Synthesis of 1,3-substituted 1H-indazole derivatives and evaluation of anti-inflammatory activity in Sprague Dawley rats

Abstract

Indazole is a very significant group of heterocyclics. Aim of the research was thus planned to synthesize novel derivatives of indazole and evaluate their anti-inflammatory activity. Novel compounds of indazole were first synthesized from reaction of 2-chlorobenzonitrile with phenylhydrazine in presence of catalyst potassium t-butoxide (t-BuOK) and the solvent diglyme. Synthesized derivatives of indazole were analyzed by ¹H-NMR and MS spectroscopic techniques. All the synthesized derivatives of indazole were evaluated for their antiinflammatory activity in Sprague Dawley rats by carrageenan-induced rat paw edema method. All the synthesized derivatives of indazole had shown very good activity in both docking and anti-inflammatory activity in rats in comparison to the standard etoricoxib. Compound 1a in a dose of 30 mg/kg body weight had shown most significant inhibition of edema as compared to toxic group and the inhibition was comparable to that of the standard drug, etoricoxib in a dose of 10 mg/kg body weight. A convenient means for the synthesis of derivatives of indazole was developed which may find applications in heterocyclic synthesis of derivatives of indazole. Compound 1a i.e., 3-(4-carboxyphenyl)amino-1-phenyl-1H-indazole had shown best anti-inflammatory activity amongst all the synthesized compounds.

Keywords

Heterocyclics / Indazole / Plethysmometer / Spectroscopy / Anti-inflammatory

References

[1] Gaikwad DD, Chapolikar AD, Devkate CG, et al. Synthesis of indazole motifs and their medicinal importance: an overview. Eur J Med Chem. 2015;90:707–731.

[2] Zhang SG, Liang CG, Zhang WH. Recent advances in indazole-containing derivatives: synthesis and biological perspectives. Molecules. 2018;23(11):2783.

[3] Cheruvallath ZS, Gwaltney II SL, Sabat M, et al. Discovery of potent and orally active 1, 4-disubstituted indazoles as novel allosteric Glucokinase Activators. Bioorg Med Chem Lett. 2017;27:2678–2682.

[4] Saketi JMR, Boddapati SNM, Raghuram M, et al. Pd(PPH₃)₄ catalyzed synthesis of indazole derivatives as potent anticancer drug. Appl Sci. 2020;10(11):3792.

[5] Kumar V, Gupta K, Sirbaiya AK, Rahman MA. A review of indazole derivatives in pharmacotherapy of inflammation. Innovat International Journal of Medical & Pharmaceutical Sciences. 2021;6(5):7–12.

[6] Awasthi A, Raju MB, Rahman MA. Current insights of inhibitors of p38 mitogenactivated protein kinase in inflammation. Med Chem. 2020;17(6):555–575.

[7] Al-Bogami AS. Mechanochemical synthesis of cyclohexenones and indazoles as potential antimicrobial agents. Res Chem Intermed. 2016;42(6):5457–5477.

[8] Awasthi A, Raju MB, Rahman MA. Synthesis, in silico studies, and in vitro anti-inflammatory activity of novel imidazole derivatives targeting P38 MAP kinase. ACS Omega. 2023;8(20):17788–17799.

[9] Meena SZ, Rahman MA, Bagga P, Mujahid M. Hepatoprotective activity of Tamarindus indica Linn stem bark ethanolic extract against hepatic damage induced by co-administration of antitubercular drugs isoniazid and rifampicin in Sprague Dawley rats. J Basic Clin Physiol Pharmacol. 2018;30(1):131–137.

[10] Tahir M, Rahman MA, Khushtar M. Gastroprotective effect of Hyssopus officinalis L. leaves via reduction of oxidative stress in indomethacin-induced gastric ulcer in experimental rats. Drug Chem Toxicol. 2022;45(1):291–300.

[11] Ugwu DI, OkoroU C, UkohaP I, Gupta A, okafor SN. Novel anti-inflammatory and analgesic agents: synthesis, molecular docking and in vivo studies. J Enzym Inhib Med Chem. 2018;33(1):405–415.

[12] Gupta K, Sirbaiya AK, Kumar V, Rahman MA. Current perspective of synthesis of medicinally relevant benzothiazole based molecules: potential for antimicrobial and anti-inflammatory activities. Mini-Rev Med Chem. 2022;22(14):1895–1935.

[13] Siddiqui AA, Rahman MA, Shaharyar M, Mishra R. Synthesis and anticonvulsant activity of some substituted 3, 5-diphenyl-2-pyrazoline-1-carboxamide derivatives. Chem Sci J. 2010. CSJ-8.

[14] Rahman MA. Chalcone: a valuable insight into the recent advances and potential pharmacological activities. Chem Sci J. 2011. CSJ-29.

[15] Yadav KP, Rahman MA, Nishad S, Maurya SK, Anas M, Mujahid M. Synthesis and biological activities of benzothiazole derivatives: a review. Intelligent Pharmacy. 2023;1(3):122–132.

[16] Shaikh F, Arif M, Khushtar M, Nematullah M, Rahman MA. Synthesis and evaluation of antibacterial activity of novel 3-methyl-1H-indazole derivative. Intelligent Pharmacy. 2023.

RIGHTS & PERMISSIONS

2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd.