In vitro Antifungal Activity of Dihydropyrimidinones/Thiones Against Candida albicans and Cryptococcus neoformans

Author(s): Gabriel O. de Azambuja*, Laura Svetaz, Itamar L. Gonçalves, Patricia F. Corbelini, Gilsane L. von Poser, Daniel F. Kawano, Susana Zacchino, Vera L. Eifler-Lima

Journal Name: Current Bioactive Compounds

Volume 15 , Issue 6 , 2019

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Abstract:

Background: Since the Monastrol discovery in 1999 as the first inhibitor of Eg5, functionalized dihydropyrimidinones/thiones (DHPMs) have emerged as prototypes for drug design in different targets. The present work aimed to evaluate the antifungal activity of a chemical library of DHPMs.

Methods: The compounds were obtained employing Biginelli reaction. Their antifungal activities were assessed against C. neoformans and C. albicans.

Results: The compounds 1-i and 1-k inhibited moderately the fungal growth of C. neoformans, with compound 2-k presenting MIC80 values of 62.5-125 µg·mL-1. Considering activity against C. albicans, the compounds 1-i and 1-n present an MIC50 value of 125-250 µg·mL-1.

Conclusion: The changes performed in DHPM scaffold appear to be valuable for generating compounds with potential antifungal effect.

Keywords: Biginelli reaction, Cryptococcus neoformans, Candida albicans, Antifungal activity, Structure activity relationship, Multicomponent reaction.

