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Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry

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ISSN (Print): 1871-5230
ISSN (Online): 1875-614X

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Research Article

Directed Search of Anti-inflammatory Agents Among (3HQuinazoline- 4-ylidene)hydrazides of N-protected Amino acids and their Heterocyclization Products

Author(s): Yulya Martynenko*, Oleksii Antypenko , Inna Nosulenko, Galina Berest and Sergii Kovalenko

Volume 19, Issue 1, 2020

Page: [61 - 73] Pages: 13

DOI: 10.2174/1871523018666190115092215

Abstract

Background: (Quinazoline-4-ylidene)hydrazides are valued intermediates in modern organic chemistry, as they are commonly used for the synthesis of substituted [1,2,4]triazolo[1,5-c]quinazolines.

Objective: Unknown N-acyl-2-([1,2,4]triazolo[1,5-c]quinazoline-2-yl)-alkyl-(alkaryl-, aryl-) amines were synthesized and evaluated for anti-inflammatory potential.

Methods: The peculiarities of the synthesized compounds structures were studied by IR-, NMR spectroscopy and chromatography-mass spectrometry and were discussed in detail. Probable molecular mechanisms of activity (inhibition of COX-1 and COX-2) were predicted due to molecular docking. Anti-inflammatory activity of synthesized compounds was determined by their ability to reduce the formalin-induced paw edema in rats. Diclofenac sodium was used as reference drug.

Results: In this study, the synthesis of N-acetyl-(benzoyl)-2-([1,2,4]triazolo[1,5-c]quinazolinе- 2-yl)alkyl-(aralkyl-, aryl-)amines, using (3H-quinazoline-4-ylidene)hydrazides of Nprotected amino acids or 4-hydrazinoquinazoline and N-prorotected amino acids as starting compounds was developed. It was established that the reaction of (3H-quinazoline-4- ylidene)hydrazides of Boc-amino acids occurred with the formation of N-acetyl-substituted triazoloquinazolines. High anti-inflammatory activity was detected for unknown (3Hquinazoline- 4-ylidene)hydrazides Boc-amino acids (1.13-1.15) and N-acetyl-(benzoyl)-2- ([1,2,4]triazolo[1,5-c]quinazoline-2-yl-)aralkyl-(aryl-)amines (3.2, 3.3, 3.11, 3.12), using the experimental formalin test.

Conclusion: The conducted SAR-analysis allowed to detect critical fragments. Namely, the Boc-aminoaralkyl-(aryl-)acid residue in (3H-quinazoline-4-ylidene)hydrazides (1.13- 1.15), benzyl and phenyl linker groups in N-acetyl-(benzoyl)-2-([1,2,4]triazolo[1,5- c]quinazoline-2-yl-)aralkyl-(aryl-) amines (3.2, 3.3, 3.11, 3.12) are believed to be substantial for anti-inflammatory activity.

Keywords: (3H-quinazoline-4-ylidene)hydrazides N-protected amino acids, [1, 2, 4]triazolo[1, 5-c]quinazolines, anti-inflammatory activity, molecular docking, SAR-analysis, heterocyclization products.

