Approaches to synthesis of ([1,2,4]triazolo[1,5-c]quinazolin-2-yl)benzoic acids as potential anti-inflammators

Keywords: heterocyclization, oxidative cyclization, ([1,2,4]triazolo[1,5-c]-quіnazolin-2-yl)benzoic acids, Dimroth rearrangement, spectral characteristics, anti-inflammatory activity

Abstract

Despite their high efficacy NSAIDs have significant side effects due to non-selective inhibition of COX-1 and COX-2. Due to this, medical chemists still pay considerable attention to their design and synthesis, in particular the creation of hybrid molecules that combine in their structure a fragment with anti-inflammatory activity and the quinazoline heterocycle.

The aim of the present study is to develop methods for the synthesis of [1,2,4]triazolo[1,5-c]quinazolin-2-yl)benzoic acids as potential anti-inflammatory agents.

Quinazolin-4(3H)-ylidene)hydrazides (hydrazones) of benzenedicarboxylic acids, their esters, products of their heterocyclization and nucleophilic degradation were the subjects of the study. The structure of the synthesized compounds was confirmed by elemental analysis and NMR spectroscopy. Anti-inflammatory activity was studied in a model of acute aseptic inflammation («carrageenan test») in rats.

Possibilities and limitations of synthesis of [1,2,4]triazolo[1,5-c]quinazolin-2-yl)benzoic acids and their esters via hetero­cyclization of the corresponding hydrazides and hydrazones oxidative cyclization are shown. It was found that the hydrolysis of 4-[(1,2,4]triazolo[1,5-c]quinazolin-2-yl)benzoic acid esters is not a preparative method for the synthesis of the target acids, due to the hydrolytic cleavage of the pyrimidine cycle. Compounds 3, 4 and 6 with moderate anti-inflammatory activity have been identified, which can be used for further structural modification.

Conclusions. It was found that quinazolin-4(3H)-ylidene)hydrazides (hydrazones) of benzenedicarboxylic acids and their esters under the conditions of heterocyclization and oxidative cyclization form [1,2,4]triazolo[1,5-c]quinazolin-2-yl)benzoic acids and their esters. The synthesized compounds are carriers of anti-inflammatory activity and promising for further research.

References

Anti-Inflammatory Drug Discovery. Edited by J. I. Levin., S. Laufer. RSC Drug Discovery Series N 26. – Cambridge: Royal Society of Chemistry, 2012. – 528 р. https://doi.org/10.1039/9781849735346

Lou Y., Zhu J. Carboxylic Acid Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). Bioactive Carboxylic Compound Classes // Pharmaceuticals and Agrochemicals. – 2016. – P. 221–236. https://doi.org/10.1002/9783527693931.ch16

Kotvitska A. A., Kostiuk V. H. Marketynhovi doslidzhennia farmatsevtychnoho rynku nesteroidnykh protyzapalnykh likarskykh zasobiv // Farmats. chasopys. – 2016. – № 2. – S. 48–53. https://doi.org/10.11603/2312-0967.2016.2.6651

Bindu S., Mazumder S., Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: a current perspective // Biochem. Pharmacol. – 2020. – V. 180. – P. 114147. https://doi.org/10.1016/j.bcp.2020.114147

Amjad M. Qandil. Prodrugs of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), More Than Meets the Eye: A Critical Review // Int. J. Mol. Sci. – 2012. – V. 13. – Р. 17244–17274. https://doi.org/10.3390/ijms131217244

Quinazolinone and Quinazoline Derivatives. Acad. Ed. Ali Gamal Al-kaf. – Sana'a University, 2020. – 126 p. https://doi.org/10.5772/intechopen.85315

Chandrika P. M., A. Rao R. R., Narsaiah B., Raju M. B. Quinazoline derivatives with potent anti-inflammatory and anti-allergic activities // Int. J. Chem. Sci. – 2008. – V. 6 (3). – Р. 1119–1146. – URL: https://www.tsijournals.com/articles/ quinazoline-derivatives-with-potent-antiinflammatory-and-antiallergic-activities.pdf

Krasovska N. I., Stavytskyi V. V., Nosulenko I. S. et al. Carboxyl-containing quinazolines and related heterocycles as carriers of anti-inflammatory activity // Zaporozhye Med. J. – 2022. – V. 24, N 1. – Р. 91–101. https://doi.org/10.14739/2310-1210.2022.1.241286

Sidhu R. S., Lee J. Y., Yuan C., Smith W. L. Comparison of Cyclooxygenase-1 Crystal Structures: Cross-Talk between Monomers Comprising Cyclooxygenase-1 Homodimers. // Biochem. – 2010. – V. 49. – P. 7069–7079. https://doi.org/10.1021/bi1003298

