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

Abstract

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.

Facile Synthesis of S‐Fused Multi‐Membered Polycyclic Heterocycles: A Construction Strategy towards Thermally Stable Thiepine Derivatives

“…[ 10 ] Therefore, thiopyran‐ and thiepine‐based heterocycles demonstrate completely different electronic structures and properties as compared with thiophene derivatives. In the past decades, they have been exploited in the fields of medicine, [ 11 ] agricultural pharmacology, [ 12 ] and organic functional materials. [ 13 ] However, in contrast to the abundant synthetic methodologies towards the construction of thiophene‐ fused heteroarenes, [ 14 ] the synthesis of the polycyclic heterocycles containing six‐membered thiopyran and seven‐membered thiepine is much less reported probably owing to their unfavorable…”

Consensus-based comparison of chromatographic and computationally estimated lipophilicity of benzothiepino[3,2-c ]pyridine derivatives as potential antifungal drugs

“…Compound 4 is again selected as the most lipophilic (phenyl substituted thiepine derivative in a position 8). This is also the most active compound against C. albicans strain . The rest of 4‐methoxy substituted phenyl compounds as well as phenyl substituted derivatives in positions 10 and 11 ( 14 , 5 , 6 , 11 , and 12 ) are located in the second group with slightly decreased lipophilicity.…”

“…The synthesis and characterization of the studied compounds were previously reported . The structures of the thiepine derivatives are summarized in Table .…”

“…The most potent derivative against Candida albicans possesses phenyl ring in the position 8 of the thiepine core. The position of the phenyl ring was essential for the antifungal activity, while the electronic effects of the substituents did not have significant influence .…”

Microwave-assisted synthesis of azepines via nucleophilic aromatic substitution

“…However, high temperatures and prolonged reaction times are usually required. 9 In continuation of ongoing studies of biologically active tricyclic heterocycles, 7,8,10 herein the synthesis of 5H-dipyrido [4,3-b:3′,4′-f]azepines using the double S N Ar reaction of 3,3′-(Z)-ethene-1,2-diylbis(4-chloropyridine) with primary aliphatic amines under microwave irradiation is reported.…”