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[1]
Karpenko, O.V.; Kovalenko, S.I. Syntez 2-R-triazolo[1,5-c]hinazoliniv. Message 1. J. Org. and Pharm. Chem., 2005, 3(2), 47-54. [transliteration from Ukranian].
[2]
Karpenko, O.V.; Kovalenko, S.I. Syntez 2-R-triazolo[1,5-c]hinazoliniv. Message 2. J. Org. and Pharm. Chem., 2005, 3(4), 61-69. [transliteration from Ukranian].
[3]
Karpenko, O.V.; Kovalenko, S.I. Syntez 2-R-triazolo[1,5-c]hinazoliniv. Message 3. J. Org. and Pharm. Chem., 2006, 4(2), 65-70. [transliteration from Ukranian].
[4]
Karpenko, O.V.; Kovalenko, S.I. Termogravimetrichni doslidjennia 4-(N-acyl)hydrazinohinazo-liniv ta heterocyclizacii na ih osnovi. Voporosi himii i himicheskoi tehnologii,, 2006, 5, 12-16. [transliteration from Ukranian].
[5]
El-Hashash, M.A.; Darwish, K.M.; Rizk, S.A.; El-Bassiouny, F.A. The reactivity of 2-ethoxy-4-chloroquinazoline and its use in synthesis of novel quinazoline derivatives. Org. Chem. Int., 2011, 1-7.
[http://dx.doi.org/10.1155/2011/295491]
[6]
Kovalenko, S.I.; Antypenko, L.M.; Bilyi, A.K.; Kholodnyak, S.V.; Karpenko, O.V.; Antypenko, O.M.; Mykhaylova, N.S.; Los, T.I.; Kolomoets, O.S. Synthesis and anticancer activity of 2-alkyl(alkaryl-, aryl-, heteryl-)-[1,2,4]triazolo[1,5-c]quinazolines. Sci. Pharm., 2013, 81(2), 359-391.
[http://dx.doi.org/10.3797/scipharm.1211-08] [PMID: 23833709]
[7]
Martynenko, Y.V.; Kazunin, M.S.; Selivanova, Y.A.; Kovalenko, S.I. 2-([1,2,4]Triazolo[1,5-c]qui-nazolin-2-yl-)alkyl-(alkaryl-, aryl-)-amines and their derivatives. (3H-quinazolin4-yliden)hydrazides (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)alkyl-(alkaryl-, aryl-) carboxylic acids: features of synthesis, modification and antibacterial activity of synthesized compounds. Zaporozhye Med. J., 2016, 4(97), 89-96.
[8]
Francis, J.E.; Cash, W.D.; Barbaz, B.S.; Bernard, P.S.; Lovell, R.A.; Mazzenga, G.C.; Friedmann, R.C.; Hyun, J.L.; Braunwalder, A.F.; Loo, P.S. Synthesis and benzodiazepine binding activity of a series of novel [1,2,4]triazolo[1,5-c]quinazolin-5(6H)-ones. J. Med. Chem., 1991, 34(1), 281-290.
[http://dx.doi.org/10.1021/jm00105a044] [PMID: 1846920]
[9]
Jantová, S.; Cipák, L.; Slamenová, D.; Horváth, V.; Rauko, P. Induction of cytotoxicity and ssDNA breaks by 9-bromo-5-morpholino-tetrazolo[1,5-c] quinazoline in tumor cells cultured in vitro. Toxicol. In Vitro, 2003, 17(4), 457-463.
[http://dx.doi.org/10.1016/S0887-2333(03)00066-3] [PMID: 12849729]
[10]
Okamura, T.; Kurogi, Y.; Hashimoto, K.; Nishikawa, H.; Nagao, Y. Facile synthesis of fused 1,2,4-triazolo[1,5-c]pyrimidine derivatives as human adenosine A3 receptor ligands. Bioorg. Med. Chem. Lett., 2004, 14(10), 2443-2446.
[http://dx.doi.org/10.1016/j.bmcl.2004.03.010] [PMID: 15109629]
[11]
Kim, Y.C.; Ji, X.D.; Jacobson, K.A. Derivatives of the triazoloquinazoline adenosine antagonist (CGS15943) are selective for the human A3 receptor subtype. J. Med. Chem., 1996, 39(21), 4142-4148.
[http://dx.doi.org/10.1021/jm960482i] [PMID: 8863790]
[12]
Kim, Y.C.; de Zwart, M.; Chang, L.; Moro, S.; von Frijtag Drabbe Künzel, J.K.; Melman, N.; IJzerman, A.P.; Jacobson, K.A. Derivatives of the triazoloquinazoline adenosine antagonist (CGS 15943) having high potency at the human A2B and A3 receptor subtypes. J. Med. Chem., 1998, 41(15), 2835-2845.
