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

Abstract

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.

Seeking heterocyclic scaffolds as antivirals against dengue virus

“…Batool et al (2021) investigated a few N -substituted 1,2-benzoisothiazol-3(2H)-ones 117 – 123 ( Table 22 ) via a one-pot and two-step protocol [ 183 ]. Upon screening the synthesized compounds, it was observed that the compounds inhibited the DENV2 NS2B/NS3 protease significantly.…”

“… Ortho-substitution displays greater inhibition as compared to the para-substitution. [ 183 ] Inhibits DENV2. Various substituents present on the phenyl ring of the truncated benzothiazole scaffolds affect greater inhibition.…”

Antiviral Agents against Flavivirus Protease: Prospect and Future Direction

“…Hybrid pharmacophores generated by a combination of two individual pharmacophores with 1,2-Benzisothiazol-3(2H)-one (BIT) as the skeleton have been proven to show synergistic effects in inhibition of the DENV-2 NS2B-NS3 [ 85 ]. It was observed that BITs bind to the protease in vicinity of the catalytic triad.…”

“…The BITs containing aromatic substitutions at the N-atom-like compounds 31 with 2-methyl-4-nitrophenyl, 32 with 2-chlorophenyl, and 33 2,6-dichlorophenyl showed the highest protease inhibition with an IC 50 of 2.56 ± 1.03 µM, 2.01 ± 0.98 µM, and 5.28 ± 1.89 µM, respectively. The DENV-2 infection assay showed that two BITs, the compound 32 reduced viral infectivity by 1.4 orders of magnitude and the compound 33 reduced the viral infectivity by about six fold [ 85 ].…”

Repurposing of investigational cancer drugs: Early phase discovery of dengue virus NS2B/NS3 protease inhibitors

“…[7][8][9] Thus, taking into account the pivotal role played in the viral replication, the DENV NS2B/NS3 protease has been extensively exploited as a drug target for the discovery and development of direct-acting antivirals against dengue. [10,11] Even though several peptidic or peptidomimetic compounds containing reactive "warheads," [12][13][14][15][16][17][18] and noncovalent small organic molecules [19][20][21][22][23][24][25][26] have been identified as inhibitors of DENV NS2B/NS3 protease, no inhibitor has reached clinical development as a specific antidengue drug. This may be due to unfavorable drug metabolism and pharmacokinetic (DMPK) properties and/or lower target affinity of known inhibitors.…”