The emergence of multidrug-resistant bacteria has created an urgent need for antibiotics with a novel mechanism of action. The bacterial cell division protein FtsZ is an attractive target for the development of novel antibiotics. The benzo[c]phenanthridinium sanguinarine and the dibenzo[a,g]quinolizin-7-ium berberine are two structurally similar plant alkaloids that alter FtsZ function. The presence of a hydrophobic functionality at either the 1-position of 5-methylbenzo[c]phenanthridinium derivatives or the 2-position of dibenzo[a,g]quinolizin-7-ium derivatives is associated with significantly enhanced antibacterial activity. 3-Phenylisoquinoline represents a subunit within the ring-systems of both of these alkaloids. Several 3-phenylisoquinolines and 3-phenylisoquinolinium derivatives have been synthesized and evaluated for antibacterial activity against Staphylococcus aureus and Enterococcus faecalis, including multidrug-resistant strains of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecalis (VRE). A number of derivatives were found to have activity against both MRSA and VRE. The binding of select compounds to S. aureus FtsZ (SaFtsZ) was demonstrated and characterized using fluorescence spectroscopy. In addition, the compounds were shown to act as stabilizers of SaFtsZ polymers and concomitant inhibitors of SaFtsZ GTPase activity. Toxicological assessment of select compounds revealed minimal cross-reaction mammalian β-tubulin as well as little or no human cytotoxicity.

多重耐药细菌的出现迫切需要具有新颖作用机制的抗生素。细菌细胞分裂蛋白 FtsZ 是新型抗生素开发的一个有吸引力的靶点。苯并[ c ]菲啶血根碱和二苯并[ a , g ]喹嗪-7-鎓小檗碱是两种结构相似的植物生物碱，可改变FtsZ功能。5-甲基苯并[ c ]菲啶鎓衍生物的1位或二苯并[ a , g ]喹嗪-7-鎓衍生物的2位上疏水性官能团的存在与显着增强的抗菌活性相关。3-苯基异喹啉代表这两种生物碱环系统内的亚基。已经合成了几种 3-苯基异喹啉和 3-苯基异喹啉鎓衍生物，并评估了其对金黄色葡萄球菌和粪肠球菌的抗菌活性，包括耐甲氧西林金黄色葡萄球菌(MRSA) 和耐万古霉素粪肠球菌(VRE)的多重耐药菌株。已发现许多衍生物对 MRSA 和 VRE 均具有活性。使用荧光光谱法证明并表征了选定化合物与金黄色葡萄球菌FtsZ (SaFtsZ)的结合。此外，这些化合物还被证明可以作为 SaFtsZ 聚合物的稳定剂和 SaFtsZ GTPase 活性的伴随抑制剂。对选定化合物的毒理学评估显示，与哺乳动物 β-微管蛋白的交叉反应极小，并且对人类细胞毒性很小或没有。