Dengue virus (DENV) infections are rampant in tropical and subtropical regions of the world with millions of people at risk. There is still no specific antiviral treatment available against these infections. Amongst the different potential therapeutic targets, DENV protease is considered an important target because of its crucial role in the viral replication cycle. We are reporting here a potent DENV protease inhibitor, eugeniin (3), which has been isolated from cloves, along with two other weaker inhibitors, isobiflorin (1) and biflorin (2). In this study, the IC 50 values of 3 against the proteases of DENV serotype-2 and -3 were found to be 94.7 nM and 7.5 μM, respectively. Mechanistically, the compounds 1−3 exhibited a competitive type of inhibition, which were further substantiated by computational docking and saturation transfer difference (STD) NMR spectroscopy. Atomic-level details of the binding of these molecules at the active site of the protease suggested extensive interactions mediated by a network of hydrogen bonds and hydrophobic contacts. With further evaluation, these inhibitors are highly promising in the context of antiviral therapeutics development against DENV.

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The COVID-19 pandemic has claimed more than a million lives worldwide within a short time span. Due to the unavailability of specific antiviral drugs or vaccine, the infections are causing panic both in general public and among healthcare providers. Therefore, an urgent discovery and development of effective antiviral drug for the treatment of COVID-19 is highly desired. Targeting the main protease (M pro) of the causative agent, SARS-CoV-2 has great potential for drug discovery and drug repurposing efforts. Published crystal structures of SARS-CoV-2 M pro further facilitated in silico investigations for discovering new inhibitors against M pro. The present study aimed to screen several libraries of synthetic flavonoids and benzisothiazolinones as potential SARS-CoV-2 M pro inhibitors using in silico methods. The short-listed compounds after virtual screening were filtered through SwissADME modeling tool to remove molecules with unfavorable pharmacokinetics and medicinal properties. The drug-like molecules were further subjected to iterative docking for the identification of top binders of SARS-CoV-2 M pro. Finally, molecular dynamic (MD) simulations and binding free energy calculations were performed for the evaluation of the dynamic behavior, stability of protein-ligand complex, and binding affinity, resulting in the identification of thioflavonol, TF-9 as a potential inhibitor of M pro. The computational studies further revealed the binding of TF-9 close to catalytic dyad and interactions with conserved residues in the S1 subsite of the substrate binding site. Our in-silico study demonstrated that synthetic analogs of flavonoids, particularly thioflavonols, have a strong tendency to inhibit the main protease M pro , and thereby inhibit the reproduction of SARS-CoV-2.

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Several new N-substituted 1,2-benzisothiazol-3(2H)-ones (BITs) were synthesised through a facile synthetic route for testing their anti-dengue protease inhibition. Contrary to the conventional multistep synthesis, we achieved structurally diverse BITs with excellent yields using a two-step, one-pot reaction strategy. All the synthesised compounds were prescreened for drug-like properties using the online Swiss Absorption, Distribution, Metabolism and Elimination (SwissADME) model, indicating their favourable pharmaceutical properties. Thus, the synthesised BITs were tested for inhibitory activity against the recombinant dengue virus serotype-2 (DENV-2) NS2BNS3 protease. Dose–response experiments and computational docking analyses revealed that several BITs bind to the protease in the vicinity of the catalytic triad with IC50 values in the micromolar range. The DENV2 infection assay showed that two BITs, 2-(2-chlorophenyl)benzo[d]isothiazol-3(2H)-one and 2-(2,6-dichlorophenyl)benzo[d]isothiazol-3(2H)-one, could suppress DENV replication and virus infectivity. These results indicate the potential of BITs for developing new anti-dengue therapeutics.