Synthesis and anti-Candida activity of novel benzothiepino[3,2-c]pyridine derivatives.
A novel series of thiepine derivatives were synthesized and evaluated as potential antimicrobials. All the synthesized compounds were evaluated for their antimicrobial activities in vitro against the fungi Candida albicans (ATCC 10231), C. parapsilosis (clinical isolate), Gram-negative bacterium Pseudomonas aeruginosa (ATCC 44752), and Gram-positive bacterium Staphylococcus aureus (ATCC 25923). Synthesized compounds showed higher antifungal activity than antibacterial activity, indicating that they could be used as selective antimicrobials. Selected thiepines efficiently inhibited Candida hyphae formation, a trait necessary for their pathogenicity. Thiepine 8-phenyl[1]benzothiepino[3,2-c]pyridine (16) efficiently killed Candida albicans at 15.6 μg/mL and showed no embryotoxicity at 75 μg/mL. Derivative 8-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl][1]benzothiepino[3,2-c]pyridine (23) caused significant hemolysis and in vitro DNA 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 in vivo embryotoxicity on zebrafish (Danio rerio) encourage further structure optimizations.
Faculty of Chemistry, University of Belgrade, Belgrade, Serbia.
Nina
N
Božinović
Institute of Chemistry, Technology, and Metallurgy, University of Belgrade, Belgrade, Serbia.
Sandra
S
Šegan
Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia.
Sandra
S
Vojnovic
Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia.
Aleksandar
A
Pavic
Faculty of Chemistry, University of Belgrade, Belgrade, Serbia. bsolaja@chem.bg.ac.rs.
Bogdan A
BA
Šolaja
Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia. jasmina.nikodinovic@imgge.bg.ac.rs.
Jasmina
J
Nikodinovic-Runic
Faculty of Chemistry, University of Belgrade, Belgrade, Serbia. igorop@chem.bg.ac.rs.
Igor M
IM
Opsenica
D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001582:Benzothiepins / Q000737:chemistry*; D002175:Candida / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D011725:Pyridines / Q000737:chemistry*; D013057:Spectrum Analysis / Q000379:methods; D013211:Staphylococcus aureus / Q000187:drug effects; D015027:Zebrafish
D000935:Antifungal Agents; D001582:Benzothiepins; D011725:Pyridines
Candida sp.; Pd-catalyzed S-arylation; Thiepine; Zebrafish; antifungal