{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:39:53Z","timestamp":1790836793148,"version":"4.1.0"},"reference-count":52,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2013,1,10]],"date-time":"2013-01-10T00:00:00Z","timestamp":1357776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The increased incidence of opportunistic fungal infections, associated with greater resistance to the antifungal drugs currently in use has highlighted the need for new solutions. In this study twenty four coumarin derivatives were screened in vitro for antifungal activity against strains of Aspergillus. Some of the compounds exhibited significant antifungal activity with MICs values ranging between 16 and 32 \u00b5g\/mL. The structure-activity relationships (SAR) study demonstrated that O-substitutions are essential for antifungal activity. It also showed that the presence of a short aliphatic chain and\/or electron withdrawing groups (NO2 and\/or acetate) favor activity. These findings were confirmed using density functional theory (DFT), when calculating the LUMO density. In Principal Component Analysis (PCA), two significant principal components (PCs) explained more than 60% of the total variance. The best Partial Least Squares Regression (PLS) model showed an r2 of 0.86 and q2cv of 0.64 corroborating the SAR observations as well as demonstrating a greater probe N1 interaction for active compounds. Descriptors generated by TIP correlogram demonstrated the importance of the molecular shape for antifungal activity.<\/jats:p>","DOI":"10.3390\/ijms14011293","type":"journal-article","created":{"date-parts":[[2013,1,10]],"date-time":"2013-01-10T13:51:26Z","timestamp":1357825886000},"page":"1293-1309","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Synthesis, Structure-Activity Relationships (SAR) and in Silico Studies of Coumarin Derivatives with Antifungal Activity"],"prefix":"10.3390","volume":"14","author":[{"given":"Rodrigo","family":"De Ara\u00fajo","sequence":"first","affiliation":[{"name":"Pharmaceutical Science Department, Federal University of Para\u00edba, Jo\u00e3o Pessoa 58051-900, PB, Brazil"},{"name":"Laboratory of Synthesis and Drug Delivery, Biological Science Department, State University of Para\u00edba, Jo\u00e3o Pessoa 58020-540, PB, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felipe","family":"Guerra","sequence":"additional","affiliation":[{"name":"Pharmaceutical Science Department, Federal University of Para\u00edba, Jo\u00e3o Pessoa 58051-900, PB, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edeltrudes","family":"De O. Lima","sequence":"additional","affiliation":[{"name":"Pharmaceutical Science Department, Federal University of Para\u00edba, Jo\u00e3o Pessoa 58051-900, PB, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"De Simone","sequence":"additional","affiliation":[{"name":"Department of Physics and Informatics, Physical Institute of S\u00e3o Carlos, University of S\u00e3o Paulo, S\u00e3o Carlos 13560-970, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josean","family":"Tavares","sequence":"additional","affiliation":[{"name":"Pharmaceutical Science Department, Federal University of Para\u00edba, Jo\u00e3o Pessoa 58051-900, PB, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1866-4107","authenticated-orcid":false,"given":"Luciana","family":"Scotti","sequence":"additional","affiliation":[{"name":"Laboratory of Synthesis and Drug Delivery, Biological Science Department, State University of Para\u00edba, Jo\u00e3o Pessoa 58020-540, PB, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4863-8057","authenticated-orcid":false,"given":"Marcus","family":"Scotti","sequence":"additional","affiliation":[{"name":"Engineering and Environment Department, Federal University of Para\u00edba, Campus IV, Rio Tinto 58297-000, PB, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thiago","family":"De Aquino","sequence":"additional","affiliation":[{"name":"Institute of Chemistry and Biotechnology, Federal University of Alagoas, Macei\u00f3 57072-970, AL, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"De Moura","sequence":"additional","affiliation":[{"name":"Laboratory of Synthesis and Drug Delivery, Biological Science Department, State University of Para\u00edba, Jo\u00e3o Pessoa 58020-540, PB, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3588-833X","authenticated-orcid":false,"given":"Francisco","family":"Mendon\u00e7a","sequence":"additional","affiliation":[{"name":"Laboratory of Synthesis and Drug Delivery, Biological Science Department, State University of Para\u00edba, Jo\u00e3o Pessoa 