Development of novel antimicrobial agent with the fullerene skeleton

抗菌素耐药性的惊人增长是药物化学中最严重的问题之一。这些威胁为寻找新型先导化合物用作药物提供了动力。一般来说，获得对全新类型化合物的耐药性似乎很困难。富勒烯是一种具有扩展π共轭体系的缩合芳环化合物，是一种新型有机化合物。我们已经报道了阳离子富勒烯衍生物。C_<60>-bis（N， N-二甲基吡咯吡啶碘化物）具有抗菌活性。在本研究中，我们研究了C_<60>-bis（N， N-二甲基吡咯吡啶碘化物）区域异构体，t-2(1), t-3(2), t-4(3)和烷基化C_<60>-bis（N， N-二甲基吡咯吡啶碘化物）衍生物的抗菌活性，从C_<60>对应的醛和N-烷基化吡啶合成了4 ~ 8.1 ~ 8。C_<60>-bis（N， N-二甲基吡咯吡啶碘化物）、1.2和3的区域异构体具有优异的抑菌活性，其抑菌活性与万古霉素（VCM）相当。三种区域异构体的抑菌效果无显著差异。这些发现表明，不需要分离区域异构体来研究它们的生物活性。C_<60>-二（2-烷基- n， n-二甲基吡咯吡啶碘化）（烷基：n- c_4h_9,4, n-C_6H_<13>, 5）也有抑菌活性，但效果较差。此外，这些衍生物，1 ~ 5，抑制了VCM抗性粪肠球菌的生长。与1 ~ 5相比，具有长烷基链的衍生物6,7和8没有抗菌活性。这些结果与呼吸链抑制的结果一致。在呼吸链抑制中，1 ~ 5是良好的抑制剂，而6、7、8从无活性到轻度活性。这些结果表明，其抑菌作用机制是抑制呼吸链，衍生物的亲脂性适宜于抑制呼吸链和抗菌活性。少

An alarming increase in antimicrobial resistance is one of the most serious problems in medicinal chemistry. These threats provide motivations to search for new types of lead compounds to be used as medicine Generally, the acquisition of the drug resistance for completely new type of compounds seems to be difficult. Fullerene, a condensed aromatic ring compound with an extended π-conjugated system is a new type of organic compound. We have reported that cationic fullerene derivatives. C_<60>-bis(N, N-dimethylpyrrolidinium iodide), had antimicrobial activity. In this study, we investigate the antibacterial activity of C_<60>-bis(N, N-dimethylpyrrolidinjum iodide) regio isomers, t-2(1), t-3(2), t-4(3), and alkylated C_<60>-bis(N, N-dimetylpyrrolidinium iodide) derivatives, 4 to 8.1 to 8 were synthesized from C_<60> corresponding aldehyde, and N-alkylated gyricine. The regio isomers of C_<60>-bis(N, N-dimethylpyrrolidinium iodide), 1.2, and 3, had excellent antibacterial activity, which w … More as comparable with that of vancomycin (VCM). The antibacterial effect of the three regio isomers was not significantly different. These findings indicate that it is not necessary to separate the regio isomers to study their biological activities. C_<60>-bis(2-alkyl-N, N-dimethylpyrrolidinium iodide) (alkyl: n-C_4H_9, 4, n-C_6H_<13>, 5) also showed antibacterial activity, but it was less effective. Moreover, these derivatives, 1 to 5, inhibited the growth of VCM--resistant E. faecalis. In contrast to 1 to5, derivatives with a long alkyl chain, 6, 7 and 8, had no antibacterial activity. These results agreed with that of respiratory chain inhibition. In the respiratory chain inhibition, 1 to 5 was good inhibitor but 6, 7, and 8 had from none to slight activity. These results indicated that the mechanism of antimicrobial activity is a respiratory chain inhibition and that appropriate lipophilicity of the derivatives was suitable for the inhibition of the respiratory chain and for antibacterial activity. Less