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

Abstract

A series of novel 4-thiazolidinone inhibitors SKYa–SKYg, containing coumarin as a core structure were synthesized via facile and efficient 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 further evaluated for their potential as anti-tubercular agents against Mycobacterium tuberculosis H37Rv ATCC 25618, and anti-bacterial agents against Escherichia coli, Enterobacter aerogenes, Salmonella typhi, Streptococcus pneumoniae and Staphylococcus aureus. Interestingly, the hybrids displayed potent bioactivity. However, compounds SKYc, SKYd, and SKYe appeared to be more effective against the tested bacterial strains, among which compound SKYb showed the highest 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 DENV flavivirus 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 synthesized hybrids exhibited potent anti-dengue activity among which compounds SKYf, SKYd, SKYc and SKYe were found to be 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 scaffold that may eventually yield useful compounds in the treatment of bacterial and viral infections.Electronic supplementary materialThe online version of this article (10.1186/s13065-018-0435-0) contains supplementary material, which is available to authorized users.

Structure‐guided screening of chemical database to identify NS3‐NS2B inhibitors for effective therapeutic application in dengue infection

“…Hence, to overcome such situation presently, available more resources, much faster, and advance scientific techniques need to be adopted and explored. Earlier, a number of studies have proposed various traditional and specific methods for the identification of different chemical entities and demonstrated their selective inhibition mechanism and inhibitory efficacy against NS3‐NS2B protease complex at different levels …”

Coumarin: An emerging antiviral agent

“…With this idea, molecular docking approaches using synthetic coumarin derivatives as ligands have been applied to check their anti-dengue protease activity that is known in the case of HIV [51]. Molecular Docking study indicates 4-thiazolidinone-coumarin derivatives have significant binding affinity with the binding site of viral protease complex suggesting its inhibitory role [70].…”

Nitrogen-Based Heterocyclic Compounds: A Promising Class of Antiviral Agents against Chikungunya Virus

“…While in the hepatitis C virus (HCV), coumarins could act against its replication, increasing the interferon-mediated antiviral responses [ 47 ]. The activity of coumarins against dengue virus (DENV) has already been reported, but its mechanisms of action requires further investigation; however, initial studies point to the NS2B/NS3 complex as a possible coumarin target [ 48 ]. The activity of coumarin against CHIKV is still under investigation [ 42 , 49 , 50 , 51 , 52 , 53 ].…”