Main Article Content
Abstract
Various 5-substituted aryl-3-(2′-carboxy-5′-methoxyindolyl)-2-pyrazolines (9-15) and 5-substituted aryl-3-(2′-carboxy-5′-methoxyindolyl)isoxazolines (16-22) have been synthesized by the cyclization of compounds 1-(2′-carboxyl-5′-methoxyindolyl-3-arylidenyl chalcones (2-8) by treating them with hydrazine hydrate/glacial acetic acid and hydroxylamine hydrochloride/2% NaOH, respectively and TLC checked for their purity. Structure of all these newly synthesized compounds was characterized by elemental (C, H, N) analysis and IR and 1H NMR spectroscopy. All the synthesized compounds were tested for their anti-inflammatory and ulcerogenic activities and acute toxicity and found to possess varying degrees of these activities. Compound 15 is 5-(3′′-methoxy-4′′-hydroxyphenyl)-3-(2′-carboxy-5′-methoxyindolyl)-2-pyrazoline found to be the most potent compound of the series, more potent than the standard drug phenylbutazone.
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Copyright (c) 2022 Asian Journal of Organic & Medicinal Chemistry
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References
- S. Sarva, J.S. Harinath, S.P. Sthanikam, S. Ethiraj, M. Vaithiyalingam and S.R. Cirandur, Synthesis, Antibacterial and Anti-inflammatory Activity of bis(Indolyl)methanes, Chin. Chem. Lett., 27, 16 (2016); https://doi.org/10.1016/j.cclet.2015.08.012
- A. Özdemir, M.D. Altintop, G. Turan-Zitouni, G.A. Çiftçi, I. Ertorun, Ö. Alatas and Z.A. Kaplancikli, Synthesis and Evaluation of New Indole-based Chalcones as Potential Antiinflammatory Agents, Eur. J. Med. Chem., 89, 304 (2015); https://doi.org/10.1016/j.ejmech.2014.10.056
- P. Rani, V.K. Srivastava and A. Kumar, Synthesis and Antiinflammatory Activity of Heterocyclic Indole Derivatives, Eur. J. Med. Chem., 39, 449 (2004); https://doi.org/10.1016/j.ejmech.2003.11.002
- C.S. Misra, C. Gejjalagere Honnappa, S.R. Jitta, K. Gourishetti, P. Daram, M.P. Singh, A. Hosur Shrungeswara, Y. Nayak and M.K. Unnikrishnan, Biological Activity of a Small Molecule Indole Analog, 1-[(1H-Indol-3-yl)methylene]-2-phenylhydrazine (HMPH), in Chronic Inflammation, Chem. Biol. Interact., 244, 71 (2016); https://doi.org/10.1016/j.cbi.2015.10.024
- N. Singh, S.K. Bhati and A. Kumar, Thiazolyl/Oxazolyl Formazanyl Indoles as Potent Anti-inflammatory Agents, Eur. J. Med. Chem., 43, 2597 (2008); https://doi.org/10.1016/j.ejmech.2007.12.024
- N.H. Amin, M.T. El-Saadi, A.A. Hefny, K.R. Abdelazeem, H.A.H. Elshemy and K.R.A. Abdellatif, Anti-inflammatory Indomethacin Analogs Endowed with Preferential COX-2 Inhibitory Activity, Future Med. Chem., 10, 2521 (2018); https://doi.org/10.4155/fmc-2018-0224
- A.S. Gurkan-Alp, M. Mumcuoglu, C.A. Andac, E. Dayanc, R. Cetin-Atalay and E. Buyukbingol, Synthesis, Anticancer Activities and Molecular Modeling Studies of Novel Indole Retinoid Derivatives, Eur. J. Med. Chem., 58, 346 (2012); https://doi.org/10.1016/j.ejmech.2012.10.013
- D. Xu and Z. Xu, Indole Alkaloids with Potential Anticancer Activity, Curr. Top. Med. Chem., 20, 1938 (2020); https://doi.org/10.2174/1568026620666200622150325
