化学
核苷
登革热病毒
奥西多尔
RNA聚合酶
对接(动物)
核糖核酸
生物化学
立体化学
登革热
病毒学
生物
医学
基因
护理部
催化作用
作者
Venkatanarayana Chowdary Maddipati,Lovika Mittal,Jasveen Kaur,Yogita Rawat,Chandra PrakashKoraboina,Sankar Bhattacharyya,Shailendra Asthana,Rambabu Gundla
标识
DOI:10.1016/j.bioorg.2022.106277
摘要
A series of thiazole linked Oxindole-5-Sulfonamide (OSA) derivatives were designed as inhibitors of RNA-dependent RNA polymerase (RdRp) activity of Dengue virus. These were synthesized and then evaluated for their efficacy in ex-vivo virus replication assay using human cell lines. Among 20 primary compounds in the series, OSA-15 was identified as a hit. A series of analogues were synthesized by replacing the difluoro benzyl group of OSA-15 with different substituted benzyl groups. The efficacy of OSA-15derivatives was less than that of the parent compound, except OSA-15-17, which has shown improved efficacy than OSA-15. The further optimization was carried out by adding dimethyl (DM) groups to both the sulfonamide and oxindole NH's to produce OSA-15-DM and OSA-15-17-DM. These two compounds were showing no detectable cytotoxicity and the latter was more efficacious. Further, both these compounds were tested for inhibition in all the serotypes of the Dengue virus using an ex-vivo assay. The EC50 of OSA-15-17-DM was observed in a low micromolar range between 2.5 and 5.0 µg/ml. Computation docking and molecular dynamics simulation studies confirmed the binding of identified hits to DENV RdRp. OSA15-17-DM blocks the RNA entrance and elongation site for their biological activity with high binding affinity. Overall, the identified oxindole derivatives are novel compounds that can inhibit Dengue replication, working as non-nucleoside inhibitors (NNI) to explore as anti-viral RdRp activity.
科研通智能强力驱动
Strongly Powered by AbleSci AI