[http://dx.doi.org/10.1021/jm980094b] [PMID: 9667972]
[13]
Gineinah, M.M.; Nasr, M.N.; Abdelal, A.M.; El-Emam, A.A.; Said, S.A. Synthesis and anti-inflammatory evaluation of new 2- and 3-substituted 1,2,4-triazolo[4,3-c]- and [1,5-c]quinazoline derivatives. Med. Chem. Res., 2000, 10(4), 243-252.
[14]
Karpenko, O.V.; Belenichev, I.F.; Kovalenko, S.I.; Sidorova, I.V. Antioxidantna ta antiradikalnaactivnist’ N′-(hinazolin-4-yl)hydrazidiv (het)arylcarbo-novih kislot i 2-(het)aryl-[1,2,4]triazolo[1,5-c]hinazo-liniv. Farmacevtichnii J., 2006, 4, 49-54. [transliteration from Ukranian].
[15]
Balo, C.; López, C.; Brea, J.M.; Fernández, F.; Caamaño, O. Synthesis and evaluation of adenosine antagonist activity of a series of [1,2,4]triazolo[1,5-c]quinazolines. Chem. Pharm. Bull. (Tokyo), 2007, 55(3), 372-375.
[http://dx.doi.org/10.1248/cpb.55.372] [PMID: 17329874]
[16]
Avendano, C.; Menendez, J.C. Medical chemistry of anticancer drugs; Elsevier’s Science & Technology Rights Department in Oxford: UK, 2008.
[17]
Mani, P.; Chandrika, A.; Raghu, R.R.; Narsaiah, B.; Bhagawan, R. Quinazoline derivatives with potent anti-inflammatory and antiallergic activities. Int. J. Chem. Sci., 2008, 6(3), 1119-1146.
[18]
Voloshina, V.A.; Sapegin, I.D.; Kovalenko, S.I.; Berest, G.G.; Biliy, A.K. Skrining novih proizvodnih 1,2,4-triazolo i 1,2,4-triazolo[1,5-c]hinazolina na osnovanii ozenki antigipoksicheskoi aktivnosti v usloviah modelirovania narushenii mozgovogo krovoobrashenia s pomoshiu antiortostaticheskoi hipokinezii. Zaporizhzhkii Medichnii J., 2009, 11(4), 72-74. [transliteration from Ukranian].
[19]
Hussein, M.A. Structure anti-inflammatory activity relationship and biochemical evaluation of some novel triazoloquinazoline and triazino-quinazoline derivatives containing sulfacetamide moiety. Int. J. Appl. Biol. Pharm. Technol., 2010, 1(3), 1054-1066.
[20]
Kehler, J.; Ritzen, A.; Langgård, M.; Petersen, S.L.; Farah, M.M.; Bundgaard, C.; Christoffersen, C.T.; Nielsen, J.; Kilburn, J.P. Triazoloquinazolines as a novel class of phosphodiesterase 10A (PDE10A) inhibitors. Bioorg. Med. Chem. Lett., 2011, 21(12), 3738-3742.
[http://dx.doi.org/10.1016/j.bmcl.2011.04.067] [PMID: 21602043]
[21]
Levin, J.; Laufe, S. Anti-Inflammatory Drug Discovery. RSC Drug Discovery; Royal Society of Chemistry: Cambridge, 2012.
[http://dx.doi.org/10.1039/9781849735346]
[22]
Khan, I.; Ibrar, A.; Abbas, N.; Saeed, A. Recent advances in the structural library of functionalized quinazoline and quinazolinone scaffolds: synthetic approaches and multifarious applications. Eur. J. Med. Chem., 2014, 76, 193-244.
[http://dx.doi.org/10.1016/j.ejmech.2014.02.005] [PMID: 24583357]
[23]
Ugale, V.G.; Bari, S.B. Quinazolines: new horizons in anticonvulsant therapy. Eur. J. Med. Chem., 2014, 80, 447-501.
[http://dx.doi.org/10.1016/j.ejmech.2014.04.072] [PMID: 24813877]
[24]
Schabelnyk, K.P.; Kholodnyak, S.V.; Berest, G.G.; Kovalenko, S.I.; Polishchuk, N.M.; Kamyshnyi, O.M. Triazolo[1,5-c]quinazolines. Synthesis, antimicrobial and antifungal activity [quinazolin-4(3H)-ylidene] hydrazides of carboxylic acids (Message 1). Zaporozhye Med. J., 2018, 20(3), 425-431.