- S.H. Zhuang, Y.C. Lin, L.C. Chou, M.H. Hsu, H.Y. Lin, C.H. Huang, J.C. Lien, S.C. Kuo and L.J. Huang, Synthesis and Anticancer Activity of 2,4-Disubstituted Furo[3,2-b]indole Derivatives, Eur. J. Med. Chem., 66, 466 (2013); https://doi.org/10.1016/j.ejmech.2013.06.012
- D. Kumar, N.M. Kumar, K.H. Chang, R. Gupta and K. Shah, Synthesis and in-vitro Anticancer Activity of 3,5-Bis(indolyl)-1,2,4-thiadiazoles, Bioorg. Med. Chem. Lett., 21, 5897 (2011); https://doi.org/10.1016/j.bmcl.2011.07.089
- M.N. Yousif, H.A. Hussein, N.M. Yousif, M.A. El-Manawaty and W.A. El-Sayed, Synthesis and Anticancer Activity of Novel 2-Phenylindole Linked Imidazolothiazole, Thiazolo-s-triazine and Imidazolyl-Sugar Systems, J. Appl. Pharm. Sci., 9, 6 (2019); https://doi.org/10.7324/JAPS.2019.90102
- A. Mandour, E. El-Sawy, K. Shaker and M. Mustafa, Synthesis, Anti-inflammatory, Analgesic and Anticonvulsant Activities of 1,8-Dihydro-1-ary1-8-alkyl pyrazolo(3,4-b)indoles, Acta Pharm., 60, 73 (2010); https://doi.org/10.2478/v10007-010-0009-8
- D.R. Kerzare, S.S. Menghani, N.R. Rarokar and P.B. Khedekar, Development of Novel Indole-Linked Pyrazoles as Anticonvulsant Agents: A Molecular Hybridization Approach, Arch. Pharm., 354, 2000100 (2021); https://doi.org/10.1002/ardp.202000100
- A. Archana, P. Rani, K. Bajaj, V. Srivastava, R. Chandra and A. Kumar, Synthesis of Newer Indolyl/Phenothiazinyl Substituted 2-Oxo/ Thiobarbituric Acid Derivatives as Potent Anticonvulsant Agents, Drug Res., 53, 301 (2011); https://doi.org/10.1055/s-0031-1297113
- G. Cihan-Ustundag, E. Gursoy, L. Naesens, N. Ulusoy-Guzeldemirci and G. Capan, Synthesis and Antiviral Properties of Novel Indole-based Thiosemicarbazides and 4-thiazolidinones, Bioorg. Med. Chem., 24, 240 (2016); https://doi.org/10.1016/j.bmc.2015.12.008
- M. Giampieri, A. Balbi, M. Mazzei, P. La Colla, C. Ibba and R. Loddo, Antiviral Activity of Indole Derivatives, Antiviral Res., 83, 179 (2009); https://doi.org/10.1016/j.antiviral.2009.05.001
- M. Tichy, R. Pohl, H.Y. Xu, Y.L. Chen, F. Yokokawa, P.Y. Shi and M. Hocek, Synthesis and Antiviral Activity of 4,6-Disubstituted Pyrimido[4,5-b]indole Ribonucleosides, Bioorg. Med. Chem., 20, 6123 (2012); https://doi.org/10.1016/j.bmc.2012.08.021
- G. Cihan-Ustundag, L. Naesens, D. Satana, G. Erkose-Genc, E. Mataraci-Kara and G. Capan, Design, Synthesis, Antitubercular and Antiviral Properties of New Spirocyclic Indole Derivatives, Monatsh. Chem., 150, 1533 (2019); https://doi.org/10.1007/s00706-019-02457-9
- A. Dixit, D. Pathak and G.K. Sharma, Synthesis, Antibacterial and Free Radical Scavenging Activity of Some Newer N-((10-Nitro-1H-indolo-[1, 2-c]quinazolin-12-yl)methylene)benzenamines, Eur. Pharm. J., 67, 7 (2019); https://doi.org/10.2478/afpuc-2020-0002
- W. Hong, J. Li, Z. Chang, X. Tan, H. Yang, Y. Ouyang, Y. Yang, S. Kaur, I.C. Paterson, Y.F. Ngeow and H. Wang, Synthesis and Biological Evaluation of Indole Core-based Derivatives with Potent Antibacterial Activity against Resistant Bacterial Pathogens, J. Antibiot. (Tokyo), 70, 832 (2017); https://doi.org/10.1038/ja.2017.55
- H. Kaur, J. Singh and B. Narasimhan, Indole Hybridized Diazenyl Derivatives: Synthesis, Antimicrobial Activity, Cytotoxicity Evaluation and Docking Studies, BMC Chem., 13, 65 (2019); https://doi.org/10.1186/s13065-019-0580-0
