Pharmaceutical Chemistry, School of Pharmacy, University of the Western Cape, Bellville 7530, South Africa.
Molecules. 2018 Jul 10;23(7):1678. doi: 10.3390/molecules23071678.
Dengue fever is a major public health concern in many tropical and sub-tropical regions. The development of agents that are able to inhibit the dengue virus (DENV) is therefore of utmost importance. This study focused on the synthesis of dual acting hybrids comprising structural features of known DENV inhibitors, amantadine () and benzsulfonamide derivatives. Hybrid compound , -(adamantan-1-yl)-4-[(adamantan-1-yl)sulfamoyl]benzamide, was synthesized by reacting amantadine () with 4-(chlorosulfonyl)benzoic acid (), after optimization, in a 2:1 ratio under microwave irradiation conditions in a one-pot reaction. Mono-adamantane derivatives and were synthesised via acyl halide formation of benzoic acid () and 4-sulfamoyl benzoic acid (), respectively, followed by conjugation with amantadine () through a conventional or microwave irradiation assisted nucleophilic addition/substitution reaction. The use of microwave irradiation lead to significant increases in yields and a reduction in reaction times. Nuclear magnetic resonance, infra-red and mass spectral data confirmed the structures. Compound and showed significant anti-DENV serotype 2 activity (IC = 22.2 µM and 42.8 µM) and low cytotoxicity (CC < 100 µM). Possible mechanisms of action are also proposed, which are based on the biological results and molecular docking studies.
登革热是许多热带和亚热带地区的主要公共卫生关注点。因此，开发能够抑制登革热病毒（DENV）的药物至关重要。本研究专注于合成具有已知 DENV 抑制剂金刚烷胺（）和苯磺酰胺衍生物结构特征的双重作用杂合体。通过在微波辐射条件下在一锅反应中以 2:1 的比例优化反应，将金刚烷胺（）与 4-（氯磺酰基）苯甲酸（）反应，合成了杂合化合物 ， -（金刚烷-1-基）-4-[(金刚烷-1-基）磺酰胺基]苯甲酰胺。通过苯甲酸（）和 4-磺酰胺基苯甲酸（）的酰卤形成分别合成了单金刚烷衍生物 和 ，然后通过常规或微波辐射辅助的亲核加成/取代反应与金刚烷胺（）共轭。微波辐射的使用导致产率显著提高，反应时间缩短。核磁共振、红外和质谱数据证实了这些结构。化合物 和 表现出显著的抗 DENV 血清型 2 活性（IC = 22.2 µM 和 42.8 µM）和低细胞毒性（CC < 100 µM）。还提出了可能的作用机制，这些机制基于生物学结果和分子对接研究。
