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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Research Article

Design, Synthesis and Evaluation of Antifungal Activity of Pyrazoleacetamide Derivatives

Author(s): Onkar G. Kachi, Hari R. Pawar*, Anuruddha R. Chabukswar*, Swati Jagdale, Vishwanath Swamy, Kadam Vinayak, Dattatray Hingane, Mahadev Shinde and Nagesh Pawar

Volume 20, Issue 10, 2024

Published on: 11 June, 2024

Page: [957 - 968] Pages: 12

DOI: 10.2174/0115734064300961240417063246

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Abstract

Background: Fungal infections have posed a big challenge in the management of their treatment. Due to the resistance and toxicity of existing drug molecules in the light of pandemic infections, like COVID-19, there is an urgent need to find newer derivatives of active molecules, which can be effective in fungal infections.

Objective: In the present study, we aimed to design pyrazole derivatives using molecular modeling studies against target 1EA1 and synthesize 10 molecules of pyrazole derivatives using a multi-step synthesis approach.

Methods: Designed pyrazole derivatives were synthesized by conventional organic methods. The newly synthesized pyrazole molecules were characterized by using FT-IR, 1HNMR, 13CNMR, and LC-MS techniques. Molecular docking studies were also performed. The antifungal activity of newly synthesized compounds was assessed in vitro against Candida albicans and Aspergillus niger using the well plate method.

Results: Two of the compounds, OK-7 and OK-8, have been found to show significant docking interaction with target protein 1EA1. These two compounds have also been found to show significant anti-fungal activity against Candida albicans and Aspergillus nigra when compared to the standard fluconazole. The Minimum Inhibitory Concentration (MIC) value of these two compounds has been found to be 50 μg/ml.

Conclusion: Pyrazole derivatives with -CH3, CH3O-, and -CN groups have been found to be active against tested fungi and can be further explored for their potential as promising anti-fungal agents for applications in the field of medicinal chemistry.

Keywords: Pyrazole, anti-fungal, 1EA1, Candida albicans, Aspergillus niger, flow chemistry.

