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Letters in Drug Design & Discovery

Author(s): Zhaochang Liang, Yuping Huang, Shiben Wang and Xianqing Deng*

DOI: 10.2174/1570180816666190325163117

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Synthesis and Biological Evaluation of Some Pyrazole Derivatives, Containing (Thio) Semicarbazide, as Dual Anti-Inflammatory Antimicrobial Agents

Page: [1020 - 1030] Pages: 11

  • * (Excluding Mailing and Handling)

Abstract

Background: Several series of pyrazole derivatives containing (thio) semicarbazide (4a-4h, 5a-5l, 6a-6f, 7a-7c) were designed and synthesized to screen dual inflammatory and antimicrobial activities.

Methods: The products were characterized by1H NMR, 13C NMR and HRMS. In vitro LPS-induced TNF-α model and in vivo xylene-induced ear-edema model were used to evaluate their antiinflammatory activity. Their in vitro antimicrobial activities were evaluated using a serial dilution method against several gram-positive strains, gram-negative strains and a fungi strain.

Results: Bioassays indicated that most of the compounds markedly inhibited the expression of TNF- α at the concentration of 20 µg/mL Compounds 5i, 6b, and 7b had comparable in vivo antiinflammatory activity to the reference drug dexamethasone at the dose of 50 mg/kg. In addition, several compounds showed antimicrobial activity against different strains, and compounds 5g and 5h exhibited potent inhibitory activities with the MIC value of 8 µg/mL against the Streptococcus pneumoniae CMCC 31968 and Staphylococcus aureus CMCC 25923, respectively. Compound 7b, which exhibited both anti-inflammatory and antimicrobial activities, should be studied as it is or after derivatization.

Conclusion: It can be concluded that pyrazoles, with (thio)-semicarbazone moieties, have the potential to be developed into new anti-inflammatory agents.

Keywords: Anti-inflammatory, antimicrobial, pyrazole, (thio) semicarbazide, TNF-α, dexamethasone.

