School of Pharmacy, Weifang Medical University, Weifang, China.
State Key Laboratory of Anti-Infective Drug Development (NO. 2015DQ780357), Sunshine Lake Pharma Co., Ltd, Dongguan 523871, China.
Bioorg Chem. 2022 Nov;128:106052. doi: 10.1016/j.bioorg.2022.106052. Epub 2022 Jul 25.
Capsid assembly modulators (CAMs) have recently been revealed to be effective in blocking HBV replication. HBV capsid protein inhibitors reduce and ultimately eliminate HBV by inhibiting virus replication and blocking hepatocyte infection. Sulfonamides are synthetic functional groups in development of different kinds of drugs. Sulfonyl benzamide clinical drugs NVR 3-778 and BA-38017 are lead compounds in discovery of antiviral compounds with increased activity and reduced cytotoxicity by drug design strategies including pharmacophore hybrid, bioisosterism and scaffold hopping. In current study, three series of target compounds were synthesized, and their anti-HBV activity was evaluated against HepAD38 cells. Compound 5a (EC = 0.50 ± 0.07 μM, CC = 48.16 ± 9.15 μM) showed better anti-HBV DNA replication activity than the lead compound BA-38017, and showed good inhibitory effect on the assembly of HBV capsid protein compared with the clinical drug NVR 3-778. In addition, preliminary structure-activity relationship (SAR) and molecular docking studies were conducted to explore potential interactions and binding modes between compounds and target proteins, which may help researchers to find more effective anti-HBV drugs.
衣壳组装调节剂（CAMs）最近被发现可有效阻断 HBV 复制。HBV 衣壳蛋白抑制剂通过抑制病毒复制和阻断肝细胞感染，减少并最终消除 HBV。磺胺类是开发各种药物的合成功能基团。磺酰苯甲酰胺类临床药物 NVR 3-778 和 BA-38017 是通过药物设计策略（包括药效团杂合、生物等排和骨架跃迁）发现具有更高活性和更低细胞毒性的抗病毒化合物的先导化合物。在本研究中，合成了三系列目标化合物，并评估了它们对 HepAD38 细胞的抗 HBV 活性。化合物 5a（EC=0.50±0.07μM，CC=48.16±9.15μM）显示出比先导化合物 BA-38017 更好的抗 HBV DNA 复制活性，并且与临床药物 NVR 3-778 相比，对 HBV 衣壳蛋白的组装显示出良好的抑制作用。此外，还进行了初步的构效关系（SAR）和分子对接研究，以探索化合物与靶蛋白之间的潜在相互作用和结合模式，这可能有助于研究人员找到更有效的抗 HBV 药物。
