Generic placeholder image

Letters in Organic Chemistry

Author(s): Luciana Terra, Daiane de Jesus Viegas, Alice Maria Rolim Bernardino, Jéssica Venância Faria, Percilene Fazolin Vegi, Rômulo Gabriel De Miranda de Paula Pinto, Maurício Silva dos Santos, Helena Carla Castro and Paula Alvarez Abreu*

DOI: 10.2174/1570178617666200210105246

DownloadDownload PDF Flyer Cite As
Synthesis of 5-amino-1-aryl-3-methyl-1H-pyrazole-4-carbonitriles, Antifungal Activity and In Silico Analysis

Page: [779 - 787] Pages: 9

  • * (Excluding Mailing and Handling)

Abstract

Serious fungal infections are increasing worldwide and have become a great concern in the medical field since antifungal drugs are restricted to a few drug classes. This work aims to evaluate the antifungal activity of a series of 5-amino-1-aryl-3-methyl-1H-pyrazole-4-carbonitriles (1a-g) and to establish a structure-activity relationship (SAR). The synthesis of these compounds was carried out in a single step followed by cyclization in good to excellent yields i.e. 73-94%. The chemical structures were confirmed by melting point, IR, 1H-NMR, 13C-NMR, and HRMS. These seven compounds were submitted to the disk diffusion test against Candida spp. and the active compound was evaluated by means of the microdilution method to determine the minimum inhibitory concentration (MIC). In addition, the stereo electronic descriptors were evaluated and pharmacokinetic and toxicological properties were calculated to predict the potential of these compounds as a drug. All the compounds presented good theoretical physicochemical parameters and one of them showed reasonably good antifungal activity.

Keywords: Pyrazoles, antifungal agents, structure-activity relationship, drug discovery, pharmacokinetic, toxicity tests, molecular modeling.