Rowlinson S. W., Kiefer J. R., Prusakiewicz J. J. et al. Novel Mechanism of Cyclooxygenase-2 Inhibition Involving Interactions with Ser-530 and Tyr-385 // J. Biol. Chem. – 2003. – V. 278, N 46 (14). – P. 45763–45769. https://doi.org/10.1074/jbc.M305481200

Selinsky B. S., Gupta K., Sharkey C. T., Loll P. J. Structural analysis of NSAID binding by prostaglandin H2 synthase: time-dependent and time-independent inhibitors elicit identical enzyme conformations // Biochem. – 2001. – V. 40, N 17. – P. 5172–5180. https://doi.org/10.1021/bi010045s

Kurumbail R. G., Stevens A. M., Gierse J. K. et al. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents // Nature. – 1996. – V. 384, N 19 (26). – P. 644–648. https://doi.org/10.1038/384644a0

Chenot E., Bernardi D., Comel A., Kirsch G. Preparation of Monoalkyl Terephthalates: An Overview // Synthetic Communications. – 2007. – V. 37, N 3. – P. 483–490. https://doi.org/10.1080/00397910601039226

Armarego W. L. F. The Chemistry of Heterocyclic Compounds, Fused Pyrimidines, Part I: «Quinazolines», Brown D. J., ed.; V. 24/1, Interscience Publishers: N.-Y.–London–Sydney, 1967. – URL: https://vdoc.pub/download/chemistry-of-heterocyclic-compounds-fused-pyrimidines-part-i-quinazolines-volume-24-7s70hjdpg490

European convention for the protection of vertebrate animal used for experimental and other scientific purposes, Council of Europe, Strasbourg, 1986. – URL: https://rm.coe.int/168007a67b

Fehrenbacher J. C., Vasko M. R., Duarte D. B. Models of inflammation: carrageenan- or complete freund’s adjuvant (cfa)-induced edema and hypersensitivity in the rat // Current Protocols in Pharmacology – 2012. – V. 56 (1). – UNIT. 5.4.1-5.4.7

Lapach S. N., Chubenko A. V., Babich P. N. Statistical methods in biomedical research using EXCEL. – Кyiv: Morion, 2001. – 408 p. – URL: https://www.scirp.org/(S(351jmbntvnsjt1aadkposzje))/reference/ReferencesPapers.aspx?ReferenceID=1723702

Kovalenko S. I., Antypenko L. M., Bilyi A. K. et al. Synthesis and Anticancer Activity of 2-(Alkyl-,Alkaryl-,Aryl-,Hetaryl-)[1,2,4]triazolo[1,5-c]quinazolines // Scientia Pharmaceutica. – 2013 – V. 81 (2). – P. 359–391. https://doi.org/10.3797/scipharm.1211-08

Karpenko O. V., Kovalenko S. I. Heterotsyklizatsii na osnovi 4-hidrazynokhinazolinu ta anhidrydiv dykarbonovykh kyslot // Visnyk NU «Lvivska politekhnika». Khimiia, tekhnolohiia rechovyn ta yikh zastosuvannia. – 2006. – № 553. – S. 77–85. – Rezhym dostupu: http://www.disslib.org/syntez-anelovanykh-hetrotsyklichnykh-spoluk-pokhidnykh--hidrazynokhinazolinu-ta-yikh.html

Potts K. T., Brugel E. G. 1,2,4-Triazoles. XXIV. Isomerization of s-Triazolo[4,3-c]quinazoline Derivatives // J. Org. Chem. – 1970. – V. 35, N 10. – P. 3448–3451. https://doi.org/10.1021/jo00835a058

Gibson M. S. Hydrazones – IV: The bromination of benzylidene 2-pyridylhydrazone // Tetrahedron. – 1963. – V. 19, N 11. – P. 1587–1589. https://doi.org/10.1016/S0040-4020(01)99232-4

Breitmaier E. Structure elucidation by NMR in organic chemistry: a practical guide, third edition. – Wiley, 2002. – 270 р. ISBN: 978-0-470-85007-7

Kholodnyak S. V., Schabelnyk K. P., Zhernova G. О. et al. Hydrolytic cleavage of pyrimidine ring in 2-aryl-[1,2,4]triazolo[1,5-c]quinazolines: physicо-chemical properties and hypoglycemia activity of the synthesized compounds // News of pharmacy. – 2015. – V. 3, N 83. – Р. 9–17. https://doi.org/10.24959/nphj.15.2054

Published
2022-06-29
How to Cite
Krasovska, N. I. (2022). Approaches to synthesis of ([1,2,4]triazolo[1,5-c]quinazolin-2-yl)benzoic acids as potential anti-inflammators. Farmatsevtychnyi Zhurnal, (3), 44-54. https://doi.org/10.32352/0367-3057.3.22.05
Section
Synthesis and analysis of biologically active compounds