Synthesis and anti‐<i>Candida</i> activity of novel benzothiepino[3,2‐c]pyridine derivatives

<jats:p>A novel series of thiepine derivatives were synthesized and evaluated as potential antimicrobials. All the synthesized compounds were evaluated for their antimicrobial activities <jats:italic>in vitro</jats:italic> against the fungi <jats:italic>Candida albicans</jats:italic> (<jats:styled-content style="fixed-case">ATCC</jats:styled-content> 10231), <jats:italic>C. parapsilosis</jats:italic> (clinical isolate), Gram‐negative bacterium <jats:italic>Pseudomonas aeruginosa</jats:italic> (<jats:styled-content style="fixed-case">ATCC</jats:styled-content> 44752), and Gram‐positive bacterium <jats:italic>Staphylococcus aureus</jats:italic> (<jats:styled-content style="fixed-case">ATCC</jats:styled-content> 25923). Synthesized compounds showed higher antifungal activity than antibacterial activity, indicating that they could be used as selective antimicrobials. Selected thiepines efficiently inhibited <jats:italic>Candida</jats:italic> hyphae formation, a trait necessary for their pathogenicity. Thiepine 8‐phenyl[1]benzothiepino[3,2‐c]pyridine (<jats:bold>16</jats:bold>) efficiently killed <jats:italic>Candida albicans</jats:italic> at 15.6 <jats:italic>μ</jats:italic>g/mL and showed no embryotoxicity at 75 <jats:italic>μ</jats:italic>g/mL. Derivative 8‐[4‐(4,5‐dihydro‐1<jats:italic>H</jats:italic>‐imidazol‐2‐yl)phenyl][1]benzothiepino[3,2‐<jats:italic>c</jats:italic>]pyridine (<jats:bold>23</jats:bold>) caused significant hemolysis and <jats:italic>in vitro </jats:italic><jats:styled-content style="fixed-case">DNA</jats:styled-content> interaction. The position of the phenyl ring was essential for the antifungal activity, while the electronic effects of the substituents did not significantly influence activity. Results obtained from <jats:italic>in vivo</jats:italic> embryotoxicity on zebrafish (<jats:italic>Danio rerio</jats:italic>) encourage further structure optimizations.</jats:p>