[25]
Martynenko, Yu.V.; Kazunin, M.S.; Nosulenko, I.S.; Berest, G.G.; Kovalenko, S.I.; Kamyshnyi, O.M.; Polishchuk, N.M. [2-([1,2,4]Triazolo[1,5-c]quinazo-line-2-yl-)alkyl-(alkaryl-,aryl-)-amines and their derivatives. The syn-thesis of (3H-quinazoline-4-ylidene) hydrazides N-protected aminoacids, using a variety of amine-protecting approaches. Physicalchemical properties and biological activity of synthesized compounds. Zaporozhye Med. J., 2018, 20(3), 413-420.
[26]
Sunel, V.; Popa, M.; Verestiuc, L.; Ivanov, C.; Popa, A. Aminoacids derivatives with a potential anti-inflammatory activity. Eurasian ChemTech J., 2003, 5, 323-326.
[http://dx.doi.org/10.18321/ectj321]
[27]
Sharma, C.S.; Nema, R.K.; Sharma, V.K. Synthesis and screening for analgesic and anti-infl ammatory activities of some novel amino acid-containing bicyclo compounds. J. Young Pharm., 2009, 1(2), 170-174.
[http://dx.doi.org/10.4103/0975-1483.55751]
[28]
Stefani, H.A.; Botteselle, G.V.; Zukerman-Schpector, J.; Caracelli, I.; da Silva Corrêa, D.; Farsky, S.H.; Machado, I.D.; Santin, J.R.; Hebeda, C.B. Synthesis, anti-inflammatory activity and molecular docking studies of 2,5-diarylfuran amino acid derivatives. Eur. J. Med. Chem., 2012, 47(1), 52-58.
[http://dx.doi.org/10.1016/j.ejmech.2011.10.018] [PMID: 22071254]
[29]
Chen, X.; Leng, J.; Rakesh, K.P.; Darshini, N.; Shubhavathi, T.; Vivek, H.K.; Mallesha, N.; Qin, H.L. Synthesis and molecular docking studies of xanthone attached amino acids as potential antimicrobial and anti-inflammatory agents. MedChemComm, 2017, 8(8), 1706-1719.
[http://dx.doi.org/10.1039/C7MD00209B] [PMID: 30108882]
[30]
Kadalipura, P.R.; Suhas, R.; Honnayakanahalli, M.; Manu, K.; Shivamallu, C.; Dase, C.G. Quinazolinones linked amino acids derivatives as a new class of promising antimicrobial, antioxidant and anti-inflammatory agents. Eur. J. Chem., 2015, 6(3), 254-260.
[http://dx.doi.org/10.5155/eurjchem.6.3.254-260.1233]
[31]
Protein Data Bank. http://www.rcsb.org/pdb/home/ (Accessed October 24, 2018).
[32]
El Sayed, H.; El Ashrya, S.N.; Muhammad, R.S.; Yeldez, K. Recent advances in the Dimroth rearrangement: a valuable tool for the synthesis of heterocycles. Adv. Heterocycl. Chem., 2010, 101(5), 161-228.
[33]
MarvinSketch version 17.21.0, ChemAxon http:// www.chemaxon.com
[34]
Trott, O.; Olson, A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[PMID: 19499576]
[35]
European convention for the protection of vertebrate animal used for experimental and other scientific purposes. - Council of Europe, Strasbourg, 1986, 53.
[36]
Stefanov, A.V. Doclinicheskie issledovania lekarstvennih sredstv. Avicenna, 2002. [transliteration from Ukranian].
[37]
Lapach, S.N.; Chubenko, A.V.; Babich, P.N. Statisticheskie methodi v medico-biologicheskih issledovaniah s ispolzovaniem EXCEL; Morion, 2001. [transliteration from Ukranian
[38]
Breitmaier, E. Structure Elucidation By NMR. Organic Chemistry: A Practical Guide; John Wiley & Sons, Ltd., 2002.

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