- T. Luthra, A.K. Nayak, S. Bose, S. Chakrabarti, A. Gupta and S. Sen, Indole based Antimalarial Compounds Targeting the Melatonin Pathway: Their Design, Synthesis and Biological Evaluation, Eur. J. Med. Chem., 168, 11 (2019); https://doi.org/10.1016/j.ejmech.2019.02.019
- S.N. Vasconcelos, K.A. Meissner, W.R. Ferraz, G.H. Trossini, C. Wrenger and H.A. Stefani, Indole-3-glyoxyl tyrosine: Synthesis and Antimalarial Activity against Plasmodium falciparum, Future Med. Chem., 11, 525 (2019); https://doi.org/10.4155/fmc-2018-0246
- S. Viveka, Dinesha, P. Shama, G.K. Nagaraja, S. Ballav and S. Kerkar, Design and sYnthesis of Some New Pyrazolyl-pyrazolines as Potential Anti-inflammatory, Analgesic and Antibacterial Agents, Eur. J. Med. Chem., 101, 442 (2015); https://doi.org/10.1016/j.ejmech.2015.07.002
- M. Mantzanidou, E. Pontiki and H. Hadjipavlou-Litina, Pyrazoles and Pyrazolines as Anti-Inflammatory Agents, Molecules, 26, 3439 (2021); https://doi.org/10.3390/molecules26113439
- R.S. Joshi, P.G. Mandhane, S.D. Diwakar, S.K. Dabhade and C.H. Gill, Synthesis, Analgesic and Anti-inflammatory Activities of Some Novel Pyrazolines Derivatives, Bioorg. Med. Chem. Lett., 20, 3721 (2010); https://doi.org/10.1016/j.bmcl.2010.04.082
- T. Chandra, N. Garg, S. Lata, K.K. Saxena and A. Kumar, Synthesis of Substituted Acridinyl Pyrazoline Derivatives and their Evaluation for Anti-inflammatory Activity, Eur. J. Med. Chem., 45, 1772 (2010); https://doi.org/10.1016/j.ejmech.2010.01.009
- S.R. Pedada, N.S. Yarla, P.J. Tambade, B.L. Dhananjaya, A. Bishayee, K.M. Arunasree, G.H. Philip, G. Dharmapuri, G. Aliev, S. Putta and G. Rangaiah, Synthesis of New Secretory Phospholipase A2-inhibitory Indole Containing Isoxazole Derivatives as Anti-inflammatory and Anticancer Agents, Eur. J. Med. Chem., 112, 289 (2016); https://doi.org/10.1016/j.ejmech.2016.02.025
- T.R. Prajapati, D.P. Pandey, V. Gupta, B. Joshi and G.K. Dhingra, Synthesis and Anti-inflammatory Activity of Some Newer Potential Isoxazoline Derivatives of Indole, Int. J. Environ. Rehab. Conserv., 9, 87 (2018); https://doi.org/10.31786/09756272.18.9.2.213
- A.G. Habeeb, P.N. Praveen Rao and E.E. Knaus, Design and Synthesis of 4,5-Diphenyl-4-isoxazolines: Novel Inhibitors of Cyclooxygenase-2 with Analgesic and Antiinflammatory Activity, J. Med. Chem., 44, 2921 (2001); https://doi.org/10.1021/jm0101287
- M. Znati, M. Debbabi, A. Romdhane, H. Ben Jannet and J. Bouajila, Synthesis of New Anticancer and Anti-inflammatory Isoxazolines and Aziridines from the Natural (-)-Deltoin, J. Pharm. Pharmacol., 70, 1700 (2018); https://doi.org/10.1111/jphp.13013
- C.A. Winter, E.A. Risley and G.W. Nuss, Carrageenin-Induced Edema in Hind Paw of the Rat as an Assay for Antiinflammatory Drugs, Proc. Soc. Exp. Biol. Med., 111, 544 (1962); https://doi.org/10.3181/00379727-111-27849
- M. Verma, J.N. Sinha, V.R. Gujrati, T.N. Bhalla, K.P. Bhargava and K. Shanker, A New Potent Anti-inflammatory Quinazolone, Pharmacol. Res. Commun., 13, 967 (1981); https://doi.org/10.1016/S0031-6989(81)80068-9
- Q.E. Smith, Pharmacological Screening Tests, Progress in Medicinal Chemistry, Butterworth: London, Ed.: 11, pp. 1-33 (1961).