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[1]
Koltin, Y.; Hitchcock, C.A. The search for new triazole antifungal agents. Curr. Opin. Chem. Biol., 1997, 1(2), 176-182.
[http://dx.doi.org/10.1016/S1367-5931(97)80007-5] [PMID: 9667858]
[2]
Vanden Bossche, H.; Dromer, F.; Improvisi, I.; Lozano-Chiu, M.; Rex, J.H.; Sanglard, D. Antifungal drug resistance in pathogenic fungi. Med. Mycol., 1998, 36(Suppl. 1), 119-128.
[PMID: 9988500]
[3]
Georgopapadakou, N.H. Antifungals: Mechanism of action and resistance, established and novel drugs. Curr. Opin. Microbiol., 1998, 1(5), 547-557.
[http://dx.doi.org/10.1016/S1369-5274(98)80087-8] [PMID: 10066533]
[4]
Al-Hatmi, A.M.S.; Mohsin, J.; Al-Huraizi, A.; Khamis, F. COVID-19 associated invasive candidiasis. J. Infect., 2021, 82(2), e45-e46.
[http://dx.doi.org/10.1016/j.jinf.2020.08.005] [PMID: 32771402]
[5]
Lansbury, L.; Lim, B.; Baskaran, V.; Lim, W.S. Co-infections in people with COVID-19: A systematic review and meta-analysis. J. Infect., 2020, 81(2), 266-275.
[http://dx.doi.org/10.1016/j.jinf.2020.05.046] [PMID: 32473235]
[6]
Yang, X.; Yu, Y.; Xu, J.; Shu, H.; Xia, J.; Liu, H.; Wu, Y.; Zhang, L.; Yu, Z.; Fang, M.; Yu, T.; Wang, Y.; Pan, S.; Zou, X.; Yuan, S.; Shang, Y. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A single-centered, retrospective, observational study. Lancet Respir. Med., 2020, 8(5), 475-481.
[http://dx.doi.org/10.1016/S2213-2600(20)30079-5] [PMID: 32105632]
[7]
Koehler, P.; Cornely, O.A.; Böttiger, B.W.; Dusse, F.; Eichenauer, D.A.; Fuchs, F.; Hallek, M.; Jung, N.; Klein, F.; Persigehl, T.; Rybniker, J.; Kochanek, M.; Böll, B.; Shimabukuro-Vornhagen, A. COVID‐19 associated pulmonary aspergillosis. Mycoses, 2020, 63(6), 528-534.
[http://dx.doi.org/10.1111/myc.13096] [PMID: 32339350]
[8]
Ravindar, L.; Hasbullah, S.A.; Rakesh, K.P.; Hassan, N.I. Pyrazole and pyrazoline derivatives as antimalarial agents: A key review. Eur. J. Pharm. Sci., 2023, 183, 106365.
[http://dx.doi.org/10.1016/j.ejps.2022.106365] [PMID: 36563914]
[9]
Faria, J.V.; Vegi, P.F.; Miguita, A.G.C.; dos Santos, M.S.; Boechat, N.; Bernardino, A.M.R. Recently reported biological activities of pyrazole compounds. Bioorg. Med. Chem., 2017, 25(21), 5891-5903.
[http://dx.doi.org/10.1016/j.bmc.2017.09.035] [PMID: 28988624]
[10]
Karrouchi, K.; Radi, S.; Ramli, Y.; Taoufik, J.; Mabkhot, Y.; Al-aizari, F.; Ansar, M. Synthesis and pharmacological activities of pyrazole derivatives: A review. Molecules, 2018, 23(1), 134.
[http://dx.doi.org/10.3390/molecules23010134] [PMID: 29329257]
[11]
Ganguly, S.; Jacob, S.K. Therapeutic outlook of pyrazole analogs: A mini review. Mini Rev. Med. Chem., 2017, 17(11), 959-983.
[http://dx.doi.org/10.2174/1389557516666151120115302] [PMID: 26586126]
[12]
Khan, M.F.; Alam, M.M.; Verma, G.; Akhtar, W.; Akhter, M.; Shaquiquzzaman, M. The therapeutic voyage of pyrazole and its analogs: A review. Eur. J. Med. Chem., 2016, 120, 170-201.
[http://dx.doi.org/10.1016/j.ejmech.2016.04.077] [PMID: 27191614]
[13]
Vijesh, A.M.; Isloor, A.M.; Telkar, S.; Peethambar, S.K.; Rai, S.; Isloor, N. Synthesis, characterization and antimicrobial studies of some new pyrazole incorporated imidazole derivatives. Eur. J. Med. Chem., 2011, 46(8), 3531-3536.
[http://dx.doi.org/10.1016/j.ejmech.2011.05.005] [PMID: 21620535]
[14]
B’Bhatt, H.; Sharma, S. Synthesis and antimicrobial activity of pyrazole nucleus containing 2-thioxothiazolidin-4-one derivatives. Arab. J. Chem., 2017, 10, S1590-S1596.
[http://dx.doi.org/10.1016/j.arabjc.2013.05.029]
[15]
Sheehan, D.J.; Hitchcock, C.A.; Sibley, C.M. Current and emerging azole antifungal agents. Clin. Microbiol. Rev., 1999, 12(1), 40-79.
