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Small-Molecule Inhibitors Targeting Sterol 14 alpha-Demethylase (CYP51): Synthesis, Molecular Modelling and Evaluation AgainstCandida albicans

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dc.contributor.authorTATAR, ESRA
dc.contributor.authorsBinjubair, Faizah A.; Parker, Josie E.; Warrilow, Andrew G.; Puri, Kalika; Braidley, Peter J.; Tatar, Esra; Kelly, Steven L.; Kelly, Diane E.; Simons, Claire
dc.date.accessioned2022-03-14T09:19:42Z
dc.date.available2022-03-14T09:19:42Z
dc.date.issued2020-07-20
dc.description.abstractFungal infections are a global issue affecting over 150 million people worldwide annually, with 750 000 of these caused by invasiveCandidainfections. Azole drugs are the frontline treatment against fungal infections; however, resistance to current azole antifungals inC. albicansposes a threat to public health. Two series of novel azole derivatives, short and extended derivatives, have been designed, synthesised and investigated for CYP51 inhibitory activity, binding affinity and minimum inhibitory concentration (MIC) againstC. albicansstrains. The short derivatives were more potent against theC. albicansstrains (e. g., MIC 2-(4-chlorophenyl)-N-(2,4-dichlorobenzyl)-3-(1H-imidazol-1-yl)propanamide (5 f) <0.03 mu g/mL,N-(4-((4-chlorophenyl)sulfonamido)benzyl)-2-phenyl-3-(1H-1,2,4-triazol-1-yl)propanamide (12 c), 1 mu g/mL, fluconazole 0.125 mu g/mL) but both displayed comparable enzyme binding and inhibition (5 fK(d)62 +/- 17 nM, IC(50)0.46 mu M;12 cK(d)43 +/- 18 nM, IC(50)0.33 mu M, fluconazoleK(d)41 +/- 13 nM, IC(50)0.31 mu M, posaconazoleK(d)43 +/- 11 nM, IC(50)0.2 mu M). The short series had poor selectivity for CaCYP51 over the human homologue, whereas the selectivity of the extended series, for example, compound12 c, was higher (21.5-fold) than posaconazole (4.7-fold) based onK(d)values, although posaconazole was more selective (615-fold) than12 c(461-fold) based on IC(50)values. Based on inhibitory activity and selectivity profile, the extended series are the better of the two series for further development.
dc.identifier.doi10.1002/cmdc.202000250
dc.identifier.eissn1860-7187
dc.identifier.issn1860-7179
dc.identifier.pubmed32459374
dc.identifier.urihttps://hdl.handle.net/11424/242968
dc.identifier.wosWOS:000541474100001
dc.language.isoeng
dc.publisherWILEY-V C H VERLAG GMBH
dc.relation.ispartofCHEMMEDCHEM
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectantifungal agents
dc.subjectazoles
dc.subjectCandida albicans
dc.subjectCYP51
dc.subjectdrug design
dc.subjectmolecular dynamics
dc.subjectCANDIDA-ALBICANS
dc.subjectAZOLE RESISTANCE
dc.subjectINVASIVE CANDIDIASIS
dc.subjectANTIFUNGALS
dc.subjectMUTATIONS
dc.subjectVT-1161
dc.subjectPOTENT
dc.subjectERG11
dc.titleSmall-Molecule Inhibitors Targeting Sterol 14 alpha-Demethylase (CYP51): Synthesis, Molecular Modelling and Evaluation AgainstCandida albicans
dc.typearticle
dspace.entity.typePublication
local.avesis.idba83da77-d693-4c21-9084-884f560ad586
local.import.packageSS16
local.indexed.atWOS
local.indexed.atSCOPUS
local.indexed.atPUBMED
local.journal.numberofpages16
local.journal.quartileQ2
oaire.citation.endPage1309
oaire.citation.issue14
oaire.citation.startPage1294
oaire.citation.titleCHEMMEDCHEM
oaire.citation.volume15
relation.isAuthorOfPublicatione2c939bf-1387-4174-802c-e714419b20af
relation.isAuthorOfPublication.latestForDiscoverye2c939bf-1387-4174-802c-e714419b20af

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