References
S. Sarva, J.S. Harinath, S.P. Sthanikam, S. Ethiraj, M. Vaithiyalingam and S.R. Cirandur, Synthesis, Antibacterial and Anti-inflammatory Activity of bis(Indolyl)methanes, Chin. Chem. Lett., 27, 16 (2016); https://doi.org/10.1016/j.cclet.2015.08.012
A. Özdemir, M.D. Altintop, G. Turan-Zitouni, G.A. Çiftçi, I. Ertorun, Ö. Alatas and Z.A. Kaplancikli, Synthesis and Evaluation of New Indole-based Chalcones as Potential Antiinflammatory Agents, Eur. J. Med. Chem., 89, 304 (2015); https://doi.org/10.1016/j.ejmech.2014.10.056
P. Rani, V.K. Srivastava and A. Kumar, Synthesis and Antiinflammatory Activity of Heterocyclic Indole Derivatives, Eur. J. Med. Chem., 39, 449 (2004); https://doi.org/10.1016/j.ejmech.2003.11.002
C.S. Misra, C. Gejjalagere Honnappa, S.R. Jitta, K. Gourishetti, P. Daram, M.P. Singh, A. Hosur Shrungeswara, Y. Nayak and M.K. Unnikrishnan, Biological Activity of a Small Molecule Indole Analog, 1-[(1H-Indol-3-yl)methylene]-2-phenylhydrazine (HMPH), in Chronic Inflammation, Chem. Biol. Interact., 244, 71 (2016); https://doi.org/10.1016/j.cbi.2015.10.024
N. Singh, S.K. Bhati and A. Kumar, Thiazolyl/Oxazolyl Formazanyl Indoles as Potent Anti-inflammatory Agents, Eur. J. Med. Chem., 43, 2597 (2008); https://doi.org/10.1016/j.ejmech.2007.12.024
N.H. Amin, M.T. El-Saadi, A.A. Hefny, K.R. Abdelazeem, H.A.H. Elshemy and K.R.A. Abdellatif, Anti-inflammatory Indomethacin Analogs Endowed with Preferential COX-2 Inhibitory Activity, Future Med. Chem., 10, 2521 (2018); https://doi.org/10.4155/fmc-2018-0224
A.S. Gurkan-Alp, M. Mumcuoglu, C.A. Andac, E. Dayanc, R. Cetin-Atalay and E. Buyukbingol, Synthesis, Anticancer Activities and Molecular Modeling Studies of Novel Indole Retinoid Derivatives, Eur. J. Med. Chem., 58, 346 (2012); https://doi.org/10.1016/j.ejmech.2012.10.013
D. Xu and Z. Xu, Indole Alkaloids with Potential Anticancer Activity, Curr. Top. Med. Chem., 20, 1938 (2020); https://doi.org/10.2174/1568026620666200622150325
S.H. Zhuang, Y.C. Lin, L.C. Chou, M.H. Hsu, H.Y. Lin, C.H. Huang, J.C. Lien, S.C. Kuo and L.J. Huang, Synthesis and Anticancer Activity of 2,4-Disubstituted Furo[3,2-b]indole Derivatives, Eur. J. Med. Chem., 66, 466 (2013); https://doi.org/10.1016/j.ejmech.2013.06.012
D. Kumar, N.M. Kumar, K.H. Chang, R. Gupta and K. Shah, Synthesis and in-vitro Anticancer Activity of 3,5-Bis(indolyl)-1,2,4-thiadiazoles, Bioorg. Med. Chem. Lett., 21, 5897 (2011); https://doi.org/10.1016/j.bmcl.2011.07.089
M.N. Yousif, H.A. Hussein, N.M. Yousif, M.A. El-Manawaty and W.A. El-Sayed, Synthesis and Anticancer Activity of Novel 2-Phenylindole Linked Imidazolothiazole, Thiazolo-s-triazine and Imidazolyl-Sugar Systems, J. Appl. Pharm. Sci., 9, 6 (2019); https://doi.org/10.7324/JAPS.2019.90102
