized by unsatisfactory pharmacokinetic properties. The structural modification of the carboxyl group, including its bioisosteric replacement, is among the most widely used approaches in medicinal chemistry to improve pharmacodynamic, pharmacokinetic and technological characteristics.

Aim. To develop the synthetic procedures for functional derivatives of 3-R-2,8-dioxo-7,8-dihydro-2Н-pyrrolo[1,2-а][1,2,4]triazino[2,3-с]quinazoline-5а(6Н)-carboxylic(-propanoic) acids, study the effect of the carboxyl group chemical modification on the LOX-inhibiting and antiradical activity as a possible mechanism of the pharmacological activity.

Results and discussion. The synthesis of esters of 3-(2,8-dioxo-3-R1-7,8-dihydro-2H-pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazolin-5a(6H)-yl)carboxylic(propanoic) acids was conducted by esterification of the corresponding acids and tandem heterocyclization of 2-(6-R1-2,5-dihydro-5-оxo-1,2,4-triazino-3-yl)anilines with diethyl 4-oxoheptanedioate. The synthesis of amides was conducted by aminolysis of N-acylimidazolides generated in situ. The antiradical and LOX-inhibiting activities of the compounds obtained were studied as possible mechanisms of the anti-inflammatory activity. The series of the compounds revealed the LOX-inhibiting activity that was comparable with the effect of the reference compound – nordihydroguaiaretic acid.

Experimental part. The synthetic procedures were conducted according to the commonly used methods. The purity and the structure of the compounds obtained were proven by modern physicochemical methods (1H and 13C NMR-spectroscopy, LC-MS-spectrometry). The antiradical activity was measured by the ability to scavenge a DPPH-radical. The study of the LOX-inhibiting activity was performed using soybean LOX as an enzyme and linolenic acid as a substrate.

Conclusions. The methods for the synthesis of esters and amides of 2,8-dioxo-3-R1-7,8-dihydro-2H-pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazolin-5a(6H)-carboxilic(propanoic) acids have been developed. The abovementioned transformations were conducted by alcoholysis of generated in situ acyl halides and aminolysis of N-acylimidazolides, respectively. The more efficient approach for the synthesis of the target esters via condensation of 2-(6-R1-2,5-dihydro-5-oxo-1,2,4-triazino-3-yl)anilines with diethyl 4-oxoheptanedioate has been proposed. It has been found that the highest radical scavenging and LOX-inhibiting activities are characteristic for hetarylpropanoic acids that contain electron withdrawing substituents in position 3, as well as fluorine atoms in positions 11 and 12. The chemical modification of the carboxylic group in most cases results in a decrease or the loss of the activity.

 

