title: Design, Synthesis and Antifungal Activity Evaluation of New Thiazolin-4-ones as Potential Lanosterol 14α-Demethylase Inhibitors.
abstract: Twenty-three thiazolin-4-ones were synthesized starting from phenylthioamide or thiourea derivatives by condensation with α-monochloroacetic acid or ethyl α-bromoacetate, followed by substitution in position 5 with various arylidene moieties. All the synthesized compounds were physico-chemically characterized and the IR (infrared spectra), ¹H NMR (proton nuclear magnetic resonance),13C NMR (carbon nuclear magnetic resonance) and MS (mass spectrometry) data were consistent with the assigned structures. The synthesized thiazolin-4-one derivatives were tested for antifungal properties against several strains ofCandidaand all compounds exhibited efficient anti-Candidaactivity, two of them (9band10) being over 500-fold more active than fluconazole. Furthermore, the compounds' lipophilicity was assessed and the compounds were subjected to in silico screening for prediction of their ADME-Tox properties (absorbtion, distribution, metabolism, excretion and toxicity). Molecular docking studies were performed to investigate the mode of action towards the fungal lanosterol 14α-demethylase, a cytochrome P450-dependent enzyme. The results of the in vitro antifungal activity screening, docking study and ADME-Tox prediction revealed that the synthesized compounds are potential anti-Candidaagents that might act by inhibiting the fungal lanosterol 14α-demethylase and can be further optimized and developed as lead compounds.
authors.affiliation: Department of Pharmaceutical Chemistry, "Iuliu Hațieganu" University of Medicine and Pharmacy, 41 Victor Babeș Street, RO-400012 Cluj-Napoca, Romania. teodora_anca@yahoo.com.
authors.forename: Anca
authors.initials: A
authors.lastname: Stana
authors.affiliation: Department of Food Science and Technology, University of Agricultural Sciences and Veterinary Medicine, 3-5 Manăştur Street, RO-400372 Cluj-Napoca, Romania. dan.vodnar@usamvcluj.ro.
authors.forename: Dan C
authors.initials: DC
authors.lastname: Vodnar
authors.affiliation: National Institute for Research and Development for Cryogenic and Isotopic Technologies, 4th Uzinei Street, RO-240050 Râmnicu Vâlcea, Romania. radu.tamaian@icsi.ro.|SC Biotech Corp SRL, 4th Uzinei Street, RO-240050 Râmnicu Vâlcea, Romania. radu.tamaian@icsi.ro.
authors.forename: Radu
authors.initials: R
authors.lastname: Tamaian
authors.affiliation: National Institute for Research and Development of Isotopic and Molecular Technologies, RO-400293 Cluj-Napoca, Romania. adrian.pirnau@itim-cj.ro.
authors.forename: Adrian
authors.initials: A
authors.lastname: Pîrnău
authors.affiliation: Department of Pharmaceutical Technology and Biopharmaceutics, "Iuliu Hațieganu" University of Medicine and Pharmacy, 41 Victor Babeș Street, RO-400012 Cluj-Napoca, Romania. vlaselaur@yahoo.com.
authors.forename: Laurian
authors.initials: L
authors.lastname: Vlase
authors.affiliation: Department of Pharmaceutical Chemistry, "Iuliu Hațieganu" University of Medicine and Pharmacy, 41 Victor Babeș Street, RO-400012 Cluj-Napoca, Romania. ionut.ioana@umfcluj.ro.
authors.forename: Ioana
authors.initials: I
authors.lastname: Ionuț
authors.affiliation: Department of Pharmaceutical Chemistry, "Iuliu Hațieganu" University of Medicine and Pharmacy, 41 Victor Babeș Street, RO-400012 Cluj-Napoca, Romania. onigao65@yahoo.com.
authors.forename: Ovidiu
authors.initials: O
authors.lastname: Oniga
authors.affiliation: Department of Pharmaceutical Chemistry, "Iuliu Hațieganu" University of Medicine and Pharmacy, 41 Victor Babeș Street, RO-400012 Cluj-Napoca, Romania. brandu32@yahoo.com.
authors.forename: Brînduşa
authors.initials: B
authors.lastname: Tiperciuc
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002175:Candida / Q000145:classification / Q000187:drug effects / Q000254:growth & development; D015195:Drug Design; D005656:Fungal Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008826:Microbial Sensitivity Tests; D008956:Models, Chemical; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011485:Protein Binding; D000072417:Protein Domains; D013055:Spectrophotometry, Infrared; D058886:Sterol 14-Demethylase / Q000737:chemistry / Q000378:metabolism; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D058888:14-alpha Demethylase Inhibitors; D000935:Antifungal Agents; D005656:Fungal Proteins; D013844:Thiazoles; D058886:Sterol 14-Demethylase
keywords: ADME-Tox predictors; antifungal activity; lanosterol 14α-demethylase; lipophilicity; molecular docking; thiazolin-4-one