Abstract
In a drug-repurposing-driven approach for speeding up the development of novel antimicrobial agents, this paper presents for the first time in the scientific literature the synthesis, physico-chemical characterization, in silico analysis, antimicrobial activity against bacterial and fungal strains in planktonic and biofilm growth state, as well as the in vitro cytotoxicity of some new 6,11-dihydrodibenz[b,e]oxepin-11(6H)one O-(arylcarbamoyl)oximes. The structures of intermediary and final substances (compounds 7a–j) were confirmed by 1H-NMR, 13C-NMR and IR spectra, as well as by elemental analysis. The in silico bioinformatic and cheminformatic studies evidenced an optimal pharmacokinetic profile for the synthesized compounds 7a–j, characterized by an average lipophilic character predicting good cell membrane permeability and intestinal absorption; low maximum tolerated dose for humans; potassium channels encoded by the hERG I and II genes as potential targets and no carcinogenic effects. The obtained compounds exhibited a higher antimicrobial activity against the planktonic Gram-positive Staphylococcus aureus and Bacillus subtilis strains and the Candida albicans fungal strain. The obtained compounds also inhibited the ability of S. aureus, B. subtilis, Escherichia coli and C. albicans strains to colonize the inert substratum, accounting for their possible use as antibiofilm agents. All the active compounds exhibited low or acceptable cytotoxicity levels on the HCT8 cells, ensuring the potential use of these compounds for the development of new antimicrobial drugs with minimal side effects on the human cells and tissues.
Highlights
Antibiotics represent one of the most important therapeutic discoveries in medical history, having contributed to reduce the mortality and morbidity caused by infectious diseases
This paper presents the synthesis, physico-chemical characterization, in silico analysis, antimicrobial activity against bacterial and fungal strains in planktonic and biofilm growth state, as well as the in vitro cytotoxicity of new 6,11-dihydro-dibenz[b,e]oxepin-11(6H)one O-(arylcarbamoyl)oximes
In a drug-repurposing-driven approach for speeding up the development of novel antimicrobial agents, this paper presents for the first time in the scientific literature the synthesis, physico-chemical characterization, in silico analysis, antimicrobial activity against bacterial and fungal strains in planktonic and biofilm growth state, as well as the in vitro cytotoxicity of new
Summary
Antibiotics represent one of the most important therapeutic discoveries in medical history, having contributed to reduce the mortality and morbidity caused by infectious diseases. They are an essential tool for modern medicine, making possible common life-saving procedures such as transplantation, chemotherapy of cancer and surgery. Antibiotics have been liable to misuse, leading to the emergence and selection of resistant microorganisms. Antibiotic resistance is one of the biggest public health challenges of our time, being responsible each year of at least 2 million cases of infection and at least 23,000 deaths in USA. In some alarming prediction models, not generally accepted and currently debated [2], the number of deaths caused by AR microorganisms threatens to reach up to 10 million by 2050 and the economic loses associated to AR are estimated at 100 trillion USD [3]
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