Received: 10.01.2019
Revised: 04.02.2020
Accepted: 27.02.2020

Supporting Agency

  • The budget theme of the Ministry of Public Health of Ukraine No. 0118U004370

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References

  1. Claria, J. Cyclooxygenase-2 Biology. Current Pharmaceutical Design 2003, 9 (27), 2177-2190. https://doi.org/10.2174/1381612033454054.
  3. Iezzi, A.; Ferri, C.; Mezzetti, A.; Cipollone, F. COX-2: Friend or Foe? Current Pharmaceutical Design 2007, 13 (16), 1715-1721. http://dx.doi.org/10.2174/138161207780831293.
  5. Rao, P.; Knaus, E. E. Evolution of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Cyclooxygenase (COX) Inhibition and Beyond. Journal of Pharmacy & Pharmaceutical Sciences 2008, 11 (2), 81s-110s. http://dx.doi.org/10.18433/j3t886.
  7. Lassalas, P.; Gay, B.; Lasfargeas, C.; James, M. J.; Tran, V.; Vijayendran, K. G.; Brunden, K. R.; Kozlowski, M. C.; Thomas, C. J.; Smith, A. B.; Huryn, D. M.; Ballatore, C. Structure Property Relationships of Carboxylic Acid Isosteres. J. Med. Chem. 2016, 59 (7), 3183-3203. http://dx.doi.org/10.1021/acs.jmedchem.5b01963.
  9. Ballatore, C.; Huryn, D. M.; Smith III, A. B. Carboxylic Acid (Bio)Isosteres in Drug Design. ChemMedChem 2013, 8 (3), 385-395. http://dx.doi.org/10.1002/cmdc.201200585.
  11. Szabó, G.; Fischer, J.; Kis-Varga, Á.; Gyires, K. New Celecoxib Derivatives as Anti-Inflammatory Agents. J. Med. Chem. 2008, 51 (1), 142-147. http://dx.doi.org/10.1021/jm070821f.
  13. Biava, M.; Porretta, G. C.; Poce, G.; Battilocchio, C.; Alfonso, S.; Rovini, M.; Valenti, S.; Giorgi, G.; Calderone, V.; Martelli, A.; Testai, L.; Sautebin, L.; Rossi, A.; Papa, G.; Ghelardini, C.; Di Cesare Mannelli, L.; Giordani, A.; Anzellotti, P.; Bruno, A.; Patrignani, P.; Anzini, M. Novel Analgesic/Anti-Inflammatory Agents: Diarylpyrrole Acetic Esters Endowed with Nitric Oxide Releasing Properties. J. Med. Chem. 2011, 54 (22), 7759-7771. http://dx.doi.org/10.1021/jm200715n.
  15. 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. Heterocycl. Chem. n/a (n/a). http://dx.doi.org/10.1002/jhet.3862.
  17. Ставицький, В. В.; Воскобойник, О. Ю.; Носуленко, І. С.; Клімова, О. О.; Брашко, О. А.; Коваленко, С. І. Заміщені 3-R-7,8-дигідро-2Н-піроло[1,2-а][1,2,4]триазино[2,3-с]хіназолін-5а(6Н)-алкілкарбонові кислоти – перспективний клас малотоксичних протизапальних агентів. Фармацевтичний часопис 2019, (3), 5-12. http://dx.doi.org/10.11603/2312-0967.2019.3.10468.
  19. Staab, H. A. New Methods of Preparative Organic Chemistry IV. Syntheses Using Heterocyclic Amides (Azolides). Angew. Chem., Int. Ed. Engl. 1962, 1 (7), 351-367. http://dx.doi.org/10.1002/anie.196203511.
  21. Breitmaier, E. Structure Elucidation by NMR in Organic Chemistry: A Practical Guide. 3rd ed.; John Willey & Sons Ltd:Chichester, 2002; p 272.
  23. Anti-Inflammatory Drug Discovery; Levin, J. I., Laufer, S., Eds.; Drug Discovery; The Royal Society of Chemistry, 2012. https://doi.org/10.1039/9781849735346.
  25. Auffinger, P.; Hays, F. A.; Westhof, E.; Ho, P. S. Halogen bonds in biological molecules. Proceedings of the NationalAcademyof Sciences 2004, 101 (48), 16789-16794. http://dx.doi.org/10.1073/pnas.0407607101.
  27. Stavytskyi, V. V.; Nosulenko, I. S.; Portna, O. O.; Shvets, V. M.; Voskoboynik, O. Yu.; Kovalenko, S. I. Substituted pyrrolo[1,2-a][1,2,4]triazolo-(triazino-)[c]quinazolines – a promising class of lipoxygenase inhibitors. Актуальні питання фармацевтичної та медичної науки та практики 2020, 1 (32), 213-221. https://doi.org.10.14739/2409-2932.2020.1.184170.
  29. Sergeieva, T. Y.; Voskoboynik, O. Y.; Okovytyy, S. I.; Kovalenko, S. I.; Shishkina, S. V.; Shishkin, O. V.; Leszczynski, J. Hydrazinolysis of 3-R-[1,2,4]Triazino[2,3-c]quinazolin-2-ones. Synthetic and Theoretical Aspects. J. Phys. Chem. A 2014, 118 (10), 1895-1905. http://dx.doi.org/10.1021/jp4052616.
  31. Kedare, S. B.; Singh, R. P. Genesis and development of DPPH method of antioxidant assay. Journal of Food Science and Technology 2011, 48 (4), 412-422. http://dx.doi.org/10.1007/s13197-011-0251-1.
  33. Szabo, M. R.; Idiţoiu, C.; Chambre, D.; Lupea, A. X. Improved DPPH determination for antioxidant activity spectrophotometric assay. Chemical Papers 2007, 61 (3), 214-216. http://dx.doi.org/10.2478/s11696-007-0022-7.
  35. Pontiki, E.; Hadjipavlou-Litina, D. Synthesis and pharmacochemical evaluation of novel aryl-acetic acid inhibitors of lipoxygenase, antioxidants, and anti-inflammatory agents. Bioorg. Med. Chem. 2007, 15 (17), 5819-5827. http://dx.doi.org/10.1016/j.bmc.2007.06.001.
  37. Korobko, D.; Hadjipavlou-Litina, D. J.; Logoyda, L. 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 2018, 11 (6). http://dx.doi.org/10.22159/ajpcr.2018.v11i6.25990.

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Published

2020-03-05

How to Cite

(1)
Stavytskyi, V. V.; Nosulenko, I. S.; Kandybey, K. I.; Voskoboinik, O. Y.; Kovalenko, S. I. Esters and Amides of 3-R-2,8-Dioxo-7,8-dihydro2H-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, 14-21.

Issue

Vol. 18 No. 1(69) (2020)

Section

Original Researches

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