http://www.revistadechimie.ro REV.CHIM.(Bucharest)♦70♦ No. 10 ♦2019 3522 Synthesis, Molecular Docking Studies and Antifungal Activity Evaluation of New Thiazolyl-methylen-1,3,4-oxadiazolines as Potential Lanosterol 14 α-demethylase Inhibitors SMARANDA ONIGA 1 , CATALIN ARANICIU 1 *, GABRIEL MARC 2 , LIVIA UNCU 3,4 , MARIANA PALAGE 1 , OVIDIU ONIGA 2 1 Iuliu Hatieganu University of Medicine and Pharmacy, Faculty of Pharmacy, Department of Therapeutic Chemistry, 12 Ion Creanga Str., 400010 Cluj Napoca, Romania 2 Iuliu Hatieganu University of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 41 Victor Babes Str., 400012, Cluj Napoca, Romania 3 Pharmaceutical Chemistry and Toxicology, Faculty of Pharmacy, Nicolae Testemitanu State University of Medicine and Pharmacy Chisinau, Republic of Moldova 4 Scientific Center of Drug Research, Nicolae Testemitanu State University of Medicine and Pharmacy Chisinau, Republic of Mo ld o va Considering the well-established antifungal activity of azole compounds, a new series of thiazolyl-methylen- 1,3,4-oxadiazolines derivatives were designed and synthesized as lanosterol-demethylase inhibitors. The final compounds were screened for antifungal activity against the Candida albicans ATCC 90028 strain. Molecular docking studies were performed to investigate the interaction modes between the compounds and the active site of lanosterol 14α-demethylase, which is a target enzyme for anticandidal azoles. Theoretical ADME predictions were also calculated for the final compounds 5a-h . Keywords: Thiazolyl-methylen-1,3,4-oxadiazolines, Candida albicans, lanosterol 14α-demethylase Candida species represent the most common fungal pathogens that affect humans and the mortality associated with invasive mycosis increased in the last decade. Candida albicans is among the most diagnosed fungal species in clinical samples. This fungal strain lives as a commensal in the microbiome of healthy individuals, but can propagate as a pathogen in immunocompromised patients [1]. The azoles are the most widely used class of antifungal drugs. These compounds affect the integrity of fungal membranes, altering their morphology and inhibiting growth. This is achieved by inhibiting ergosterol biosynthesis via the inhibition of cytochrome P450’s enzyme 14- α demethylase, which catalyzes the conversion of lanosterol to ergosterol. However, since this enzyme is similar to one found in the human liver, drug interactions due to metabolism can occur [2,3]. Prolonged use of azoles as antifungal agents has resulted in the emergence of drug resistance among certain fungal strains [4]. A novel strategy of generating a new class of azole based antifungal agents is the merger of two or more biologically important azole scaffolds, to achieve a target compound with improved activity [5-7]. To this end we chose two biologically important azole scaffolds: thiazole and 1,3,4-oxadiazole and fused them together into one hybrid molecule taking account that compounds comprising each of these type of azoles are associated with a broad spectrum of biological properties, including antifungal activity [8-14]. Following our research of novel azole based antimicrobial agents [15-17], we propose here the synthesis of some novel thiazolyl-methylen-1,3,4- oxadiazolines derivatives as possible antifungal agents. To investigate the interaction modes between the compounds and active site of lanosterol 14-5 α-demethylase, a molecular docking study was performed. Experimental part Chemistry Melting points were determined using open capillary tube method and are uncorrected. The purity of the synthesized compounds was verified by thin layer chromatography (TLC) and was carried out on pre-coated Silica Gel 60F254 sheets using heptan–ethyl-acetate 7:3 as developpant and UV absorption for visualization. The 1 H NMR spectra were recorded at room temperature on a Bruker Avance NMR spectrometer operating at 500 MHz. Chemical shift values were reported relative to tetramethylsilane (TMS) as internal standard. The samples were prepared by dissolving the synthesized powder of the compounds in DMSO d6 ( δH= 2.51ppm) as solvent and the spectra were recorded using a single excitation pulse of 12µs. GC-MS analyses were performed with an Agilent gas chromatograph 6890 equipped with an apolar Macherey Nagel Permabond SE 52 capillary column. Elemental analysis was registered with a Vario El CHNS instrument. All new compounds yielded spectral data consistent with the proposed structure and microanalysis within 0.4% of the theoretical values . Synthesis of ethyl 2-(aryl)-thiazole-4-yl-acetate (2a-b) - general procedure Compounds 2a-b were synthesized by refluxing a mixture of benzothioamide or 4-methyl-benzothioamide (30 mmol) with ethyl 4-bromo-3-oxobutanoate (30 mmol) in absolute ethanol (30 mL) for 1 h. After cooling, the mixture was poured in cold water and the oily liquid formed was separated by ether extraction and filtration over anhydrous sodium sulfate. * email: araniciu.catalin@umfcluj.ro