[http://dx.doi.org/10.1128/CMR.12.1.40] [PMID: 9880474]
[16]
Ragavan, R.V.; Vijayakumar, V.; Kumari, N.S. Synthesis and antimicrobial activities of novel 1,5-diaryl pyrazoles. Eur. J. Med. Chem., 2010, 45(3), 1173-1180.
[http://dx.doi.org/10.1016/j.ejmech.2009.12.042] [PMID: 20053480]
[17]
Menozzi, G.; Merello, L.; Fossa, P.; Schenone, S.; Ranise, A.; Mosti, L.; Bondavalli, F.; Loddo, R.; Murgioni, C.; Mascia, V.; La Colla, P.; Tamburini, E. Synthesis, antimicrobial activity and molecular modeling studies of halogenated 4-[1H-imidazol-1-yl(phenyl)methyl]-1,5-diphenyl-1H-pyrazoles. Bioorg. Med. Chem., 2004, 12(20), 5465-5483.
[http://dx.doi.org/10.1016/j.bmc.2004.07.029] [PMID: 15388173]
[18]
Holla, B.S.; Mahalinga, M.; Karthikeyan, M.S.; Akberali, P.M.; Shetty, N.S. Synthesis of some novel pyrazolo[3,4-d]pyrimidine derivatives as potential antimicrobial agents. Bioorg. Med. Chem., 2006, 14(6), 2040-2047.
[http://dx.doi.org/10.1016/j.bmc.2005.10.053] [PMID: 16310361]
[19]
Song, Y.G. The history of antimicrobial drug development and the current situation. Infect. Chemother., 2012, 44(4), 263-268.
[http://dx.doi.org/10.3947/ic.2012.44.4.263]
[20]
Chalkha, M.; Akhazzane, M.; Moussaid, F.Z.; Daoui, O.; Nakkabi, A.; Bakhouch, M.; Chtita, S.; Elkhattabi, S.; Housseini, A.I.; El Yazidi, M. Design, synthesis, characterization, in vitro screening, molecular docking, 3D-QSAR, and ADME-Tox investigations of novel pyrazole derivatives as antimicrobial agents. New J. Chem., 2022, 46(6), 2747-2760.
[http://dx.doi.org/10.1039/D1NJ05621B]
[21]
Karati, D.; Mahadik, K.R.; Trivedi, P.; Kumar, D. A molecular insight into pyrazole congeners as antimicrobial, anticancer, and antimalarial agents. Med. Chem., 2022, 18(10), 1044-1059.
[http://dx.doi.org/10.2174/1573406418666220303150640] [PMID: 35240964]
[22]
Muhammad, Z.A.; Alshehrei, F.; Zayed, M.E.M.; Farghaly, T.A.; Abdallah, M.A. Synthesis of novel bis-pyrazole derivatives as antimicrobial agents. Mini Rev. Med. Chem., 2019, 19(15), 1276-1290.
[http://dx.doi.org/10.2174/1389557519666190313095545] [PMID: 30864524]
[23]
Bazgir, A.; Khanaposhtani, M.M.; Soorki, A.A. One-pot synthesis and antibacterial activities of pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidine-dione derivatives. Bioorg. Med. Chem. Lett., 2008, 18(21), 5800-5803.
[http://dx.doi.org/10.1016/j.bmcl.2008.09.057] [PMID: 18842404]
[24]
Liu, H.; Ren, Z.L.; Wang, W.; Gong, J.X.; Chu, M.J.; Ma, Q.W.; Wang, J.C.; Lv, X.H. Novel coumarin-pyrazole carboxamide derivatives as potential topoisomerase II inhibitors: Design, synthesis and antibacterial activity. Eur. J. Med. Chem., 2018, 157, 81-87.
[http://dx.doi.org/10.1016/j.ejmech.2018.07.059] [PMID: 30075404]
[25]
Zhang, T.Y.; Zheng, C.J.; Wu, J.; Sun, L.P.; Piao, H.R. Synthesis of novel dihydrotriazine derivatives bearing 1,3-diaryl pyrazole moieties as potential antibacterial agents. Bioorg. Med. Chem. Lett., 2019, 29(9), 1079-1084.
[http://dx.doi.org/10.1016/j.bmcl.2019.02.033] [PMID: 30842033]
[26]
Verma, R.; Verma, S.K.; Rakesh, K.P.; Girish, Y.R.; Ashrafizadeh, M.; Sharath Kumar, K.S.; Rangappa, K.S. Pyrazole-based analogs as potential antibacterial agents against methicillin-resistance Staphylococcus aureus (MRSA) and its SAR elucidation. Eur. J. Med. Chem., 2021, 212, 113134.
[http://dx.doi.org/10.1016/j.ejmech.2020.113134] [PMID: 33395624]
[27]
Gudmundsson, K.S.; Johns, B.A.; Allen, S.H. Pyrazolopyridines with potent activity against herpesviruses: Effects of C5 substituents on antiviral activity. Bioorg. Med. Chem. Lett., 2008, 18(3), 1157-1161.
[http://dx.doi.org/10.1016/j.bmcl.2007.11.120] [PMID: 18086523]
[28]