A. Mandour, E. El-Sawy, K. Shaker and M. Mustafa, Synthesis, Anti-inflammatory, Analgesic and Anticonvulsant Activities of 1,8-Dihydro-1-ary1-8-alkyl pyrazolo(3,4-b)indoles, Acta Pharm., 60, 73 (2010); https://doi.org/10.2478/v10007-010-0009-8
D.R. Kerzare, S.S. Menghani, N.R. Rarokar and P.B. Khedekar, Development of Novel Indole-Linked Pyrazoles as Anticonvulsant Agents: A Molecular Hybridization Approach, Arch. Pharm., 354, 2000100 (2021); https://doi.org/10.1002/ardp.202000100
A. Archana, P. Rani, K. Bajaj, V. Srivastava, R. Chandra and A. Kumar, Synthesis of Newer Indolyl/Phenothiazinyl Substituted 2-Oxo/ Thiobarbituric Acid Derivatives as Potent Anticonvulsant Agents, Drug Res., 53, 301 (2011); https://doi.org/10.1055/s-0031-1297113
G. Cihan-Ustundag, E. Gursoy, L. Naesens, N. Ulusoy-Guzeldemirci and G. Capan, Synthesis and Antiviral Properties of Novel Indole-based Thiosemicarbazides and 4-thiazolidinones, Bioorg. Med. Chem., 24, 240 (2016); https://doi.org/10.1016/j.bmc.2015.12.008
M. Giampieri, A. Balbi, M. Mazzei, P. La Colla, C. Ibba and R. Loddo, Antiviral Activity of Indole Derivatives, Antiviral Res., 83, 179 (2009); https://doi.org/10.1016/j.antiviral.2009.05.001
M. Tichy, R. Pohl, H.Y. Xu, Y.L. Chen, F. Yokokawa, P.Y. Shi and M. Hocek, Synthesis and Antiviral Activity of 4,6-Disubstituted Pyrimido[4,5-b]indole Ribonucleosides, Bioorg. Med. Chem., 20, 6123 (2012); https://doi.org/10.1016/j.bmc.2012.08.021
G. Cihan-Ustundag, L. Naesens, D. Satana, G. Erkose-Genc, E. Mataraci-Kara and G. Capan, Design, Synthesis, Antitubercular and Antiviral Properties of New Spirocyclic Indole Derivatives, Monatsh. Chem., 150, 1533 (2019); https://doi.org/10.1007/s00706-019-02457-9
A. Dixit, D. Pathak and G.K. Sharma, Synthesis, Antibacterial and Free Radical Scavenging Activity of Some Newer N-((10-Nitro-1H-indolo-[1, 2-c]quinazolin-12-yl)methylene)benzenamines, Eur. Pharm. J., 67, 7 (2019); https://doi.org/10.2478/afpuc-2020-0002
W. Hong, J. Li, Z. Chang, X. Tan, H. Yang, Y. Ouyang, Y. Yang, S. Kaur, I.C. Paterson, Y.F. Ngeow and H. Wang, Synthesis and Biological Evaluation of Indole Core-based Derivatives with Potent Antibacterial Activity against Resistant Bacterial Pathogens, J. Antibiot. (Tokyo), 70, 832 (2017); https://doi.org/10.1038/ja.2017.55
H. Kaur, J. Singh and B. Narasimhan, Indole Hybridized Diazenyl Derivatives: Synthesis, Antimicrobial Activity, Cytotoxicity Evaluation and Docking Studies, BMC Chem., 13, 65 (2019); https://doi.org/10.1186/s13065-019-0580-0
T. Luthra, A.K. Nayak, S. Bose, S. Chakrabarti, A. Gupta and S. Sen, Indole based Antimalarial Compounds Targeting the Melatonin Pathway: Their Design, Synthesis and Biological Evaluation, Eur. J. Med. Chem., 168, 11 (2019); https://doi.org/10.1016/j.ejmech.2019.02.019