58020-540, PB, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Barbosa-Filho","sequence":"additional","affiliation":[{"name":"Pharmaceutical Science Department, Federal University of Para\u00edba, Jo\u00e3o Pessoa 58051-900, PB, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2013,1,10]]},"reference":[{"key":"ref_1","first-page":"1492","article-title":"Synthesis and evaluation of the antifungal activity of 2-(substituted-amino)-4,5-dialkyl-thiophene-3-carbonitrile derivatives","volume":"30","author":"Oliveira","year":"2011","journal-title":"Lat. Am. J. Pharm"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.tim.2006.06.005","article-title":"Tools to study molecular mechanisms of Aspergillus pathogenicity","volume":"14","author":"Krappmann","year":"2006","journal-title":"Trends Microbiol"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1099\/mic.0.2007\/007641-0","article-title":"Aspergillus flavus: Human pathogen, aleergen and mycotoxin producer","volume":"153","author":"Hedayati","year":"2007","journal-title":"Microbiology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1016\/j.fitote.2011.08.011","article-title":"HPLC quantification of coumarin in bastard balm (Melittis melissophyllum L., Lamiaceae)","volume":"82","author":"Maggi","year":"2011","journal-title":"Fitoterapia"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9245","DOI":"10.3390\/molecules17089245","article-title":"3-Phenylcoumarins as inhibitors of HIV-1 replication","volume":"17","author":"Olmedo","year":"2012","journal-title":"Molecules"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/S1665-2681(19)31530-3","article-title":"Citrus auraptene: A potential multifunctional therapeutic agent for nonalcoholic fatty liver disease","volume":"10","author":"Sahebkar","year":"2011","journal-title":"Ann. Hepatol"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.niox.2011.02.003","article-title":"Development of a quantitative bioassay to assess preventive compounds against inflammation-based carcinogenesis","volume":"25","author":"Onuma","year":"2011","journal-title":"Nitric Oxide"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"9321","DOI":"10.3390\/molecules17089321","article-title":"Synthesis and characterization of new thiazolidinones containing coumarin moieties and their antibacterial and antioxidant activities","volume":"17","author":"Hamdi","year":"2012","journal-title":"Molecules"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1080\/10426500500536523","article-title":"The behavior of certain coumarins and furanocoumarins toward sulfur reagents","volume":"181","author":"Ibrahim","year":"2006","journal-title":"Phosphorus Sulfur"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"11010","DOI":"10.3390\/molecules170911010","article-title":"Novel coumarin derivatives containing 1,2,4-triazole, 4,5-dicyanoimidazole and purine moieties: Synthesis and evaluation of their cytostatic activity","volume":"17","author":"Benci","year":"2012","journal-title":"Molecules"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4294","DOI":"10.3390\/molecules15064294","article-title":"Design of novel 4-hydroxy-chromene-2-one derivatives as antimicrobial agents","volume":"15","author":"Sukdolak","year":"2010","journal-title":"Molecules"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1590\/S1517-83822011000300027","article-title":"Antifungal activity of five species of Polygala","volume":"42","author":"Johann","year":"2011","journal-title":"Braz. J. Microbiol"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1002\/ps.891","article-title":"Screening study for potential lead compounds for natural product-based fungicides: I. Synthesis and in vitro evaluation of coumarins against Botrytis cinerea","volume":"60","author":"Daoubi","year":"2004","journal-title":"Pest Manag. Sci"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1515\/znc-2005-1-216","article-title":"Morning glory systematically accumulates scopoletin and scopolin after interaction with Fusariumoxysporum","volume":"60","author":"Shimizu","year":"2005","journal-title":"Z. Naturforsch"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1016\/j.poly.2005.03.006","article-title":"Synthesis and antimicrobial activity of copper(II) and silver(I) complexes of hydroxyl-nitrocoumarins: X-ray crystal structures of [Cu(hnc)2(H2O)2]\u00b72H2O and [Ag(hnc)] (hnc = 4-hydroxy-3-nitro-2H-chromen-2-one)","volume":"24","author":"Creaven","year":"2005","journal-title":"Polyhedron"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2965","DOI":"10.1016\/S0031-9422(00)97333-3","article-title":"Antimicrobial properties of umbelliferone