4.5 Article

Facile Synthesis and In Vitro Activity of N-Substituted 1,2-Benzisothiazol-3(2H)-ones against Dengue Virus NS2BNS3 Protease

Journal

PATHOGENS
Volume 10, Issue 4, Pages -

Publisher

MDPI
DOI: 10.3390/pathogens10040464

Keywords

dengue virus; direct-acting antivirals; 1,2-benzisothiazolinone; drug discovery; infectivity assays

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Funding

  1. Higher Education Commission (HEC), Pakistan, under the National Research Programme for Universities (NRPU) [5912]
  2. Lahore University of Management Sciences (LUMS) under the Faculty Initiative fund mechanism
  3. Deutscher Akademischer Austauschdienst (DAAD)

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This study synthesized several new N-substituted 1,2-benzisothiazol-3(2H)-ones (BITs) through a simplified synthetic route and tested their inhibitory activity against dengue virus protease. The results indicate the potential of two BITs for developing new anti-dengue therapeutics.
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.

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