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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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    Antifungal screening and in silico mechanistic studies of an in-house azole library
    (Wiley, 2019) Sari, Suat; Kart, Didem; Sabuncuoglu, Suna; Dogan, Inci Selin; Ozdemir, Zeynep; Bozbey, Irem; Gencel, Melis
    Systemic Candida infections pose a serious public health problem with high morbidity and mortality. C. albicans is the major pathogen identified in candidiasis; however, non-albicans Candida spp. with antifungal resistance are now more prevalent. Azoles are first-choice antifungal drugs for candidiasis; however, they are ineffective for certain infections caused by the resistant strains. Azoles block ergosterol synthesis by inhibiting fungal CYP51, which leads to disruption of fungal membrane permeability. In this study, we screened for antifungal activity of an in-house azole library of 65 compounds to identify hit matter followed by a molecular modeling study for their CYP51 inhibition mechanism. Antifungal susceptibility tests against standard Candida spp. including C. albicans revealed derivatives 12 and 13 as highly active. Furthermore, they showed potent antibiofilm activity as well as neglectable cytotoxicity in a mouse fibroblast assay. According to molecular docking studies, 12 and 13 have the necessary binding characteristics for effective inhibition of CYP51. Finally, molecular dynamics simulations of the C. albicans CYP51 (CACYP51) homology model's catalytic site complexed with 13 were stable demonstrating excellent binding.
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    Synthesis, anticonvulsant activity, and molecular modeling studies of novel 1-phenyl/1-(4-chlorophenyl)-2-(1H-triazol-1-yl)ethanol ester derivatives
    (Springer Birkhauser, 2018) Dogan, Inci Selin; Ozdemir, Zeynep; Sari, Suat; Bozbey, Irem; Karakurt, Arzu; Sarac, Selma
    A series of new ester derivatives were synthesized by the reaction of various acids with 1-phenyl/1-(4-chlorophenyl)-2-(1H-triazol-1-yl)ethanol and in vivo screened for their anticonvulsant activity. The title compounds were screened against MES and ScM seizure tests according to a modified version of the Epilepsy Therapy Screening Program (ETSP) protocol of the National Institutes of Health (NIH). Their neurotoxic effects were evaluated by the rotarod test. All the compounds showed protection against MES and/or ScM-induced seizures at 30 mg/kg without neurotoxicity. More compounds were found active in the ScM test and at lower dose than the MES test. Physicochemical and pharmacokinetic profiles of the compounds were predicted by QikProp. Using molecular docking approach we tried to get insights into their possible anticonvulsant mechanisms.