derivatives","volume":"10","author":"Jurd","year":"1971","journal-title":"Phytochemistry"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2971","DOI":"10.1016\/S0031-9422(00)97334-5","article-title":"Antimicrobial properties of 6,7-dihydroxy-, 7,8-dihydroxy-, 6-hydroxy- and 8-hydroxycoumarins","volume":"10","author":"Jurd","year":"1971","journal-title":"Phytochemistry"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2298","DOI":"10.3390\/molecules17032298","article-title":"Experimental methodologies and evaluations of computer-aided drug design methodologies applied to a series of 2-aminothiophene derivatives with antifungal activities","volume":"17","author":"Scotti","year":"2012","journal-title":"Molecules"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5882","DOI":"10.3390\/molecules17055882","article-title":"Synthesis of 1,2,3-triazole derivatives and in vitro antifungal evaluation on Candida strains","volume":"17","author":"Cavalcante","year":"2012","journal-title":"Molecules"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1590\/S1517-83822008000100021","article-title":"Effect of Cinnamomum zeylanicum Blume essential oil on the grow and morphogenesis of some potentially pathogenic Aspergillus species","volume":"39","author":"Carmo","year":"2008","journal-title":"Braz. J. Microbiol"},{"key":"ref_21","unstructured":"Beebe, K.R., Pell, R.J., and Seasholtz, M.B. (1998). Chemometrics: A Practical Guide, Wiley."},{"key":"ref_22","unstructured":"Cohen, N.C. (1996). Guidebook on Molecular Modeling in Drug Design, Academic Press."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1002\/smll.201102263","article-title":"Photoresponsive coumarin-stabilized polymeric nanoparticles as a detectable drug carrier","volume":"8","author":"Chung","year":"2012","journal-title":"Small"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.reactfunctpolym.2008.10.006","article-title":"Synthesis and properties of some aromatic polyamides with coumarin chromophores","volume":"69","author":"Nechifor","year":"2009","journal-title":"React. Funct. Polym"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5083","DOI":"10.1021\/jo900613u","article-title":"Total synthesis of (+)-angelmarin","volume":"74","author":"Magolan","year":"2009","journal-title":"J. Org. Chem"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3130","DOI":"10.1016\/j.bmcl.2012.03.057","article-title":"Nelumal A, the active principle from Ligulariane lumbifolia, is a novel farnesoid X receptor agonist","volume":"22","author":"Epifano","year":"2012","journal-title":"Bioorg. Med. Chem. Lett"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1002\/(SICI)1522-2675(19990210)82:2<191::AID-HLCA191>3.0.CO;2-P","article-title":"Geiparvarin analogues: Synthesis and anticancer evaluation of \u03b1-methylidene-\u03b3-butyrolactone-bearing coumarins","volume":"82","author":"Chen","year":"1999","journal-title":"Helv. Chim. Acta"},{"key":"ref_28","unstructured":"Josudong, K. (2010). Trifoliate orange extract with anti-inflammatory activity, with potential anti-inflammatory activity of 7\u2014including Zera Neil oxy coumarin induced Bodies and to include them for the anti-inflammatory drug. (10-2010-0023690), Korean Patent."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1007\/s10886-011-9968-6","article-title":"Antifeedant and termiticidal activities of 6-alkoxycoumarins and related analogs against Coptotermes formosanus Shiraki","volume":"37","author":"Adfa","year":"2011","journal-title":"J. Chem. Ecol"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1134\/S1070428006070244","article-title":"Synthesis on the basis of 2H-chromen-2-one and 2H-chromene-2-thione","volume":"42","author":"Avetisyan","year":"2006","journal-title":"Russ. J. Org. Chem"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6833","DOI":"10.3390\/molecules16086833","article-title":"The use of umbelliferone in the synthesis of new heterocyclic compounds","volume":"16","author":"Musa","year":"2011","journal-title":"Molecules"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1590\/S0100-40422000000200017","article-title":"O efeito do ultra-som em rea\u00e7\u00f5es qu\u00edmicas","volume":"23","author":"Martines","year":"2000","journal-title":"Quim. Nova"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2966","DOI":"10.1021\/jo01271a081","article-title":"5-Aroyl- (or -Acyl-) 4-hydroxycoumarins","volume":"33","author":"Woods","year":"1968","journal-title":"J. Org. Chem"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1080\/00397910601038616","article-title":"Facile total synthesis of xanthoxol","volume":"37","author":"He","year":"2007","journal-title":"Synth. Commun"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.1016\/j.tetlet.2006.02.057","article-title":"Highly