Carboxyl-containing quinazolines and related heterocycles as carriers of anti-inflammatory activity

Authors

DOI:

https://doi.org/10.14739/2310-1210.2022.1.241286

Keywords:

quinazolines, triazoles, heterocyclic compounds, fused-ring, molecular docking simulation, computational prediction of drug-target interactions, anti-inflammatory agents

Abstract

Active pharmaceutical ingredients whose structure combines aromatic or heterocyclic fragments with pharmacophore carboxylic group are widespread on pharmaceutical market. The isolation of COX-NSAIDs complexes and following X-ray studies allowed to explain the key role of pharmacophore carboxylic group in the formation of enzyme-ligand interactions and the effect of its presence on the activity and selectivity. The introduction of selective COX-2-inhibitors to medicinal practice resulted in a significant decrease of side effects and complication frequencies. However, the problem of NSAIDs toxicity has not been solved. Thus, the search for the novel anti-inflammatory drugs using in silico methods and approaches including structural modification of known NSAIDs by “bioisosteric” replacements of aromatic and heterocyclic fragments with other structural elements with carboxylic group as the carrier of pharmacological effect, is a current trend of medicinal chemistry.

The aim of present study is to purposefully search for anti-inflammatory agents among carboxyl-containing quinazolines and related heterocycles using in silico and in vivo methods, as well as to evaluate carboxylic group effect on the level of anti-inflammatory activity.

Materials and methods. Quinazoline-4(3H)-ylidene)hydrazides of mono-(di-)carboxylic acids, 2-R-[1,2,4]triazolo[1,5-c]quinazolines, 3-R-5-(2-aminophenyl)-1H-1,2,4-triazoles, 5-carboxyalkyl[1,2,4]triazolo[1,5-c]quinazolines and 2-R-7-oxo-6,7-dihydropyrrolo[1,2-a][1,2,4]triazolo[1,5-c]quinazoline-4a(5H)-carboxylic acids were screened for their anti-inflammatory activity. MarvinSketch 20.19.0, AutoDock Vina and AutoDockTools 1.5.6, HyperChem 7.5, Discovery Studio were used for in silico research. “Drug-like” characteristics were evaluated using an online service. Prediction of toxicity and Ames mutagenicity of the studied compounds were performed in silico using Test software. Evaluation of the anti-inflammatory activity of the synthesized compounds was carried out on white Wistar rats (150–160 g of weight) using carrageenan induced paw edema model. Phlogogen (1 % aqueous solution of λ-carrageenan) was subplantarly injected in the dose of 0.1 ml in the rats’ hind right paw. The left one was used as a control. The studied compounds were intragastrically administered with atraumatic probe as water solution or finely dispersed suspension stabilized by Tween-80 in the dose of 10 mg/kg 1 hour before the injection of phlogogen. The reference drug Diclofenac sodium was administered intragastrically in a recommended for pre-clinical studies dose of 8 mg/kg. The paw volume was measured before the experiment and in 4 hours after phlogogen injection. The activity of these substances was determined by their ability to reduce the swelling compared with control group and was expressed in percentage. The experiments were carried out with respect to Bioethical rules and norms.

Results. The search for anti-inflammatory agents among carboxylic-containing quinazolines and related heterocycles was theoretically substantiated using results of molecular docking, druglike criteria calculations and predicted parameters of toxicity. Experimental in vivo methods (“carrageenan” test) confirmed the anti-inflammatory activity of studied compounds and showed that (quinazoline-4(3H)-ylidene)hydrazides of dicarboxylic acids inhibit edema by 17.0–50.0 %, 2-carboxyalkyl-(phenyl-)-[1,2,4]triazolo[1,5-c]quinazolines – by 0.00–40.63 %, 2-(5-(2-aminophenyl)-1H-1,2,4-triazol-3-yl)alkyl-(phenyl-)carboxylic acids – by 2.43–49.65 %, 2-R-5-carboxyalkyl[1,2,4]triazolo[1,5-c]quinazolines – by 0.47–22.93 % and 2-R-7-oxo-6,7-dihydropyrrolo[1,2-a][1,2,4]triazolo[1,5-c]quinazoline-4a(5H)-carboxylic acids – by 0.94–17.16 %. Among them, there are compounds that compete with the reference drug “Diclofenac sodium”. The SAR analysis showed that both conformation of the molecule and the nature of the “pharmacophore” moiety (carboxyalkyl residue length) at the corresponding positions of the heterocycle have a significant effect on the anti-inflammatory activity. It was shown that the test compounds, according to molecular docking visualization data, have other enzyme-ligand interactions and probably a different mechanism of activity.

