Batool Farwa, Saeed Muhammad, Saleem Hafiza Nosheen, Kirschner Luisa, Bodem Jochen
Department of Chemistry and Chemical Engineering, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore 54692, Pakistan.
Institut für Virologie und Immunbiologie, Versbacher Straße 7, 97078 Würzburg, Germany.
Pathogens. 2021 Apr 12;10(4):464. doi: 10.3390/pathogens10040464.
Several new -substituted 1,2-benzisothiazol-3(2)-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 IC values in the micromolar range. The DENV2 infection assay showed that two BITs, 2-(2-chlorophenyl)benzo[d]isothiazol-3(2)-one and 2-(2,6-dichlorophenyl)benzo[]isothiazol-3(2)-one, could suppress DENV replication and virus infectivity. These results indicate the potential of BITs for developing new anti-dengue therapeutics.
通过简便的合成路线合成了几种新的取代1,2-苯并异噻唑-3(2)-酮（BITs），以测试它们对登革热蛋白酶的抑制作用。与传统的多步合成不同，我们采用两步一锅法反应策略，以优异的产率获得了结构多样的BITs。使用在线瑞士药物吸收、分布、代谢和排泄（SwissADME）模型对所有合成化合物进行类药性质预筛选，表明它们具有良好的药学性质。因此，对合成的BITs进行了针对重组登革热病毒2型（DENV-2）NS2B/NS3蛋白酶的抑制活性测试。剂量反应实验和计算对接分析表明，几种BITs在催化三联体附近与蛋白酶结合，IC值在微摩尔范围内。DENV2感染试验表明，两种BITs，即2-(2-氯苯基)苯并[d]异噻唑-3(2)-酮和2-(2,6-二氯苯基)苯并[d]异噻唑-3(2)-酮，能够抑制DENV复制和病毒感染性。这些结果表明BITs在开发新型抗登革热疗法方面具有潜力。