efficient nitration of phenolic compounds by zirconyl nitrate","volume":"47","author":"Selvam","year":"2006","journal-title":"Tetrahedron Lett"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1039\/B312641B","article-title":"Electronic properties of Ru(II) complexes bound to a bisphenolate bridge with low lying \u03c0* orbitals","volume":"2","author":"Brady","year":"2004","journal-title":"Dalton Trans"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1016\/j.ejmech.2004.09.007","article-title":"Synthesis, antitumor and antimicrobial activities of new peptidyl derivatives containing the 1,3-benzodioxole system","volume":"39","author":"Leite","year":"2004","journal-title":"Eur. J. Med. Chem"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1081\/SCC-120028628","article-title":"Mono-nitration of coumarin by nitric oxide","volume":"34","author":"Lei","year":"2004","journal-title":"Synth. Commun"},{"key":"ref_39","unstructured":"Sharaf, M.A., Illman, D.L., and Kowalski, B.R. (1986). Chemometrics, John Wiley & Sons."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"221","DOI":"10.2478\/v10007-012-0017-y","article-title":"Preliminary antifungal and citotoxic evaluation of synthetic cycloalkyl[b]thiophene derivatives with PLS-DA analysis","volume":"62","author":"Souza","year":"2012","journal-title":"Acta Pharm"},{"key":"ref_41","unstructured":"Available online: http:\/\/www.moldiscovery.com\/soft_pentacle.php."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3233","DOI":"10.1021\/jm000941m","article-title":"Grid-Independent descriptors (GRIND): A novel class of alignment-independent three-dimensional molecular descriptors","volume":"43","author":"Pastor","year":"2000","journal-title":"Med. Chem"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2204","DOI":"10.1021\/jm990968+","article-title":"Predicting blood-brain barrier permeation from three-dimensional molecular structure","volume":"43","author":"Crivori","year":"2000","journal-title":"J. Med. Chem"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1021\/ci900228x","article-title":"Suitability of GRIND-based principal properties for the description of molecular similarity and ligand-based virtual screening","volume":"49","author":"Zamora","year":"2009","journal-title":"J. Chem. Inf. Model."},{"key":"ref_45","first-page":"337","article-title":"Effects of Citrus sinensis (L.) Osbeckepicarp essential oil on growth and morphogenesis of Aspergillusniger (L.) Van Tieghem","volume":"163","author":"Sahin","year":"2006","journal-title":"Microbiol. Res"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1590\/S1517-83822010000100006","article-title":"Chemical composition and antifungal activity of Hyptissuaveolens (L.) poit leaves essential oil against Aspergillusspecies","volume":"41","author":"Moreira","year":"2010","journal-title":"Braz. J. Microbiol"},{"key":"ref_47","unstructured":"Pereira, F.O. (2009). Atividade antif\u00fangica do \u00f3leo essencial de Cymbopogonwinterianus JowittexBor sobre dermat\u00f3fitos do g\u00eanero Trichophyton. [M.Sc. Thesis, Post-Graduate Program in Natural and Synthetic Bioactive Produts, Federal University of Paraiba]."},{"key":"ref_48","unstructured":"(2009). HyperChem, Version 8.0, Hybercube Inc."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"8127","DOI":"10.1021\/ja00467a001","article-title":"A hydrocarbon force field utilizing V1 and V2 torsional terms","volume":"99","author":"Allinger","year":"1977","journal-title":"J. Am. Chem. Soc"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1002\/jcc.20425","article-title":"RM1: A reparameterization of AM1 for H, C, N, O, P, S, F, Cl, Br and I","volume":"27","author":"Rocha","year":"2006","journal-title":"J. Comput. Chem"},{"key":"ref_51","unstructured":"Leach, A.R. (2001). Molecular Modeling: Principles and Applications, Prentice Hall."},{"key":"ref_52","unstructured":"(2008). Spartan model homepage for windows, Version 8.0, Wavefunction, Inc.. Available online: http:\/\/www.wavefun.com\/products\/windows\/SpartanModel\/win_model.html."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/14\/1\/1293\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:44:11Z","timestamp":1760219051000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/14\/1\/1293"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,1,10]]},"references-count":52,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2013,1]]}},"alternative-id":["ijms14011293"],"URL":"https:\/\/doi.org\/10.3390\/ijms14011293","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,1,10]]}}}