Conclusions. The predicted affinity values, calculated “drug-like” criteria and toxicity parameters, visualization of the docking of studied molecules in active site of biological targets as well as experimental studies results showed that investigated compounds are promising in scope of purposeful search for anti-inflammatory drugs. The conducted in vivo screening of anti-inflammatory activity among carboxyl-containing quinazolines and related heterocyclic compounds allowed to detect series of substances that by the level of anti-inflammatory activity compete with reference-compound “Diclofenac sodium” on the carrageenan-induced paw edema model. Presented data may be considered as a theoretical basis for further structural modification of studied compounds aimed on elaboration of novel anti-inflammatory agents and evaluation of their activity mechanism (lipoxygenase inhibitors, phospholipase inhibitors, etc.).

Author Biographies

N. I. Krasovska, Zaporizhzhia State Medical University, Ukraine

PhD student of the Department of Organic and Bioorganic Chemistry

V V. Stavytskyi, Zaporizhzhia State Medical University, Ukraine

PhD, Assistant of the Department of Organic and Bioorganic Chemistry


I. S. Nosulenko, Zaporizhzhia State Medical University, Ukraine

PhD, Senior Lecturer of the Department of Pharmacognosy, Pharmacology and Botany

 

O. Yu. Voskoboinik, Zaporizhzhia State Medical University, Ukraine

PhD, DSc, Associate Professor of the Department of Organic and Bioorganic Chemistry

S. I. Kovalenko, Zaporizhzhia State Medical University, Ukraine

PhD, DSc, Professor, Head of the Department of Organic and Bioorganic Chemistry

References

Bacchi, S., Palumbo, P., Sponta, A., & Coppolino, M. F. (2012). Clinical Pharmacology of Non-Steroidal Anti-Inflammatory Drugs: A Review. Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 11(1), 52-64. https://doi.org/10.2174/187152312803476255

Simmons, D. L., Botting, R. M., & Hla, T. (2004). Cyclooxygenase Isozymes: The Biology of Prostaglandin Synthesis and Inhibition. Pharmacological Reviews, 56(3), 387-437. https://doi.org/10.1124/pr.56.3.3

Sidhu, R. S., Lee, J. Y., Yuan, C., & Smith, W. L. (2010). Comparison of Cyclooxygenase-1 Crystal Structures: Cross-Talk between Monomers Comprising Cyclooxygenase-1 Homodimers. Biochemistry, 49(33), 7069-7079. https://doi.org/10.1021/bi1003298

Rowlinson, S. W., Kiefer, J. R., Prusakiewicz, J. J., Pawlitz, J. L., Kozak, K. R., Kalgutkar, A. S., Stallings, W. C., Kurumbail, R. G., & Marnett, L. J. (2003). A Novel Mechanism of Cyclooxygenase-2 Inhibition Involving Interactions with Ser-530 and Tyr-385*. Journal of Biological Chemistry, 278(46), 45763-45769. https://doi.org/10.1074/jbc.M305481200

Selinsky, B. S., Gupta, K., Sharkey, C. T., & Loll, P. J. (2001). Structural Analysis of NSAID Binding by Prostaglandin H2 Synthase: Time-Dependent and Time-Independent Inhibitors Elicit Identical Enzyme Conformations†. Biochemistry, 40(17), 5172-5180. https://doi.org/10.1021/bi010045s

Kurumbail, R. G., Stevens, A. M., Gierse, J. K., McDonald, J. J., Stegeman, R. A., Pak, J. Y., Gildehaus, D., Miyashiro, J. M., Penning, T. D., Seibert, K., Isakson, P. C., & Stallings, W. C. (1996). Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature, 384(6610), 644-648. https://doi.org/10.1038/384644a0

Sostres, C., Gargallo, C. J., Arroyo, M. T., & Lanas, A. (2010). Adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs, aspirin and coxibs) on upper gastrointestinal tract. Best Practice & Research Clinical Gastroenterology, 24(2), 121-132. https://doi.org/10.1016/j.bpg.2009.11.005

Varga, Z., Sabzwari, S., & Vargova, V. (2017). Cardiovascular Risk of Nonsteroidal Anti-Inflammatory Drugs: An Under-Recognized Public Health Issue. Cureus, 9(4), Article e1144. https://doi.org/10.7759/cureus.1144

Pagadala, N. S., Syed, K., & Tuszynski, J. (2017). Software for molecular docking: a review. Biophysical Reviews, 9(2), 91-102. https://doi.org/10.1007/s12551-016-0247-1

