Synthesis and biological evaluation of some novel benzoxazin-4-one and quinazolin-4-one derivatives based on anti-inflammatory commercial drugs
DOI:
https://doi.org/10.5564/mjc.v25i51.3121Keywords:
anti-inflammatory, analgesic, Benzoxazinone, Heterocyclic, QuinazolinoneAbstract
Benzoxazine and quinazoline are nitrogen-containing heterocyclic scaffolds found in various biologically active compounds. Due to their diverse biological actions, these heterocyclic rings serve as crucial frameworks for designing medicinal compounds. This study aimed to synthesize and assess in vivo anti-inflammatory, analgesic, and low ulcerogenic potential of a few novel benz[d][1,3]-oxazin-4-one and quinazolinone derivatives. Benzoxazinones (3a-e) were synthesized by cyclizing the carboxylic group (-COOH) of five nonsteroidal anti-inflammatory drugs viz., aceclofenac, ibuprofen, diclofenac, mefenamic acid and ketoprofen (2a-e) with anthranilic acid (1) using dry phosphorus oxychloride (POCl3) in pyridine. The corresponding quinazolinone derivatives (5a-e) were obtained by reacting 3a-e with isonicotinic acid hydrazide (4). Both sets of compounds were evaluated for their anti-inflammatory, analgesic effects, and ulcerogenicity in animal models. Structural characterization was performed using spectral analysis. Among the benzoxazinone derivatives, compound 2-(2-((2,6-dichlorophenyl) amino) benzyl)-4H-benzo[d][1,3]oxazin-4-one (3d) exhibited significant anti-inflammatory activity (62.61% inhibition of rat paw edema) and analgesic activity (62.36% protection in acetic acid-induced writhings) with tolerable gastrointestinal toxicity (2.67 ulcerogenicity index) compared to quinazolinone derivatives. The results of anti-inflammatory and analgesic activities of both the series are comparable with the respective, positive control. Compound 3d, a benzoxazinone-diclofenac hybrid, emerged as a lead molecule with potent anti-inflammatory, analgesic activities and moderate gastric toxicity showcasing the promising potential for further development.
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Bindu S., Mazumder S., Bandyopadhyay U. (2020) Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: a current perspective. Biochem. Pharmacol., 180, 114147. https://doi.org/10.1016/j.bcp.2020.114147
Knights K.M., Mangoni A.A., Miners J.O. (2010) Defining the COX inhibitor selectivity of NSAIDs: implications for understanding toxicity. Expert Rev. Clin. Pharmacol., 3, 769-776. https://doi.org/10.1586/ecp.10.120
Brzozowski T., Konturek P.C.,Konturek S.J., Sliwowski Z., Pajdo R., et al. (2001) Classic NSAID and selective cyclooxygenase (COX)‐1 and COX‐2 inhibitors in healing of chronic gastric ulcers. Microsc. Res. Tech., 53, 343-353. https://doi.org/10.1002/jemt.1102
Davies N.M., Jamali F. (2004) COX-2 selective inhibitors cardiac toxicity: getting to the heart of the matter. J. Pharm. Pharm. Sci., 7, 332-336.
Sun S.X., Lee K.Y., Bertram C.T., Goldstein J.L. (2007) Withdrawal of COX-2 selective inhibitors rofecoxib and valdecoxib: impact on NSAID and gastroprotective drug prescribing and utilization. Curr. Med. Res. Opin., 23, 1859-1866. https://doi.org/10.1185/030079907X210561
Gatti D., Adami S. (2010) Coxibs: a significant therapeutic opportunity. Acta Biomed., 81, 217-224.
