Candida albicansis a common human fungal pathogen that causes disease ranging from superficial to lethalinfections.C. albicansgrows as budding yeast which can transform into hyphae in response to various en-vironmentalorbiologicalstimuli.Althoughbothformshavebeenassociatedwithvirulence,thehyphaeformisresponsible for the formation of multi-drug resistance biofilm. Here, new compounds were designed to selec-tivelyinhibitC.albicanshyphaeformationwithoutaffectinghumancellstoaffordsufficientsafety.Thenewlydesigned5-[3-substitued-4-(4-substituedbenzyloxy)-benzylidene]-2-thioxo-thiazolidin-4-onederivatives,namedSR,showedveryspecificandeffectiveinhibitionactivityagainstC.albicanshyphaeformation.SRcompoundscausedhyphaeinhibitionactivityatconcentrations10–40foldlowerthantheconcentrationrequiredtoinhibitCandidayeastandbacterialgrowths.Theanti-hyphaeinhibitionactivitiesofSRcompoundswereviaactivationofthehyphaetranscriptionrepressorgene,TUP1.CorrelationstudiesbetweentheexpressionofTUP1geneandtheactivityofSRcompoundsconfirmedthattheanti-C.albicansactivitiesofSRcompoundswereviainhibitionof hyphae formation. The newly designed SR compounds showed 10–40% haemolytic activity on human ery-throcyteswhencomparedto100%haemolysisby0.1%tritonemployedaspositivecontrol.Furthermore,the-oretical prediction of absorption, distribution,metabolism, excretion,and toxicity (ADMET) of SR compoundsconfirmed their safety, efficient metabolism and possible oral bioavailability. With the minimal toxicity andsignificantactivityofthenewly-designedSRcompounds,afutureoptimizationofpharmaceuticalformulationmay develop a promising inhibitor of hyphal formation not only forC. albicansbut also for otherTUP1- de-pendentdimorphicfungalinfections.