Azoles containing naphthalene with activity against Gram-positive bacteria: in vitro studies and in silico predictions for flavohemoglobin inhibition


SARI S. , SABUNCUOĞLU S. , KOÇAK ASLAN E. , AVCI A. , KART D. , ÖZDEMİR Z., ...More

JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, 2021 (Journal Indexed in SCI) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume:
  • Publication Date: 2021
  • Doi Number: 10.1080/07391102.2021.1940285
  • Title of Journal : JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
  • Keywords: Azole, antibacterial, Staphylococcus aureus, Enterococcus faecalis, flavohemoglobin, cytotoxicity, molecular docking, pharmacophore modeling, ACCURATE DOCKING, DERIVATIVES, ANTICONVULSANT, GLIDE, ANTIBACTERIAL, PROTEIN, MODEL, OXIME

Abstract

Azoles are first-line drugs used in fungal infections. Topical antifungals, such as miconazole and econazole, are known to be active against Gram-positive bacteria, which was reported to result from bacterial flavohemoglobin (flavoHb) inhibition. Dual antibacterial/antifungal action is believed to have benefits for antimicrobial chemotherapy. In this study, we tested antibacterial effects of an in-house library of naphthalene-bearing azoles, some of which were reported as potent antifungals, in an attempt to find dual-acting hits. Several potent derivatives were obtained against the Gram-positive bacteria, Enterococcus faecalis and Staphylococcus aureus. 9 was active at a minimum inhibitor concentration (MIC) less than 1 mu g/ml against E. faecalis and S. aureus, and 10 against S. aureus. 16 was also potent against E. faecalis and S. aureus (MIC = 1 and 2 mu g/ml, respectively). Six more were active against S. aureus with MIC <= 4 mu g/ml. In vitro cytotoxicity studies showed that the active compounds were safe for healthy cells within their MIC ranges. According to the calculated descriptors, the library was found within the drug-like chemical space and free of pan-assay interference compounds (PAINS). Molecular docking studies suggested that the compounds might be bacterial flavohemoglobin (flavoHb) inhibitors and the azole and naphthalene rings were important pharmacophores, which was further supported by pharmacophore modeling study. As a result, the current study presents several non-toxic azole derivatives with antibacterial effects. In addition to their previously reported antifungal properties, they could set a promising starting point for the future design of dual acting antimicrobials. Communicated by Ramaswamy H. Sarma