2-Acryloyl-4,5-methylenedioxyphenol: A Small Molecule Endowed with Antidermatophytic Activity

Author(s): Marco Zuccolo, Sabrina Dallavalle*, Raffaella Cincinelli, Luce Mattio, Stefania Mazzini, Michelandrea De Cesare, Loana Musso.

Journal Name: Letters in Drug Design & Discovery

Volume 16 , Issue 4 , 2019

Submit Manuscript
Submit Proposal

Graphical Abstract:


Abstract:

Background: Superficial fungal infections are the most common fungal diseases in humans, affecting more than 25% of the population worldwide.

Methods: In the present study, we have investigated the activity of kakuol, a natural compound isolated from the rhizomes of Asarum sieboldii, and some analogues, against various dermatophytes and pharmacologically relevant yeasts.

Results: One of the tested compounds, 2-acryloyl-4,5-methylenedioxyphenol, showed a broadspectrum activity against most of the fungal species assayed, resulting particularly effective against dermatophyte strains (MIC values in the range of 0.25-0.5 µg/mL, two/four-fold lower than the positive control miconazole).

Conclusion: The results suggest that this molecule can be considered a promising starting point for the development of new antifungal compounds.

Keywords: Kakuol, Asarum sieboldii, antifungal agents, Candida albicans, dermatophytes, 3, 4-methylenedioxyphenol.

[1]
Campoy, S.J.; Adrio, J.L. Antifungals. Biochem. Pharmacol., 2016, 133, 86-96.
[2]
Brown, G.D.; Denning, D.W.; Neil, A.R. Gow. N.A.R.; Levitz, S.M.; Netea, M.G.; White, T.C. Hidden Killers: Human Fungal Infections. Sci. Transl. Med., 2012, 4, 165rv13.
[3]
Zahur, M.; Afroz, A.; Rashid, U.; Khaliq, S. Dermatomycoses: Challenges and Human Immune Responses. Curr. Protein Pept. Sci., 2014, 15, 437-444.
[4]
Pfaller, M.A.; Rhomberg, P.R.; Messer, S.A.; Jones, R.N.; Castanheira, M. Isavuconazole, micafungin, and 8 comparator antifungal agents’ susceptibility profiles for common and uncommon opportunistic fungi collected in 2013: Temporal analysis of antifungal drug resistance using CLSI species-specific clinical breakpoints and proposed epidemiological cutoff values. Diagn. Microbiol. Infect. Dis., 2015, 82, 303-313.
[5]
Pianalto, K.M.; Alspaugh, J.A. New horizons in antifungal therapy. J. Fungi , 2016, 2, 1-24.
[6]
Perfect, J.R. Is there an emerging need for new antifungals? Expert Opin. Emerg. Drugs, 2016, 21, 129-131.
[7]
Newman, D.J.; Cragg, G.M. Natural Products as Sources of New Drugs from 1981 to 2014. J. Nat. Prod., 2016, 79, 629-661.
[8]
Lee, J.Y.; Moon, S.S.; Hwang, B.K. Isolation and antifungal activity of kakuol, a propiophenone derivative from Asarum sieboldii rhizome. Pest Manag. Sci., 2005, 61, 821-825.
[9]
Musso, L.; Dallavalle, S.; Merlini, L.; Farina, G. Synthesis and antifungal activity of 2-Hydroxy-4,5-methylenedioxyaryl ketones as analogues of kakuol. Chem. Biodivers., 2007, 7, 887-897.
[10]
Rodriguez-Tudela, J.L.; Barchiesi, F.; Bille, J.; Chryssanthou, E.; Cuenca-Estrella, M.; Denning, D.; Donnelly, J.P.; Dupont, B.; Fegeler, W.; Moore, C.; Richardson, M.; Verweij, P.E. Method for the determination of Minimum Inhibitory Concentration (MIC) by broth dilution of fermentative yeasts European Committee for Antimicrobial Susceptibility Testing (EUCAST). Clin. Microbiol. Infect., 2003, 9, 1-8.
[11]
da Silva Barros, M.E.; de Assis Santos, D.; Hamdan, J.S. In vitro methods for antifungal susceptibility testing of Trichophyton spp. Mycol. Res., 2006, 110, 1355-1360.
[12]
Amslinger, S. The Tunable Functionality of α, β-Unsaturated carbonyl compounds enables their differential application in biological systems. ChemMedChem, 2010, 5, 351-356.
[13]
Singh, J.; Petter, R.C.; Baillie, T.A.; Whitty, A. The resurgence of covalent drugs. Nat. Rev. Drug Discov., 2011, 10, 307-317.
[14]
Avonto, C.; Taglialatela-Scafati, O.; Pollastro, F.; Minassi, A.; Di Marzo, V.; De Petrocelli, L.; Appendino, G. An NMR spectroscopic method to identify and classify thiol-trapping agents: Revival of michael acceptors for drug discovery? Angew. Chem. Int. Ed., 2011, 50, 467-471.
[15]
Pouliot, M.; Jeanmart, S. Pan assay interference compounds (PAINS) and other promiscuous compounds in antifungal research. J. Med. Chem., 2016, 59, 497-503.
[16]
Backus, K.M.; Correia, B.E.; Lum, K.M.; Forli, S.; Horning, B.D.; Gonzalez-Paez, G.E.; Chatterjee, S.; Lanning, B.R.; Teijaro, J.R.; Olson, A.J.; Wolan, D.W.; Cravatt, B.F. Proteome-wide covalent ligand discovery in native biological systems. Nature, 2016, 534, 570-574.
[17]
Plettenburg, O. What do reactive fragments actually do in cells? Angew. Chem. Int. Ed., 2017, 56, 446-448.
[18]
Kathman, S.G.; Xu, Z.; Statsyuk, A.V. A fragment-based method to discover irreversible covalent inhibitors of cysteine proteases. J. Med. Chem., 2014, 57, 4969-4974.
[19]
Jöst, C.; Nitsche, C.; Scholz, T.; Roux, L.; Klein, C.D. Promiscuity and selectivity in covalent enzyme inhibition: A systematic study of electrophilic fragments. J. Med. Chem., 2014, 57, 7590-7599.
[20]
Kathman, S.G.; Statsyuk, A.V. Covalent tethering of fragments for covalent probe discovery. MedChemComm, 2016, 7, 576-585.
[21]
Miller, R.M.; Paavilainen, V.O.; Krishnan, S.; Serafimova, I.M.; Taunton, J. Electrophilic fragment-based design of reversible covalent kinase inhibitors. J. Am. Chem. Soc., 2013, 135, 5298-5301.


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 16
ISSUE: 4
Year: 2019
Page: [461 - 466]
Pages: 6
DOI: 10.2174/1570180815666180803115347
Price: $58

Article Metrics

PDF: 17
HTML: 2