Development of novel antimicrobial agent with the fullerene skeleton

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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