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Design, synthesis, and evaluation of isoniazid derivatives acting as potent anti-inflammatory and anthelmintic agents via Betti reaction

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Abstract

A novel synthesis of isoniazid derivatives achieved by the condensation of aldehydes, isoniazid, and phenols via Betti reaction has been described. The reactions were carried out at room temperature using fluorite as catalyst. The catalyst is efficient, benign, reusable, cost-effective, and ecofriendly. The novel synthesized moieties were characterized on the basis of 1H NMR, 13C NMR, mass spectrometry, and elemental analysis. All the synthesized agents 4(aj) were examined for their potential in vivo anti-inflammatory activity on Wistar albino rats using a standard reference drug, diclofenac. These synthesized derivatives were further screened for their potent in vitro anthelmintic activity using a standard reference drug, albendazole on Indian earthworms, Pheretima posthuma. A correlation of structure and activity relationship of these compounds with respect to Lipinski’s rule of five, drug likeness, toxicity profiles, and other physico-chemical properties of drugs is described.

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References

  • Akhter M, Husain A, Azad B, Ajmal M (2010) Aroylpropionic acid based 2,5-disubstituted-1,3,4-oxadiazoles: synthesis and their anti-inflammatory and analgesic activities. Eur J Med Chem 44:2372–2378

    Article  Google Scholar 

  • Ali A, Mohammad T, Davood B, Abbas S (2005) Synthesis and analgesic activity of N-aryl hydrazone derivatives of mefenamic acid. J Pharm Pharm Sci 8:419–425

    Google Scholar 

  • Banerjee A, Dubnau E, Quemard A, Balasubramanian V, Um KS, Wilson T, Collins D, Lisle GD Jr, Jacobs WR (1994) inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science 263:227–230

    Article  CAS  PubMed  Google Scholar 

  • Bayrak H, Demirbas A, Demirbas N, Karaoglu SA (2009) Synthesis of some new 1,2,4-triazoles starting from isonicotinic acid hydrazide and evaluation of their antimicrobial activities. Eur J Med Chem 44:4362–4366

    Article  CAS  PubMed  Google Scholar 

  • Bekhit AA, Aziem TA (2004) Design, synthesis and biological evaluation of some pyrazole derivatives as anti-inflammatory-antimicrobial agents. Bioorg Med Chem 12:1935–1945

    Article  CAS  PubMed  Google Scholar 

  • Bekhit AA, Fahmy HTY, Rostom SAF, Baraka AM (2003) Design and synthesis of some substituted 1H-pyrazolyl-thiazolo[4,5-d]pyrimidines as anti-inflammatory-antimicrobial agents. Eur J Med Chem 38:27–36

    Article  CAS  PubMed  Google Scholar 

  • Betti M (1941) β-Naphthol phenylaminomethane. Org Synth 1:381–383

    Google Scholar 

  • Bhandari SV, Bothara KG, Raut MK, Patil AA, Sarkate AP, Mokale VJ (2008) Design, synthesis and evaluation of anti-inflammatory, analgesic and ulcerogenicity studies of novel S-substituted phenacyl-1,3,4-oxadiazole-2-thiol and Schiff bases of diclofenac acid as nonulcerogenic derivatives. Bioorg Med Chem 16:1822–1831

    Article  CAS  PubMed  Google Scholar 

  • Bhatt KR, Mehta RK, Srivastava PN (1977) Simple methods for recording anti-inflammatory effect on rat paw oedema. Indian J Physiol Pharmacol 21:399–400

    CAS  PubMed  Google Scholar 

  • Bukhari SNA, Jantan I, Jasamai M (2013) Anti-inflammatory trends of 1,3-diphenyl-2-propen-1-one derivatives. Mini Rev Med Chem 13:87–94

    Article  CAS  PubMed  Google Scholar 

  • Deretic V, Pagan-Ramos E, Zhang Y, Dhandayuthapani S, Via LE (1996) The extreme sensitivity of Mycobacterium tuberculosis to the front-line antituberculosis drug isoniazid. Nat Biotechnol 14:1557–1561

    Article  CAS  PubMed  Google Scholar 

  • Dimmock JR, Jonnalagadda SS, Phillips OA, Erciyas E, Shyam K, Semple HA (1992) Anticonvulsant properties of some Mannich bases of conjugated arylidene ketones. J Pharm Sci 81:436–440

    Article  CAS  PubMed  Google Scholar 

  • Gbolade AA, Adeyemi AA (2008) Anthelmintic activities of three medicinal plants from Nigeria. Fitoterapia 79:223–225

    Article  CAS  PubMed  Google Scholar 

  • Gemma S, Kukreja G, Fattorusso C, Persico M, Romano MP, Altarelli M, Savini L, Campiani G, Fattorusso E, Basilico N, Taramelli D, Yardley V, Butini S (2006) Synthesis of N1-arylidene-N2-quinolyl-and N2-acrydinylhydrazone as potent antimalarial agents active against CQ resistant P. falciparum strains. Bioorg Med Chem Lett 16:5384–5388

    Article  CAS  PubMed  Google Scholar 

  • Gokce E, Bakir G, Sahin MF, Kupeli E, Yesilada E (2005) Synthesis of new Mannich bases of arylpyridazinones as analgesic and anti-inflammatory agents. Arzneimittelforschung 55:318–325

