Antibacterial azole derivatives: Antibacterial activity, cytotoxicity, and in silico mechanistic studies

SARI S., AVCI A., Kocak E., KART D., SABUNCUOĞLU S., DOĞAN İ. S., ...Daha Fazla

DRUG DEVELOPMENT RESEARCH, cilt.81, sa.8, ss.1026-1036, 2020 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 81 Sayı: 8
  • Basım Tarihi: 2020
  • Doi Numarası: 10.1002/ddr.21721
  • Dergi Adı: DRUG DEVELOPMENT RESEARCH
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Agricultural & Environmental Science Database, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, EMBASE, International Pharmaceutical Abstracts, MEDLINE, Veterinary Science Database
  • Sayfa Sayıları: ss.1026-1036
  • Hacettepe Üniversitesi Adresli: Evet

Özet

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.