Fused Imidazo[2,1‐b][1,2,3]triazolo[4,5‐d][1,3]thiazines: One‐Pot Synthesis, Antibiofilim, Bactericidal Effects, and in silico Studies

Abstract

AbstractIt has been reported that biologically active organic probe underwent a highly adaptive, efficient and selective “Click followed by C−N bond coupling” by the use of PEG‐400 in microwave irradiation. In less time and with good to excellent yields, this method enables the synthesis of fused 1,2,3‐triazoles via Cu(I)‐catalyzed cycloaddition and C−N bond coupling. Later, Minimum Inhibitory Concentration of the synthesized compounds (5 a–5 o) was determined against three Staphylococcus aureus mutant strains by the broth dilution method. The obtained results were compared with standard drugs Clindamycin and Dicloxacillin. Among the compounds investigated, 1‐(3,5‐dimethoxyphenyl)‐1,4‐dihydroimidazo[2,1‐b] [1,2,3]triazolo[4,5‐d] [1,3] thiazine 5,5‐dioxide (5 c), 1‐(3,4,5‐trimethoxyphenyl)‐1,4‐dihydro imidazo[2,1‐b][1,2,3]triazolo[4,5‐d][1,3]thiazine 5,5‐dioxide (5 d), 1‐(4‐chloro‐3,5‐dimethoxyphenyl)‐1,4‐dihydroimidazo[2,1‐b][1,2,3]triazolo [4,5‐d][1,3]thiazine 5,5‐dioxide (5 e), 1‐(3,5‐dichlorophenyl)‐1,4‐dihydroimidazo[2,1‐b][1,2,3]triazolo[4,5‐d][1,3]thiazine 5,5‐dioxide (5 h), 1‐(4‐(trifluoromethyl)phenyl)‐1,4‐dihydroimidazo[2,1‐b][1,2,3]triazolo [4,5‐d][1,3]thiazine 5,5‐dioxide (5 m), and 1‐(4‐(trifluoromethoxy) phenyl)‐1,4‐dihydroimidazo[2,1‐b][1,2,3]triazolo[4,5‐d][1,3]thiazine 5,5‐dioxide (5 n) demonstrated the most promising Minimum Inhibitory Concentration values comparing to others. The MIC values were ranged from 1.56 μg to 12.5 μg, especially compounds 5 c, 5 d, and 5 e displayed superior activity against tested strains compared to the standards. We also documented the results of anti‐biofilm profiles for the compounds 5 c, 5 d, 5 e, 5 h, 5 m and 5 n. Based on the result, we noted that, the active derivatives 5 c, 5 d, and 5 e were strongly inhibited the biofilm of MSSA and MRSA biofilm growth with BFIC values ranging from 3.34±0.05 to 8.32±0.32 μg/mL. In accordance to the results of antibiofilm property, the compounds 5 c, 5 d and 5 e were further evaluated for bactericidal effect against selected Staphylococcus aureus mutant strains. In concern to the results, we confirmed that, the bactericidal effect was found significant with compound 5 d and followed by 5 c and 5 e. In silico docking simulation studies were performed to evaluate the molecular interactions of 5 c, 5 d, 5 e, 5 h, 5 m and 5 n compounds with the S.aureus (MRSA), Penicillin‐binding protein (PDB ID: 1MWT, co‐crystallised ligand inhibitor Pencillin G). Finally, the in silico pharmacokinetic profile was predicted for potent compounds using SWISS/ADME and pkCSM.