Kaur A., Pathak D.P., Sharma V., Wakode S. (2018) Synthesis, biological evaluation and docking study of a new series of di-substituted benzoxazole derivatives as selective COX-2 inhibitors and anti-inflammatory agents. Bioorg. Med. Chem., 26, 891-902. https://doi.org/10.1016/j.bmc.2018.01.007
Khan S.A., Imam S.M., Ahmad A., Basha S.H. (2018) Synthesis, molecular docking with COX 1& II enzyme, ADMET screening and in vivo anti-inflammatory activity of oxadiazole, thiadiazole and triazole analogs of felbinac. J. Saudi Chem. Soc., 22, 469-484. https://doi.org/10.1016/j.jscs.2017.05.006
Amir M., Oberoi A., Alam S. (1999) Synthesis and antiinflammatory activity of some new 6‐methoxy‐α‐methyl‐2‐naphthalene acetic acid derivatives. Ind. J. Chem., 38, 237-239. https://doi.org/10.1002/chin.199931054
Sharma S., Kumar D., Singh G., Monga V., Kumar B. (2020) Recent advancements in the development of heterocyclic anti-inflammatory agents. Euro. J. Med. Chem., 200, 112438. https://doi.org/10.1016/j.ejmech.2020.112438
Hekal M.H., Abu El-Azm F.S. (2018) New potential antitumor quinazolinones derived from dynamic 2-undecyl benzoxazinone: synthesis and cytotoxic evaluation. Synth. Commun., 48, 2391-2402. https://doi.org/10.1080/00397911.2018.1490433
Bollu R., Banu S., Kasaboina S., Bantu R., Nagarapu L., et al. (2017) Potential anti-proliferative agents from 1,4-benzoxazinone-quinazolin-4(3H)-one templates. Bioorg. Med. Chem. Lett., 27, 5481-5484. https://doi.org/10.1016/j.bmcl.2017.10.044
Sakr A., Kothayer H., Ibrahim S.M., Baraka M.M., Rezq S. (2019) 1,4-dihydroquinazolin-3(2H)-yl benzamide derivatives as anti-inflammatory and analgesic agents with an improved gastric profile: Design, synthesis, COX-1/2 inhibitory activity and molecular docking study. Bioorg. Chem., 84, 76-86. https://doi.org/10.1016/j.bioorg.2018.11.030
Laddha S.S., Wadodkar S.G., Meghal S.K. (2006) Studies on some biologically active substituted 4(3H)-quinazolinones. Part 1. Synthesis, characterization and anti-inflammatory-antimicrobial activity of 6,8-disubstituted 2-phenyl-3-[substituted-benzothiazol-2-yl]-4(3H)-quinazolinones. Arkivoc., 11, 1-20. https://doi.org/10.3998/ark.5550190.0007.b01
Bollu R., Palem J.D., Bantu R., Guguloth V., Nagarapu L., et al. (2015) Rational design, synthesis and anti-proliferative evaluation of novel 1,4-benzoxazine-[1,2,3]triazole hybrids. Eur. J. Med. Chem., 89, 138-146. https://doi.org/10.1016/j.ejmech.2014.10.051
Zahoor A.F., Yousaf M., Siddique R., Ahmad S., Naqvi S.A.R., et al. (2017) Synthetic strategies toward the synthesis of enoxacin-, levofloxacin-, and gatifloxacin-based compounds: A review. Synth. Commun., 47, 1021-1039. https://doi.org/10.1080/00397911.2017.1300921
Giubellina N., Stabile P., Laval G., Perboni A.D., Cimarosti Z., et al. (2010) Development of an efficient large-scale synthesis for a 4h-imidazo [5,1-c][1,4] benzoxazine-3-carboxamide derivative for depression and anxiety. Org. Process Res. Dev., 14, 859-867. https://doi.org/10.1021/op100103v
Foroumadi A., Emami S., Mansouri S., Javidnia A., Saeid-Adeli N., et al. (2007) Synthesis and antibacterial activity of levofloxacin derivatives with certain bulky residues on piperazine ring. Euro. J. Med. Chem., 42, 985-992. https://doi.org/10.1016/j.ejmech.2006.12.034
Khalaj A., Abdollahi M., Kebriaeezadeh A., Adibpour N., Pandi Z., et al. (2002) The antinociceptive and antiinflammatory activities and lack of ulcerogenicity of a benzodioxin-4-one and its analog benzoxazine as cyclic acetal-like derivatives of salicylic acid and salicylamide in mice and rats. Indian J. Pharmacol., 34, 184-188.