Paul, D., Sanap, G., Shenoy, S., Kalyane, D., Kalia, K., & Tekade, R. K. (2021). Artificial intelligence in drug discovery and development. Drug Discovery Today, 26(1), 80-93. https://doi.org/10.1016/j.drudis.2020.10.010

Silverstein, F. E., Faich, G., Goldstein, J. L., Simon, L. S., Pincus, T., Whelton, A., Makuch, R., Eisen, G., Agrawal, N. M., Stenson, W. F., Burr, A. M., Zhao, W. W., Kent, J. D., Lefkowith, J. B., Verburg, K. M., & Geis, G. S. (2000). Gastrointestinal Toxicity With Celecoxib vs Nonsteroidal Anti-inflammatory Drugs for Osteoarthritis and Rheumatoid Arthritis: The CLASS Study: A Randomized Controlled Trial. JAMA, 284(10), 1247-1255. https://doi.org/10.1001/jama.284.10.1247

Bombardier, C., Laine, L., Reicin, A., Shapiro, D., Burgos-Vargas, R., Davis, B., Day, R., Ferraz, M. B., Hawkey, C. J., Hochberg, M. C., Kvien, T. K., Schnitzer, T. J., & VIGOR Study Group. (2000). Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis. The New England Journal of Medicine, 343(21), 1520-1528. https://doi.org/10.1056/NEJM200011233432103

Krasovska, N., Stavytskyi, V., Nosulenko, I., Karpenko, O., Voskoboinik, O., & Kovalenko, S. (2021). Quinazoline-containing Hydrazydes of Dicarboxylic Acids and Products of Their Structural Modification: A Novel Class of Anti-inflammatory Agents. Acta Chimica Slovenica, 68(2), 395-403. https://doi.org/10.17344/acsi.2020.6440

Kholodnyak, S. V., Schabelnyk, K. P., Zhernova, G. О., Sergeieva, T. Yu., Ivchuk, V. V., Voskoboynik, O. Yu., Kоvalenko, S. І., Trzhetsinskii, S. D., Okovytyy, S. I., & Shishkina, S. V. (2015). Hydrolytic cleavage of the pyrimidine ring in 2-aryl-[1,2,4]triazole[1,5-c]quinazolines: physicо-chemical properties and the hypoglycemiC activity of the compounds synthesized. Visnyk farmatsii, (3), 9-17.

Voloschyna, V. O., Lytvynenko, M. O., Sapehyn, I. D., Berest, H. H., Kovalenko, S. I., Babanin, A. A., & Synyak, R. S. (2010). Heterotsyklizatsii na osnovi [2-(3-R-1Н-[1,2,4]triazol-5-il)fenil]aminiv ta anhidrydiv alkildykarbonovykh kyslot [Heterocyclization based on [2-(3-R-1Н-[l,2,4]triazolo-5-yl)phenyl]amines and alkyldicarboxylic acid anhydrides]. Medychna khimiia, 12(3), 98-107. [in Ukrainian].

Stavytskyi, V., Voskoboinik, O., Antypenko, O., Krasovska, N., Shabelnyk, K., Konovalova, I., Shishkyna, S., Kholodniak, S., & Kovalenko, S. (2019). Tandem heterocyclization of 2-(azolyl-(azinyl-))anilines as an efficient method for preparation of substituted pyrrolo[1,2-a]azolo-(azino-)[c]quinazolines. Journal of Heterocyclic Chemistry, 57(3), 1249-1260. https://doi.org/10.1002/jhet.3862

Research Collaboratory for Structural Bioinformatics Protein Data Bank (n.d.). RCSB PDB. http://www.rcsb.org/pdb/home/home.do

ChemAxon. (n.d.). MarvinSketch version 19.24. http://www.chemaxon.com

Trott, O., & Olson, A. J. (2010). 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

Accelrys Software Inc. (n.d.). Discovery Studio Visualizer v19.1.018287. https://www.3dsbiovia.com

Molinspiration Cheminformatic. (n.d.). Molinspiration. https://www.molinspiration.com/

United States Environmental Protection Agency. (n.d.). Toxicity Estimation Software Tool (TEST). https://www.epa.gov/chemical-research/toxicity-estimation-software-tool-test

Yap, C. W. (2011). PaDEL-descriptor: An open source software to calculate molecular descriptors and fingerprints. Journal of Computational Chemistry, 32(7), 1466-1474. https://doi.org/10.1002/jcc.21707

World Legal Information Institute. (n.d.). European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes - Explanatory Report - [1986] COETSER 1 (18 March 1986) (Report No. 123). WorldLII. http://www.worldlii.org/int/other/treaties/COETSER/1986/1.html