    PubMed  Google Scholar 

  • Holla BS, Shivananda MK, Shenoy MS, Antony G (1998) Synthesis and characterization of some Mannich bases carrying halophenylfuryl moieties as promising antibacterial agents. Farmaco 53:531–535

    Article  CAS  PubMed  Google Scholar 

  • Holla BS, Veerendra B, Shivananda MK, Poojary B (2003) Synthesis, characterization and anticancer activity studies on some Mannich bases derived from 1,2,4-triazoles. Eur J Med Chem 38:759–767

    Article  Google Scholar 

  • Kaymakcioglu KB, Oruc EE, Unsalan S, Kandemirli F, Shvets N, Rollas S, Anatholy D (2006) Synthesis and characterization of novel hydrazide-hydrazones and the study of their structure antituberculosis activity. Eur J Med Chem 41:1253–1261

    Article  Google Scholar 

  • Knabe J, Buch HP, Schmitt W (1983) Derivatives of barbituric acid cytostatic and CNS activities of chiral barbiturate Mannich-bases. Arch Pharm Chem Life Sci 316:1051–1053

    Article  CAS  Google Scholar 

  • Lembege MV, Moreau S, Larrouture S, Montaudon D, Robert J, Nuhrich A (2008) Synthesis and antiproliferative activity of aryl- and heteroarylhydrazones derived from xanthone carbaldehydes. Eur J Med Chem 43:1336–1343

    Article  Google Scholar 

  • Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46:3–26

    Article  CAS  PubMed  Google Scholar 

  • Lopes F, Capela R, Goncaves JO, Horton PN, Hursthouse MB, Iley J, Casimiro CM, Bom J, Moreire R (2004) Amidomethylation of amodiaquine: antimalarial N-Mannich base derivatives. Tetrahedron Lett 45:7663–7666

    Article  CAS  Google Scholar 

  • Mannich C, Krosche W (1912) About a condensation product of formaldehyde, ammonia, and antipyrine. Arch Pharm Pharm Med Chem 250:647–667

    Article  CAS  Google Scholar 

  • Mohareb RM, El-Sharkawy KA, Hussein MM, El-Sehrawi HM (2010) Hydrazide hydrazone derivatives as antidepressant, sedative and analgesic agents. J Pharm Sci Res 2:185–196

    CAS  Google Scholar 

  • Nath M, Pokharia S, Eng G, Song X, Kumar A (2005) New triorganotin(IV) derivatives of dipeptides as anti-inflammatory-antimicrobial agents. Eur J Med Chem 40:289–298

    Article  CAS  PubMed  Google Scholar 

  • Nayyar A, Monga V, Malde AK, Coutinho E, Jaina R (2007) Synthesis, anti-tuberculosis activity and 3D-QSAR study of 4-(adamantan-1-yl)-2-substituted quinolines. Bioorg Med Chem 15:626–640

    Article  CAS  PubMed  Google Scholar 

  • Osama I, Sabbagh E, Rady HM (2009) Synthesis of new acridines and hydrazones derived from cyclic beta-diketone for cytotoxic and antiviral evaluation. Eur J Med Chem 44:3680–3686

    Article  Google Scholar 

  • Rozwarski DA, Grant GA, Barton DH Jr, Jacobs WR, Sacchettini JC (1998) Modification of the NADH of the isoniazid target (InhA) from Mycobacterium tuberculosis. Science 279:98–102

    Article  CAS  PubMed  Google Scholar 

  • Sriram D, Bal TR, Yogeesswari P (2005) Synthesis, antiviral and antibacterial activities of isatin Mannich bases. Med Chem Res 14:11–28

    Article  Google Scholar 

  • Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD (2002) Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 45:2615–2623

    Article  CAS  PubMed  Google Scholar 

  • Wada S, Suzuki H (2003) Calcite and fluorite as catalyst for the Knoevenagel condensation of malononitrile and methyl cyanoacetate under solvent-free conditions. Tetrahedron Lett 44:399–401

    Article  CAS  Google Scholar 

  • Winter CA, Risley EA, Nuss GW (1962) Carrageenin-induced edema in hind paw of the rats as an assay for anti-inflammatory drugs. Proc Soc Exp Biol Med 3:544–547

    Article  Google Scholar 

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Acknowledgments

The authors are thankful to Rajiv Gandhi National Fellowship [RGNF-SC-UTT-2299], University Grants Commission, New Delhi for financial support. The authors thank Head, Department of Chemistry, RTM, Nagpur University for providing laboratory facilities, Director, SAIF, Chandigarh for spectral data and Head, Sharad Pawar College of Pharmacy, RTM Nagpur University for assistance in biological screening.

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Correspondence to Ipsita Mohanram.

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Mohanram, I., Meshram, J. Design, synthesis, and evaluation of isoniazid derivatives acting as potent anti-inflammatory and anthelmintic agents via Betti reaction. Med Chem Res 23, 939–947 (2014). https://doi.org/10.1007/s00044-013-0693-2

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  • DOI: https://doi.org/10.1007/s00044-013-0693-2

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