Mhaske S.B., Argade N.P. (2006) The chemistry of recently isolated naturally occurring quinazolinone alkaloids. Tetrahedron, 62, 9787-9826. https://doi.org/10.1016/j.tet.2006.07.098
Sharma P.C., Kaur G., Pahwa R., Sharma A., Rajak H. (2011) Quinazolinone analogs as potential therapeutic agents. Curr. Med. Chem., 18, 4786-4812. https://doi.org/10.2174/092986711797535326
He D., Wang M., Zhao S., Shu Y., Zeng H., et al. (2017) Pharmaceutical prospects of naturally occurring quinazolinone and its derivatives. Fitoterapia, 119, 136-149. https://doi.org/10.1016/j.fitote.2017.05.001
Auti P.S., George G., Paul A.T. (2020) Recent advances in the pharmacological diversification of quinazoline/quinazolinone hybrids. RSC Adv., 10, 41353-41392. https://doi.org/10.1039/D0RA06642G
Alsibaee A.M., Al-Yousef H.M., Al-Salem H.S. (2023) Quinazolinones, the winning horse in drug discovery. Molecules, 28(3), 978 https://doi.org/10.3390/molecules28030978
Al-Deeb A.O., Alafeefy A.M. (2008) Synthesis of some new 3H-quinazolin-4-one derivatives as potential antitubercular agents. World Appl. Sci. J., 5, 94-99.
Alagarsamy V., Muthukumar V., Pavalarani N., Vasanthanathan P., Revathi R. (2003) Synthesis, analgesic and anti-inflammatory activities of some novel 2,3-disubstituted quinazolin-4(3H)-ones. Biol. Pharm. Bull., 26, 557-559. https://doi.org/10.1248/bpb.26.557
El-Hashash M.A.E.A., Azab M.E., Faty R.A.E.A., Amr A.E.G.E. (2016) Synthesis, antimicrobial and anti-inflammatory activity of some new benzoxazinone and quinazolinone candidates. Chem. Pharm. Bull., 64, 263-271. https://doi.org/10.1248/cpb.c15-00904
Tomić M., Micov A., Pecikoza U., Stepanović-Petrović R. (2017) Clinical uses of nonsteroidal anti-inflammatory drugs (NSAIDs) and potential benefits of NSAIDs modified-release preparations. In Microsized and nanosized carriers for nonsteroidal anti-inflammatory drugs; Elsevier, 1-29. https://doi.org/10.1016/B978-0-12-804017-1.00001-7
Husain A., AlAsmari A.F., Azmi S.N.H., Ali N., Sarker M.M.R. et al. (2022) Rational drug design, synthesis, and in vivo biological activity of new indolyl-imidazolone hybrids as potential and safer non-steroidal anti-inflammatory agents. J. King Saud Univ.Sci., 34, 102023. https://doi.org/10.1016/j.jksus.2022.102023
Husain A., Ahuja P., Ahmad A., Khan S.A. (2016) Synthesis, biological evaluation and pharmacokinetic studies of mefenamic acid-N-hydroxymethylsuccinimide ester prodrug as safer NSAID. Med. Chem., 12, 585-591. https://doi.org/10.2174/1573406412666160107113548
Husain A., Ahmad A., Khan S.A., Asif M., Bhutani R., et al. (2016) Synthesis, molecular properties, toxicity and biological evaluation of some new substituted imidazolidine derivatives in search of potent anti-inflammatory agents. Saudi Pharm. J., 24, 104-114. https://doi.org/10.1016/j.jsps.2015.02.008
Akhter M., Husain A., Akhter N., Khan M.S.Y. (2011) Synthesis, anti-inflammatory and antimicrobial activity of some new 1-(3-Phenyl-3,4-Dihydro-2H-1,3-Benzoxazin-6-yl)-ethanone derivatives. Indian J. Pharm. Sci., 73, 101. https://doi.org/10.4103/0250-474X.89767
Zayed M.F., Hassan M.H. (2014) Synthesis and biological evaluation studies of novel quinazolinone derivatives as antibacterial and anti-inflammatory agents. Saudi Pharm. J., 22, 157-162. https://doi.org/10.1016/j.jsps.2013.03.004
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