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    Antibacterial azole derivatives: Antibacterial activity, cytotoxicity, and in silico mechanistic studies
    (Wiley, 2020) Sari, Suat; Avci, Ahmet; Kocak, Ebru; Kart, Didem; Sabuncuoglu, Suna; Dogan, Inci Selin; Ozdemir, Zeynep
    Azole antifungal drugs are commonly used in antifungal chemotherapy. Antibacterial effects of some topical antifungals, such as miconazole and econazole, have lately been revealed, which suggests a promising venue in antimicrobial chemotherapy. In this study, we tested an in-house azole collection with antifungal properties for their antibacterial activity to identify dual-acting hits using the broth microdilution method. The in vitro screen yielded a number of potent derivatives against gram-positive bacteria,Enterococcus faecalisandStaphylococcus aureus.Compound73's minimum inhibitory concentration (MIC) value less than 1 mu g/ml againstS. aureus; however, none of the compounds showed noteworthy activity against methicillin-resistantS. aureus(MRSA). All the active compounds were found safe at their MIC values against the healthy fibroblast cells in the in vitro cytotoxicity test. Molecular docking studies of the most active compounds using a set of docking programs with flavohemoglobin (flavoHb) structure, the proposed target of the azole antifungals with antibacterial activity, presented striking similarities regarding the binding modes and interactions between the tested compounds and the antifungal drugs with crystallographic data. In addition to being noncytotoxic, the library was predicted to be drug-like and free of pan-assay interference compounds (PAINS). As a result, the current study revealed several potential azole derivatives with both antifungal and antibacterial activities. Inhibition of bacterial flavoHb was suggested as a possible mechanism of action for the title compounds.
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    Azole derivatives with naphthalene showing potent antifungal effects against planktonic and biofilm forms ofCandidaspp.: an in vitro and in silico study
    (Springer, 2021) Sari, Suat; Kocak, Ebru; Kart, Didem; Ozdemir, Zeynep; Acar, M. Fahir; Sayoglu, Burcu; Karakurt, Arzu
    Candidainfections pose a serious public health threat due to increasing drug resistance. Azoles are first-line antifungal drugs for fungal infections. In this study, we tested an in-house azole collection incorporating naphthalene ring to find hits against planktonic and biofilm forms of resistantCandidaspp. In the collection, potent derivatives were identified against the susceptible strains ofCandidawith minimum inhibitory concentration (MIC) values lower than those of the reference drug, fluconazole. MIC values of 0.125 mu g/ml againstC. albicans, 0.0625 mu g/ml againstC. parapsilosis, and 2 mu g/ml againstC. krusei, an intrinsically azole-resistant non-albicans Candida, were obtained. Some of the derivatives were highly active against fluconazole-resistant clinical isolate ofC. tropicalis. Inhibition ofC. albicansbiofilms was also observed at 4 mu g/ml similar as amphotericin B, the reference drug known for its antibiofilm activity. Through molecular docking studies, affinities and key interactions of the compounds with fungal lanosterol 14 alpha-demethylase (CYP51), the target enzyme of azoles, were predicted. The interactions of imidazole with heme cofactor and of the naphthalene with Tyr118 were highlighted in line with the literature data. As a result, this study proves the importance of naphthalene for the antifungal activity of azoles againstCandidaspp. in both planktonic and biofilm forms.