4-Thiazolidinone coumarin derivatives as two-component NS2B/NS3 DENV flavivirus serine protease inhibitors: synthesis, molecular docking, biological evaluation and structure–activity relationship studies

摘要

A series of novel 4-thiazolidinone inhibitors SKYa–SKYg, containing coumarin as a core structure were synthesizedvia facile and efcient method. The structures of the synthesized compounds were established by extensive spectroscopic studies (FT IR, 1D NMR, 2D NMR, LC–MS) and elemental analysis. All the synthesized hybrids were furtherevaluated for their potential as anti-tubercular agents against Mycobacterium tuberculosis H37Rv ATCC 25618, andanti-bacterial agents against Escherichia coli, Enterobacter aerogenes, Salmonella typhi, Streptococcus pneumoniae andStaphylococcus aureus. Interestingly, the hybrids displayed potent bioactivity. However, compounds SKYc, SKYd, andSKYe appeared to be more efective against the tested bacterial strains, among which compound SKYb showed thehighest inhibition against all the bacterial strains ranging from 41 to 165 μg/mL, as compared to the standards, streptomycin, kanamycin and vancomycin. Moreover, derivative SKYa was found to be the strongest against M. tuberculosis(83 μg/mL). Additionally, the anti-dengue potential of the coumarin hybrids as two-component NS2B/NS3 DENVfavivirus serine protease inhibitors was calculated using computational molecular docking approach, with reference to the standards 4-hydroxypanduratin, panduratin and ethyl 3-(4-(hydroxymethyl)-2-methoxy-5-nitrophenoxy)propanoate with DS of ? 3.379, ? 3.189 and ? 3.381, respectively. The docking results revealed that the synthesizedhybrids exhibited potent anti-dengue activity among which compounds SKYf, SKYd, SKYc and SKYe were found tobe the best ones with docking scores of ? 4.014, ? 3.964, ? 3.905 and ? 3.889. In summary, we discovered 4-thiazolidinone coumarin derivatives as a new scafold that may eventually yield useful compounds in the treatment ofbacterial and viral infections.