S.N. Vasconcelos, K.A. Meissner, W.R. Ferraz, G.H. Trossini, C. Wrenger and H.A. Stefani, Indole-3-glyoxyl tyrosine: Synthesis and Antimalarial Activity against Plasmodium falciparum, Future Med. Chem., 11, 525 (2019); https://doi.org/10.4155/fmc-2018-0246
S. Viveka, Dinesha, P. Shama, G.K. Nagaraja, S. Ballav and S. Kerkar, Design and sYnthesis of Some New Pyrazolyl-pyrazolines as Potential Anti-inflammatory, Analgesic and Antibacterial Agents, Eur. J. Med. Chem., 101, 442 (2015); https://doi.org/10.1016/j.ejmech.2015.07.002
M. Mantzanidou, E. Pontiki and H. Hadjipavlou-Litina, Pyrazoles and Pyrazolines as Anti-Inflammatory Agents, Molecules, 26, 3439 (2021); https://doi.org/10.3390/molecules26113439
R.S. Joshi, P.G. Mandhane, S.D. Diwakar, S.K. Dabhade and C.H. Gill, Synthesis, Analgesic and Anti-inflammatory Activities of Some Novel Pyrazolines Derivatives, Bioorg. Med. Chem. Lett., 20, 3721 (2010); https://doi.org/10.1016/j.bmcl.2010.04.082
T. Chandra, N. Garg, S. Lata, K.K. Saxena and A. Kumar, Synthesis of Substituted Acridinyl Pyrazoline Derivatives and their Evaluation for Anti-inflammatory Activity, Eur. J. Med. Chem., 45, 1772 (2010); https://doi.org/10.1016/j.ejmech.2010.01.009
S.R. Pedada, N.S. Yarla, P.J. Tambade, B.L. Dhananjaya, A. Bishayee, K.M. Arunasree, G.H. Philip, G. Dharmapuri, G. Aliev, S. Putta and G. Rangaiah, Synthesis of New Secretory Phospholipase A2-inhibitory Indole Containing Isoxazole Derivatives as Anti-inflammatory and Anticancer Agents, Eur. J. Med. Chem., 112, 289 (2016); https://doi.org/10.1016/j.ejmech.2016.02.025
T.R. Prajapati, D.P. Pandey, V. Gupta, B. Joshi and G.K. Dhingra, Synthesis and Anti-inflammatory Activity of Some Newer Potential Isoxazoline Derivatives of Indole, Int. J. Environ. Rehab. Conserv., 9, 87 (2018); https://doi.org/10.31786/09756272.18.9.2.213
A.G. Habeeb, P.N. Praveen Rao and E.E. Knaus, Design and Synthesis of 4,5-Diphenyl-4-isoxazolines: Novel Inhibitors of Cyclooxygenase-2 with Analgesic and Antiinflammatory Activity, J. Med. Chem., 44, 2921 (2001); https://doi.org/10.1021/jm0101287
M. Znati, M. Debbabi, A. Romdhane, H. Ben Jannet and J. Bouajila, Synthesis of New Anticancer and Anti-inflammatory Isoxazolines and Aziridines from the Natural (-)-Deltoin, J. Pharm. Pharmacol., 70, 1700 (2018); https://doi.org/10.1111/jphp.13013
C.A. Winter, E.A. Risley and G.W. Nuss, Carrageenin-Induced Edema in Hind Paw of the Rat as an Assay for Antiinflammatory Drugs, Proc. Soc. Exp. Biol. Med., 111, 544 (1962); https://doi.org/10.3181/00379727-111-27849
M. Verma, J.N. Sinha, V.R. Gujrati, T.N. Bhalla, K.P. Bhargava and K. Shanker, A New Potent Anti-inflammatory Quinazolone, Pharmacol. Res. Commun., 13, 967 (1981); https://doi.org/10.1016/S0031-6989(81)80068-9
Q.E. Smith, Pharmacological Screening Tests, Progress in Medicinal Chemistry, Butterworth: London, Ed.: 11, pp. 1-33 (1961).