Graphical Abstract

[1]
Ferrero-Miliani, L.; Nielsen, O.H.; Andersen, P.S.; Girardin, S.E. Chronic inflammation: Importance of NOD2 and NALP3 in interleukin-1beta generation. Clin. Exp. Immunol., 2007, 147, 227-235.
[2]
Tilg, H.; Moschen, A.R. Adipocytokines: Mediators linking adipose tissue, inflammation and immunity. Nat. Rev. Immunol., 2006, 6, 772-783.
[3]
Philip, M.D.A.; Rowley, H.; Schreiber, H. Inflammation as a tumor promoter in cancer induction. Semin. Cancer Biol., 2004, 14, 433-439.
[4]
Grivennikov, S.I.; Greten, F.R.; Karin, M. Immunity, inflammation, and cancer. Cell, 2010, 140, 883-899.
[5]
Duncan, S.A.; Baganizi, D.R.; Sahu, R.; Singh, S.R.; Dennis, V.A. SOCS proteins as regulators of inflammatory responses induced by bacterial infections: A review. Front. Microbiol., 2017, 8, 2431.
[6]
Bekhit, A.A.; Abdel-Aziem, T. Design, synthesis and biological evaluation of some pyrazole derivatives as anti-inflammatory-antimicrobial agents. Bioorg. Med. Chem., 2004, 12, 1935-1945.
[7]
Palomer, A.; Cabré, F.; Pascual, J.; Campos, J.; Trujillo, M.A.; Entrena, A.; Gallo, M.A.; García, L.; Mauleón, D.; Espinosa, A. Identification of novel cyclooxygenase-2 selective inhibitors using pharmacophore models. J. Med. Chem., 2002, 45, 1402-1411.
[8]
Mandour, A.H.; El-Sawy, E.R.; Shaker, K.H.; Mustafa, M.A. Synthesis, anti-inflammatory, analgesic and anticonvulsant activities of 1,8-dihydro-1-ary1-8-alkyl pyrazolo(3,4-b)indoles. Acta Pharm., 2010, 60, 73-88.
[9]
Tageldin, G.N.; Fahmy, S.M.; Ashour, H.M.; Khalil, M.A.; Nassra, R.A.; Labouta, I.M. Design, synthesis and evaluation of some pyrazolo[3,4-d] pyrimidines as anti-inflammatory agents. Bioorg. Chem., 2018, 78, 358-371.
[10]
Gupta, S.K.; Khanal, P.; Kumar, A.; Kumar, A.; Srivastava, N.; Yogi, B.; Sinha, A. Synthesis, characterization of ethyl 5-(substituted)-1H-pyrazole-3-carboxylate derivative as potent anti- inflammatory agents. Antiinflamm. Antiallergy Agents Med. Chem., 2018, 17, 32-38.
[11]
Song, M.X.; Zheng, C.J.; Deng, X.Q.; Sun, L.P.; Wu, Y.; Hong, L.; Li, Y.J.; Liu, Y.; Wei, Z.; Jin, M.J.; Piao, H.R. Synthesis and antibacterial evaluation of rhodanine-based 5-aryloxy pyrazoles against selected methicillin resistant and quinolone-resistant Staphylococcus aureus (MRSA and QRSA). Eur. J. Med. Chem., 2013, 60, 376-385.
[12]
Barakat, A.; Al-Majid, A.M.; Al-Qahtany, B.M.; Ali, M.; Teleb, M.; Al-Agamy, M.H.; Naz, S.; Ul-Haq, Z. Synthesis, antimicrobial activity, pharmacophore modeling and molecular docking studies of new pyrazole-dimedone hybrid architectures. Chem. Cent. J., 2018, 12, 29.
[13]
Bhat, M.; Poojary, B.; Kalal, B.S.; Gurubasavaraja-Swamy, P.M.; Kabilan, S.; Kumar, V.; Shruthi, N.; Alias Anand, S.A.; Pai, V.R. Synthesis and evaluation of thiazolidinone-pyrazole conjugates as anticancer and antimicrobial agents. Future Med. Chem., 2018, 10, 1017-1036.
[14]
Abdellatif, K.R.A.; Bakr, R.B. New advances in synthesis and clinical aspects of pyrazolo[3,4-d] pyrimidine scaffolds. Bioorg. Chem., 2018, 78, 341-357.
[15]
Mathew, B.; Suresh, J.; Anbazhagan, S.; Dev, S. Molecular Docking Studies of Some Novel Antidepressant 5-Substituted Phenyl-3-(Thiophen-2-yl)-4, 5-Dihydro-1h-Pyrazole-1-Carboxamides Against Monoamine Oxidase Isoforms. Cent. Nerv. Syst. Agents Med. Chem., 2016, 16, 75-80.
[16]
Wu, Y.; Huang, Y.P.; Zhou, S.C.; Tan, Y.Q.; Xu, B.G.; Liang, Z.; Deng, X.Q. Synthesis of 1,3-diaryl pyrazole derivatives and evaluation of anticonvulsant and antimicrobial activities. Lat. Am. J. Pharm., 2018, 37, 1017-1027.
[17]
Wang, Y.; Gu, W.; Shan, Y.; Liu, F.; Xu, X.; Yang, Y.; Zhang, Q.; Zhang, Y.; Kuang, H.; Wang, Z.; Wang, S. Design, synthesis and anticancer activity of novel nopinone-based thiosemicarbazone derivatives. Bioorg. Med. Chem. Lett., 2017, 27, 2360-2363.
[18]
Hariri, E.; Mahboubi, A.; Fathi, M.; Rahmani, P.; Mohammad, E.T.K.; Babaeian, M.; Mashayekhi, V.; Kobarfard, F. Synthesis and antibacterial activity of novel hydroxysemicarbazone derivatives. Iran. J. Pharm. Res., 2016, 15(Suppl.), 29-35.
[19]
Mohsin, A.S.M.; Jesmin, M.; Abul-Kalam, A.M.; Khairul Islam, M.; Zahan, R. Anti-inflammatory and analgesic activities of acetophenonesemicarbazone and benzophenone semicarbazone. Asian Pac. J. Trop. Biomed., 2012, 2, S1036-S1039.
[20]
Subhashree, G.R.; Haribabu, J.; Saranya, S.; Yuvaraj, P.; Anantha-Krishnan, D.; Karvembu, R.; Gayathri, D. In vitro antioxidant, anti-inflammatory and in silico molecular docking studies of thiosemicarbazones. J. Mol. Struct., 2017, 1145, 160-169.
[21]
Wang, Y.; Chen, P.; Tang, C.; Wang, Y.; Li, Y.; Zhang, H. Antinociceptive and anti-inflammatory activities of extract and two isolated flavonoids of Carthamustinctorius L. J. Ethnopharmacol., 2014, 151, 944-950.
[22]
Wen, X.; Wang, S.B.; Liu, D.C.; Gong, G.H.; Quan, Z.S. Synthesis and evaluation of the anti-inflammatory activity of quinoline derivatives. Med. Chem. Res., 2015, 24, 2591-2603.
[23]
Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, Approved Standard M7-A6; Clinical and Laboratory Standards Institute: Wayne, PA, USA, 2003.
[24]
Waseem, T.; Duxbury, M.; Ito, H.; Ashley, S.W.; Robinson, M.K. Exogenous ghrelin modulates release of pro-inflammatory and anti-inflammatory cytokines in LPS-stimulated macrophages through distinct signaling pathways. Surgery, 2008, 143, 334-342.
[25]
Luber-Narod, J.; Austin-Ritchie, T.; Hollins, C.; Menon, M.; Malhotra, R.K.; Baker, S.; Carraway, R.E. Role of substance P in several models of bladder inflammation. Urol. Res., 1997, 25, 395-399.
[26]
Kim, H.D.; Cho, H.R.; Moon, S.B.; Shin, H.D.; Yang, K.J.; Park, B.R.; Jang, H.J.; Kim, L.S.; Lee, H.S.; Ku, S.K. Effects of β-glucan from Aureobasidium pullulans on acute inflammation in mice. Arch. Pharm. Res., 2007, 30, 323-328.