[1]
Welsch, M.E.; Snyder, S.A.; Stockwell, B.R. Privileged scaffolds for library design and drug discovery. Curr. Opin. Chem. Biol., 2010, 14(3), 347-361.
[http://dx.doi.org/10.1016/j.cbpa.2010.02.018] [PMID: 20303320]
[2]
de Fátima, Â.; Braga, T.C. Neto, Lda.S.; Terra, B.S.; Oliveira, B.G.F.; da Silva, D.L.; Modolo, L.V. A mini-review on Biginelli adducts with notable pharmacological properties. J. Adv. Res., 2015, 6(3), 363-373.
[http://dx.doi.org/10.1016/j.jare.2014.10.006] [PMID: 26257934]
[3]
Chitra, S.; Devanathan, D.; Pandiarajan, K. Synthesis and in vitro microbiological evaluation of novel 4-aryl-5-isopropoxycarbonyl-6-methyl-3,4-dihydropyrimidinones. Eur. J. Med. Chem., 2010, 45(1), 367-371.
[http://dx.doi.org/10.1016/j.ejmech.2009.09.018] [PMID: 19800716]
[4]
Beena, K.; Akelesh, T. Synthesis and screening of some dihydropyrimidine derivatives as antimicrobial agents. Int. Res. J. Pharm., 2012, 3(9), 303-304.
[5]
Sedaghati, B.; Fassihi, A.; Arbabi, S.; Ranjbar, M.; Memarian, H.R.; Saghaie, L.; Omidi, A.; Sardari, A.; Jalali, M.; Abedi, D. Synthesis and antimicrobial activity of novel derivatives of Biginelli pyrimidines. Med. Chem. Res., 2012, 21(12), 3973-3983.
[http://dx.doi.org/10.1007/s00044-011-9931-7]
[6]
Sandhu, J. S. Past, present and future of the Biginelli reaction: A critical perspective. Archive organic chem., 2011, 2012(1), 66-133.
[7]
Nagarajaiah, H.; Mukhopadhyay, A.; Moorthy, J.N. Biginelli reaction: An overview. Tetrahedron Lett., 2016, 57(47), 5135-5149.
[http://dx.doi.org/10.1016/j.tetlet.2016.09.047]
[8]
Gonçalves, I.L.; Azambuja, G.O.; Kawano, D.F.; Eifler-Lima, V.L. Thioureas as building blocks for generation of heterocycles and compounds with pharmacological activity: A mini review. Mini Rev. Org. Chem., 2017, 14, 1-1.
[9]
Brown, G.D.; Denning, D.W.; Gow, N.A.; Levitz, S.M.; Netea, M.G.; White, T.C. Hidden killers: Human fungal infections. Science Translational Medicine, , 2012, 4(165), 165rv13-165rv13.
[http://dx.doi.org/10.1126/scitranslmed.3004404]
[10]
Silva, M.G.C.; Rodrigues, G.S.; Gonçalves, I.L.; Grazziotin, N.A. Candida species distribution and fluconazole susceptibility of blood isolates at a regional hospital in Passo Fundo, RS, Brazil. J. Bras. Patol. Med. Lab., 2015, 51(3), 158-161.
[http://dx.doi.org/10.5935/1676-2444.20150027]
[11]
Brown, E.D.; Wright, G.D. New targets and screening approaches in antimicrobial drug discovery. Chem. Rev., 2005, 105(2), 759-774.
[http://dx.doi.org/10.1021/cr030116o] [PMID: 15700964]
[12]
Perkins, A.; Gomez-Lopez, A.; Mellado, E.; Rodriguez-Tudela, J.L.; Cuenca-Estrella, M. Rates of antifungal resistance among Spanish clinical isolates of Cryptococcus neoformans var. neoformans. J. Antimicrob. Chemother., 2005, 56(6), 1144-1147.
[http://dx.doi.org/10.1093/jac/dki393] [PMID: 16282208]
[13]
Pfaller, M.A.; Messer, S.A.; Boyken, L.; Rice, C.; Tendolkar, S.; Hollis, R.J.; Doern, G.V.; Diekema, D.J. Global trends in the antifungal susceptibility of Cryptococcus neoformans (1990 to 2004). J. Clin. Microbiol., 2005, 43(5), 2163-2167.
[http://dx.doi.org/10.1128/JCM.43.5.2163-2167.2005] [PMID: 15872236]
[14]
Pfaller, M.A.; Diekema, D.J. Epidemiology of invasive candidiasis: A persistent public health problem. Clin. Microbiol. Rev., 2007, 20(1), 133-163.
[http://dx.doi.org/10.1128/CMR.00029-06] [PMID: 17223626]
[15]
Canto, R.F.; Bernardi, A.; Battastini, A.M.O.; Russowsky, D.; Eifler-Lima, V.L. Synthesis of dihydropyrimidin-2-one/thione library and cytotoxic activity against the human U138-MG and Rat C6 glioma cell lines. J. Braz. Chem. Soc., 2011, 22(7), 1379-1388.
[http://dx.doi.org/10.1590/S0103-50532011000700025]
[16]
Trpković, A.; Pekmezović, M.; Barać, A.; Crnčević Radović, L.; Arsić Arsenijević, V. vitro antifungal activities of amphotericin B, 5-fluorocytosine, fluconazole and itraconazole against Cryptococcus neoformans isolated from cerebrospinal fluid and blood from patients in Serbia. J. Med. Mycol., 2012, 22(3), 243-248.
[17]
May, R.C.; Stone, N.R.; Wiesner, D.L.; Bicanic, T.; Nielsen, K. Cryptococcus: From environmental saprophyte to global pathogen. Nat. Rev. Microbiol., 2016, 14(2), 106-117.
[http://dx.doi.org/10.1038/nrmicro.2015.6] [PMID: 26685750]
[18]
Cordeiro, Rde. A.; Nogueira, G.C.; Brilhante, R.S.N.; Teixeira, C.E.C.; Mourão, C.I.; Castelo-Branco, Dde.S.; Paiva, Mde.A.; Ribeiro, J.F.; Monteiro, A.J.; Sidrim, J.J.C.; Rocha, M.F. Farnesol inhibits in vitro growth of the Cryptococcus neoformans species complex with no significant changes in virulence-related exoenzymes. Vet. Microbiol., 2012, 159(3-4), 375-380.
[http://dx.doi.org/10.1016/j.vetmic.2012.04.008] [PMID: 22580194]
[19]
Alexander, B.D. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts, 4th Ed; Wayne, Pennsylvania, USA, 2008.
[20]
Ernst, E.J.; Roling, E.E.; Petzold, C.R.; Keele, D.J.; Klepser, M.E. In vitro activity of micafungin (FK-463) against Candida spp.: microdilution, time-kill, and postantifungal-effect studies. Antimicrob. Agents Chemother., 2002, 46(12), 3846-3853.
[http://dx.doi.org/10.1128/AAC.46.12.3846-3853.2002] [PMID: 12435687]
[21]
Voda, K.; Boh, B.; Vrtačnik, M. A quantitative structure-antifungal activity relationship study of oxygenated aromatic essential oil compounds using data structuring and PLS regression analysis. J. Mol. Model., 2004, 10(1), 76-84.
[http://dx.doi.org/10.1007/s00894-003-0174-5] [PMID: 14689256]
[22]
Lipinski, C.A. Lead- and drug-like compounds: The rule-of-five revolution. Drug Discov. Today. Technol., 2004, 1(4), 337-341.
[http://dx.doi.org/10.1016/j.ddtec.2004.11.007] [PMID: 24981612]
[23]
Stuepp, C.S.; Figueiró, F.; Mendes, F.B.; Braganhol, E.; Bernardi, A.; Frozza, R.L.; Salbego, C.G.; Canto, R.F.; Russowsky, D.; Eifler-Lima, V.L.; Battastini, A.M. Activity of LaSOM 65, a monastrol-derived compound, against Glioblastoma multiforme cell lines. Anticancer Res., 2013, 33(10), 4463-4468.
[PMID: 24123016]
[24]
Torres, B.G. Uchôa, Fde.T.; Pigatto, M.C.; Azeredo, F.J.; Haas, S.E.; Dallegrave, E.; Canto, R.F.; Eifler-Lima, V.L.; Dalla Costa, T. Pre-clinical pharmacokinetics and acute toxicological evaluation of a monastrol derivative anticancer candidate LaSOM 65 in rats. Xenobiotica, 2014, 44(3), 254-263.
[http://dx.doi.org/10.3109/00498254.2013.822131] [PMID: 23937080]


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Article Details

VOLUME: 15
ISSUE: 6
Year: 2019
Page: [648 - 655]
Pages: 8
DOI: 10.2174/1573407214666180926115745
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