Cichero, E.; Fossa, P. Docking-based 3D-QSAR analyses of pyrazole derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors. J. Mol. Model., 2012, 18(4), 1573-1582.
[http://dx.doi.org/10.1007/s00894-011-1190-5] [PMID: 21805124]
[29]
Kuo, C.J.; Liu, H.G.; Lo, Y.K.; Seong, C.M.; Lee, K.I.; Jung, Y.S.; Liang, P.H. Individual and common inhibitors of coronavirus and picornavirus main proteases. FEBS Lett., 2009, 583(3), 549-555.
[http://dx.doi.org/10.1016/j.febslet.2008.12.059] [PMID: 19166843]
[30]
Karati, D.; Mahadik, K.R.; Kumar, D. Pyrazole scaffolds: Centrality in anti-inflammatory and antiviral drug design. Med. Chem., 2022, 18(10), 1060-1072.
[http://dx.doi.org/10.2174/1573406418666220410181827] [PMID: 35410619]
[31]
Matta, R.; Pochampally, J.; Dhoddi, B.N.; Bhookya, S.; Bitla, S.; Akkiraju, A.G. Synthesis, antimicrobial and antioxidant activity of triazole, pyrazole containing thiazole derivatives and molecular docking studies on COVID-19. BMC Chem., 2023, 17(1), 61.
[http://dx.doi.org/10.1186/s13065-023-00965-8] [PMID: 37330518]
[32]
Silva, V.L.M.; Elguero, J.; Silva, A.M.S. Current progress on antioxidants incorporating the pyrazole core. Eur. J. Med. Chem., 2018, 156, 394-429.
[http://dx.doi.org/10.1016/j.ejmech.2018.07.007] [PMID: 30015075]
[33]
Vijesh, A.M.; Isloor, A.M.; Shetty, P.; Sundershan, S.; Fun, H.K. New pyrazole derivatives containing 1,2,4-triazoles and benzoxazoles as potent antimicrobial and analgesic agents. Eur. J. Med. Chem., 2013, 62, 410-415.
[http://dx.doi.org/10.1016/j.ejmech.2012.12.057] [PMID: 23385092]
[34]
Bekhit, A.A.; Nasralla, S.N.; El-Agroudy, E.J.; Hamouda, N.; El-Fattah, A.A.; Bekhit, S.A.; Amagase, K.; Ibrahim, T.M. Investigation of the anti-inflammatory and analgesic activities of promising pyrazole derivative. Eur. J. Pharm. Sci., 2022, 168, 106080.
[http://dx.doi.org/10.1016/j.ejps.2021.106080] [PMID: 34818572]
[35]
Abdel-Aziz, M.; Abuo-Rahma, G.E.D.A.; Hassan, A.A. Synthesis of novel pyrazole derivatives and evaluation of their antidepressant and anticonvulsant activities. Eur. J. Med. Chem., 2009, 44(9), 3480-3487.
[http://dx.doi.org/10.1016/j.ejmech.2009.01.032] [PMID: 19268406]
[36]
Gao, M.; Qu, K.; Zhang, W.; Wang, X. Pharmacological activity of pyrazole derivatives as an anticonvulsant for benefit against epilepsy. Neuroimmunomodulation, 2021, 28(2), 90-98.
[http://dx.doi.org/10.1159/000513297] [PMID: 33774633]
[37]
Li, X.; Yu, Y.; Tu, Z. Pyrazole scaffold synthesis, functionalization, and applications in Alzheimer’s disease and Parkinson’s disease treatment (2011–2020). Molecules, 2021, 26(5), 1202.
[http://dx.doi.org/10.3390/molecules26051202] [PMID: 33668128]
[38]
Gutti, G.; Kumar, D.; Paliwal, P.; Ganeshpurkar, A.; Lahre, K.; Kumar, A.; Krishnamurthy, S.; Singh, S.K. Development of pyrazole and spiropyrazoline analogs as multifunctional agents for treatment of Alzheimer’s disease. Bioorg. Chem., 2019, 90, 103080.
[http://dx.doi.org/10.1016/j.bioorg.2019.103080] [PMID: 31271946]
[39]
Koca, İ.; Özgür, A.; Coşkun, K.A.; Tutar, Y. Synthesis and anticancer activity of acyl thioureas bearing pyrazole moiety. Bioorg. Med. Chem., 2013, 21(13), 3859-3865.
[http://dx.doi.org/10.1016/j.bmc.2013.04.021] [PMID: 23664495]
[40]
Dawood, K.M.; Eldebss, T.M.A.; El-Zahabi, H.S.A.; Yousef, M.H.; Metz, P. Synthesis of some new pyrazole-based 1,3-thiazoles and 1,3,4-thiadiazoles as anticancer agents. Eur. J. Med. Chem., 2013, 70, 740-749.
[http://dx.doi.org/10.1016/j.ejmech.2013.10.042] [PMID: 24231309]
[41]
Oliveira, S.; Pizzuti, L.; Quina, F.; Flores, A.; Lund, R.; Lencina, C.; Pacheco, B.; de Pereira, C.; Piva, E. Anti-Candida, anti-enzyme activity and cytotoxicity of 3,5-diaryl-4,5-dihydro-1H-pyrazole-1-carboximidamides. Molecules, 2014, 19(5), 5806-5820.