Graphical Abstract

[1]
Silva, S.; Negri, M.; Henriques, M.; Oliveira, R.; Williams, D.W.; Azeredo, J. FEMS Microbiol. Rev., 2012, 36(2), 288-305.
[http://dx.doi.org/10.1111/j.1574-6976.2011.00278.x] [PMID: 21569057]
[2]
Vallabhaneni, S.; Mody, R.K.; Walker, T.; Chiller, T. Infect. Dis. Clin. North Am., 2016, 30(1), 1-11.
[http://dx.doi.org/10.1016/j.idc.2015.10.004] [PMID: 26739604]
[3]
Antinori, S.; Milazzo, L.; Sollima, S.; Galli, M.; Corbellino, M. Eur. J. Intern. Med., 2016, 34, 21-28.
[http://dx.doi.org/10.1016/j.ejim.2016.06.029] [PMID: 27394927]
[4]
Doi, A.M.; Pignatari, A.C.C.; Edmond, M.B.; Marra, A.R.; Camargo, L.F.A.; Siqueira, R.A.; da Mota, V.P.; Colombo, A.L. PLoS One, 2016, 11(1)e0146909
[http://dx.doi.org/10.1371/journal.pone.0146909] [PMID: 26808778]
[5]
Cowen, L.E.; Sanglard, D.; Howard, S.J.; Rogers, P.D.; Perlin, D.S. Cold Spring Harb. Perspect. Med., 2014, 5(7)a019752
[http://dx.doi.org/10.1101/cshperspect.a019752] [PMID: 25384768]
[6]
Vandeputte, P.; Ferrari, S.; Coste, A.T. Int. J. Microbiol., 2012, 2012, 1-26.
[http://dx.doi.org/10.1155/2012/713687]
[7]
Antimicrobial resistance, global report on surveillance., https://www.who.int/drugresistance/documents/surveillancereport/en/
[8]
Ernst, J.F.; Schmidt, A. Dimorphism in Human Pathogenic and Apathogenic Yeasts; , 2000, Vol. 5, .
[http://dx.doi.org/10.1159/000060348]
[9]
Wissing, H.; Ballus, J.; Bingold, T.M.; Nocea, G.; Krobot, K.J.; Kaskel, P.; Kumar, R.N.; Mavros, P. Infect. Drug Resist., 2013, 6, 15-25.
[PMID: 23386790]
[10]
Wang, E.; Farmakiotis, D.; Yang, D.; McCue, D.A.; Kantarjian, H.M.; Kontoyiannis, D.P.; Mathisen, M.S. J. Antimicrob. Chemother., 2015, 70(8), 2362-2368.
[http://dx.doi.org/10.1093/jac/dkv087] [PMID: 25855759]
[11]
Zhao, Y.; Chan, J.F.W.; Tsang, C.C.; Wang, H.; Guo, D.; Pan, Y.; Xiao, Y.; Yue, N.; Chen, J.H.; Lau, S.K.; Xu, Y.; Woo, P.C. J. Clin. Microbiol., 2015, 53(11), 3639-3645.
[http://dx.doi.org/10.1128/JCM.01985-15] [PMID: 26311865]
[12]
Kaur, R.; Dhakad, M.S.; Goyal, R.; Kumar, R. Asian Pac. J. Trop. Biomed., 2016, 6, 455-460.
[http://dx.doi.org/10.1016/j.apjtb.2015.12.019]
[13]
Faria, J.V.; Vegi, P.F.; Miguita, A.G.C.; Dos Santos, M.S.; Boechat, N.; Bernardino, A.M.R. Bioorg. Med. Chem., 2017, 25(21), 5891-5903.
[http://dx.doi.org/10.1016/j.bmc.2017.09.035] [PMID: 28988624]
[14]
Karrouchi, K.; Radi, S.; Ramli, Y.; Taoufik, J.; Mabkhot, Y.N.; Al-Aizari, F.A.; Ansar, M. Molecules, 2018, 23(1), 1-86.
[http://dx.doi.org/10.3390/molecules23010134] [PMID: 29329257]
[15]
Fustero, S.; Sánchez-Roselló, M.; Barrio, P.; Simón-Fuentes, A. Chem. Rev., 2011, 111(11), 6984-7034.
[http://dx.doi.org/10.1021/cr2000459] [PMID: 21806021]
[16]
Knorr, L.; Laubmann, H. Ber, 1888, 21, 1205-1212.
[http://dx.doi.org/10.1002/cber.188802101230]
[17]
Pechmann, H.V. Ber, 1898, 31, 2950-2951.
[http://dx.doi.org/10.1002/cber.18980310363]
[18]
Faria, J.V.; dos Santos, M.S.; Bernardino, A.M.R.; Becker, K.M.; Machado, G.M.C.; Rodrigues, R.F.; Canto-Cavalheiro, M.M.; Leon, L.L. Bioorg. Med. Chem. Lett., 2013, 23(23), 6310-6312.
[http://dx.doi.org/10.1016/j.bmcl.2013.09.062] [PMID: 24125880]
[19]
Rosa, G.S.; Souto, B.A.; Pereira, C.N.; Teixeira, B.C.; Santos, M.S. J. Heterocycl. Chem., 2019, 56, 1825-1830.
[http://dx.doi.org/10.1002/jhet.3557]
[20]
Khatab, T.K.; Hassan, A.S.; Hafez, T.S. Bull. Chem. Soc. Ethiop., 2019, 33(1), 135-142.
[http://dx.doi.org/10.4314/bcse.v33i1.13]
[21]
Konwar, M.; Phukan, P.; Chaliha, A.K.; Buragohain, A.K.; Damarla, K.; Gogoi, D.; Kumar, A.; Sarma, D. ChemistrySelect, 2019, 4, 10236-10245.