Fehrenbacher, J. C., Vasko, M. R., & Duarte, D. B. (2012). Models of Inflammation: Carrageenan- or Complete Freund's Adjuvant (CFA)-Induced Edema and Hypersensitivity in the Rat. Current Protocols in Pharmacology, Chapter 5, 5.4.1-5.4.7. https://doi.org/10.1002/0471141755.ph0504s56

Lapach, S. N., Chubenko, A. V., & Babich, P. N. (2001). Statisticheskie metody v mediko-biologicheskikh issledovaniyakh s ispol'zovaniem Excel [Statistical Methods for Biomedical Research Using Excel] (2nd ed). MORION. [in Russian].

Chandrika, P., Raghu, A., Rao, R., Narsaiah, B., & Raju, M. (2008). Quinazoline derivatives with potent anti-inflammatory and anti-allergic activities. International Journal of Chemical Sciences, 6(3), 1119-1146. https://www.tsijournals.com/articles/quinazoline-derivatives-with-potent-antiinflammatory-and-antiallergic-activities.pdf

Alafeefy, A. M., Kadi, A. A., Al-Deeb, O. A., El-Tahir, K. E., & Al-Jaber, N. A. (2010). Synthesis, analgesic and anti-inflammatory evaluation of some novel quinazoline derivatives. European Journal of Medicinal Chemistry, 45(11), 4947-4952. https://doi.org/10.1016/j.ejmech.2010.07.067

El-Feky, S. A., Imran, M., & Nayeem, N. (2017). Design, Synthesis, and Anti-Inflammatory Activity of Novel Quinazolines. Oriental Journal of Chemistry, 33(2), 707-716. https://doi.org/10.13005/ojc/330217

Rakesh K. P., Darshini N., Shubhavathi T., & Mallesha N. (2017). Biological Applications of Quinazolinone Analogues: A Review. Organic & Medicinal Chemistry International Journal, 2(2), Article 555585. https://doi.org/10.19080/OMCIJ.2017.02.555585

Dvorakova, M., Langhansova, L., Temml, V., Pavicic, A., Vanek, T., & Landa, P. (2021). Synthesis, Inhibitory Activity, and In Silico Modeling of Selective COX-1 Inhibitors with a Quinazoline Core. ACS Medicinal Chemistry Letters, 12(4), 610-616. https://doi.org/10.1021/acsmedchemlett.1c00004

Patel, R, Saraswat, R., & Pillai, S. (2021). Synthesis, characterization and biological evaluation of novel quinazolinone derivatives as anti-inflammatory agents. International Journal of Pharmaceutical Sciences and Research, 12(4), 2296-2305. https://doi.org/10.13040/IJPSR.0975-8232.12(4).2296-05

Kolomoets, O., Voskoboynik, О., Antypenko, O., Berest, G., Nosulenko, I., Palchikov, V., Karpenko, O., & Kovalenko, S. (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, Y., Antypenko, O., Nosulenko, I., Berest, G., & Kovalenko, S. (2020). Directed Search of Anti-inflammatory Agents Among (3HQuinazoline- 4-ylidene)hydrazides of N-protected Amino acids and their Heterocyclization Products. Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 19(1), 61-73. https://doi.org/10.2174/1871523018666190115092215

Stavytskyi, V., Voskoboinik, Î., Kazunin, Ì., Nosulenko, I., Shishkina, S., & Kovalenko, S. (2020). Substituted pyrrolo[1,2-a][1,2,4]triazolo-([1,2,4]triazino-)[c]quinazoline-4a(5a)-propanoic acids: synthesis, spectral characteristics and anti-inflammatory activity. Voprosy khimii i khimicheskoi tekhnologii, (1), 61-70. https://doi.org/10.32434/0321-4095-2020-128-1-61-70

Stavytskyi, V., Antypenko, O., Nosulenko, I., Berest, G., Voskoboinik, O., & Kovalenko, S. (2021). 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 in Medicinal Chemistry, 20(1), 75-88. https://doi.org/10.2174/1871523019666200505073232

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Published

2022-01-26

How to Cite

1.
Krasovska NI, Stavytskyi VV, Nosulenko IS, Voskoboinik OY, Kovalenko SI. Carboxyl-containing quinazolines and related heterocycles as carriers of anti-inflammatory activity. Zaporozhye Medical Journal [Internet]. 2022Jan.26 [cited 2024Nov.24];24(1):91-101. Available from: http://zmj.zsmu.edu.ua/article/view/241286

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Basic research