[http://dx.doi.org/10.3390/molecules19055806] [PMID: 24806580]
[42]
Mor, S.; Khatri, M.; punia, R.; Sindhu, S. Recent progress in anticancer agents incorporating pyrazole scaffold. Mini Rev. Med. Chem., 2022, 22(1), 115-163.
[http://dx.doi.org/10.2174/1389557521666210325115218] [PMID: 33823764]
[43]
Ramajayam, R.; Tan, K.P.; Liu, H.G.; Liang, P.H. Synthesis and evaluation of pyrazolone compounds as SARS-coronavirus 3C-like protease inhibitors. Bioorg. Med. Chem., 2010, 18(22), 7849-7854.
[http://dx.doi.org/10.1016/j.bmc.2010.09.050] [PMID: 20947359]
[44]
Branković, J.; Milovanović, V.M.; Simijonović, D.; Novaković, S.; Petrović, Z.D.; Trifunović, S.S.; Bogdanović, G.A.; Petrović, V.P. Pyrazolone-type compounds: Synthesis and in silico assessment of antiviral potential against key viral proteins of SARS-CoV-2. RSC Advances, 2022, 12(25), 16054-16070.
[http://dx.doi.org/10.1039/D2RA02542F] [PMID: 35733695]
[45]
Rakesh, K.P.; Ramesh, S.; Shivakumar; Gowda, D.C. Shivakumar, Gowda DC. Effect of low charge and high hydrophobicity on antimicrobial activity of the quinazolinone-peptide conjugates. Russ. J. Bioorganic Chem., 2018, 44(2), 158-164.
[http://dx.doi.org/10.1134/S1068162018020036]
[46]
Can, N.Ö.; Acar Çevik, U.; Sağlık, B.N.; Levent, S.; Korkut, B.; Özkay, Y.; Kaplancıklı, Z.A.; Koparal, A.S. Synthesis, molecular docking studies, and antifungal activity evaluation of new benzimidazole-triazoles as potential lanosterol 14α-demethylase inhibitors. J. Chem., 2017, 2017, 1-15.
[http://dx.doi.org/10.1155/2017/9387102]
[47]
Park, J.S.; Yu, K.A.; Kang, T.H.; Kim, S.; Suh, Y.G. Discovery of novel indazole-linked triazoles as antifungal agents. Bioorg. Med. Chem. Lett., 2007, 17(12), 3486-3490.
[http://dx.doi.org/10.1016/j.bmcl.2007.03.074] [PMID: 17433670]
[48]
Chalkha, M.; Nour, H.; Chebbac, K.; Nakkabi, A.; Bahsis, L.; Bakhouch, M.; Akhazzane, M.; Bourass, M.; Chtita, S.; Bin Jardan, Y.A.; Augustyniak, M.; Bourhia, M.; Aboul-Soud, M.A.M.; El Yazidi, M. Synthesis, characterization, DFT mechanistic study, antimicrobial activity, molecular modeling, and ADMET properties of novel pyrazole-isoxazoline hybrids. ACS Omega, 2022, 7(50), 46731-46744.
[http://dx.doi.org/10.1021/acsomega.2c05788] [PMID: 36570248]
[49]
Chalkha, M.; Moussaoui, A.E.; Hadda, T.B.; Berredjem, M.; Bouzina, A.; Almalki, F.A.; Saghrouchni, H.; Bakhouch, M.; Saadi, M.; Ammari, L.E.; Abdellatiif, M.H.; Yazidi, M.E. Crystallographic study, biological evaluation and DFT/POM/Docking analyses of pyrazole linked amide conjugates: Identification of antimicrobial and antitumor pharmacophore sites. J. Mol. Struct., 2022, 1252, 131818.
[http://dx.doi.org/10.1016/j.molstruc.2021.131818]
[50]
Jacob K, S.; Ganguly, S.; Kumar, P.; Poddar, R.; Kumar, A. Homology model, molecular dynamics simulation and novel pyrazole analogs design of Candida albicans CYP450 lanosterol 14 α-demethylase, a target enzyme for antifungal therapy. J. Biomol. Struct. Dyn., 2017, 35(7), 1446-1463.
[http://dx.doi.org/10.1080/07391102.2016.1185380] [PMID: 27142238]
[51]
Chabukswar, A.; Kuchekar, B.; Lokhande, P.; Tryambake, M.; Pagare, B.; Kadam, V.; Jagdale, S.; Chabukswar, V. Design, synthesis and evaluation of antibacterial activity of novel indazole derivatives. Curr. Bioact. Compd., 2013, 9(4), 263-269.
[http://dx.doi.org/10.2174/1573407209999131231095550]
[52]
Kaplancıklı, Z.A.; Levent, S.; Osmaniye, D.; Sağlık, B.N.; Çevik, U.A.; Çavuşoğlu, B.K.; Özkay, Y.; Ilgın, S. Synthesis and anticandidal activity evaluation of new benzimidazole-thiazole derivatives. Molecules, 2017, 22(12), 2051.
[http://dx.doi.org/10.3390/molecules22122051] [PMID: 29168743]

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