[http://dx.doi.org/10.1002/slct.201902266]
[22]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Adv. Drug Deliv. Rev., 2001, 46(1-3), 3-26.
[http://dx.doi.org/10.1016/S0169-409X(00)00129-0] [PMID: 11259830]
[23]
Gleeson, M.P. J. Med. Chem., 2008, 51(4), 817-834.
[http://dx.doi.org/10.1021/jm701122q] [PMID: 18232648]
[24]
Hughes, J.D.; Blagg, J.; Price, D.A.; Bailey, S.; Decrescenzo, G.A.; Devraj, R.V.; Ellsworth, E.; Fobian, Y.M.; Gibbs, M.E.; Gilles, R.W.; Greene, N.; Huang, E.; Krieger-Burke, T.; Loesel, J.; Wager, T.; Whiteley, L.; Zhang, Y. Bioorg. Med. Chem. Lett., 2008, 18(17), 4872-4875.
[http://dx.doi.org/10.1016/j.bmcl.2008.07.071] [PMID: 18691886]
[25]
Bruns, R.F.; Watson, I.A. J. Med. Chem., 2012, 55(22), 9763-9772.
[http://dx.doi.org/10.1021/jm301008n] [PMID: 23061697]
[26]
Baell, J.B.; Holloway, G.A. J. Med. Chem., 2010, 53(7), 2719-2740.
[http://dx.doi.org/10.1021/jm901137j] [PMID: 20131845]
[27]
Yadav, J.S.S.; Bezawada, J.; Yan, S.; Tyagi, R.D.; Surampalli, R.Y. Can. J. Microbiol., 2012, 58(8), 937-952.
[http://dx.doi.org/10.1139/w2012-077] [PMID: 22823163]
[28]
Feng, W.; Yang, J.; Wang, Y.; Chen, J.; Xi, Z.; Qiao, Z. Can. J. Microbiol., 2016, 62(11), 938-943.
[http://dx.doi.org/10.1139/cjm-2016-0055] [PMID: 27622981]
[29]
Pappas, P.G. Infect. Dis. Clin. North Am., 2006, 20(3), 485-506.
[http://dx.doi.org/10.1016/j.idc.2006.07.004] [PMID: 16984866]
[30]
Yapar, N. Ther. Clin. Risk Manag., 2014, 10, 95-105.
[http://dx.doi.org/10.2147/TCRM.S40160] [PMID: 24611015]
[31]
Farag, A.M.; Mayhoub, A.S.; Barakat, S.E.; Bayomi, A.H. Bioorg. Med. Chem., 2008, 16(8), 4569-4578.
[http://dx.doi.org/10.1016/j.bmc.2008.02.043] [PMID: 18313934]
[32]
Matysiak, J.; Niewiadomy, A. Bioorg. Med. Chem., 2003, 11(10), 2285-2291.
[http://dx.doi.org/10.1016/S0968-0896(03)00110-X] [PMID: 12713839]
[33]
Rizk, H.F.; Ibrahim, S.A.; El-Borai, M.A. Dyes Pigm., 2015, 112, 86-92.
[http://dx.doi.org/10.1016/j.dyepig.2014.06.026]
[34]
Goel, N.; Drabu, S.; Afzal, O.; Bawa, S. J. Pharm. Bioallied Sci., 2014, 6(4), 253-259.
[http://dx.doi.org/10.4103/0975-7406.142956] [PMID: 25400408]
[35]
Prakash, O.; Hussain, K.; Aneja, K.R.; Sharma, C. Indian J. Pharm. Sci., 2011, 73(5), 586-590.
[http://dx.doi.org/10.4103/0250-474X.99023] [PMID: 22923876]
[36]
Curatolo, W. Pharm. Sci. Technol. Today, 1998, 1, 387-393.
[http://dx.doi.org/10.1016/S1461-5347(98)00097-2]
[37]
Veber, D.F.; Johnson, S.R.; Cheng, H.Y.; Smith, B.R.; Ward, K.W.; Kopple, K.D. J. Med. Chem., 2002, 45(12), 2615-2623.
[http://dx.doi.org/10.1021/jm020017n] [PMID: 12036371]
[38]
Sander, T.; Freyss, J.; von Korff, M.; Reich, J.R.; Rufener, C. J. Chem. Inf. Model., 2009, 49(2), 232-246.
[http://dx.doi.org/10.1021/ci800305f] [PMID: 19434825]
[39]
Hill, A.P.; Young, R.J. Drug Discov. Today, 2010, 15(15-16), 648-655.
[http://dx.doi.org/10.1016/j.drudis.2010.05.016] [PMID: 20570751]
[40]
Deeb, O.; Goodarzi, M. Curr. Drug Saf., 2012, 7(4), 289-297.
[http://dx.doi.org/10.2174/157488612804096533] [PMID: 23062241]
[41]
Ghannoum, M.A. Method for antifungal disk diffusion susceptibility testing of yeasts; approved guideline. 2nd ed., replaces M44-A. Wayne, PA, Committee for Clinical Laboratory Standards, , 2009.
[42]
Rex, J.H. Reference method for broth dilution antifungal susceptibility testing of yeasts, approved standard. 3rd ed;. Wayne, PA, National Committee for Clinical Laboratory Standards 2008.
[43]
Lagorce, D.; Bouslama, L.; Becot, J.; Miteva, M.A.; Villoutreix, B.O. Bioinformatics 2017, 33(22), 3658-3660.
[http://dx.doi.org/10.1093/bioinformatics/btx491] [PMID: 28961788]