Acta Pharmacologica Sinica 2008 February; 29 (2): 267-277; doi: 10.1111/j.1745-7254.2008.00720.x

Acta Pharmacologica Sinica 2008 February; 29 (2): 267-277; doi: 10.1111/j.1745-7254.2008.00720.x

Original Article

Derivatives of aryl-4-guanidinomethylbenzoate and N-aryl-4-guanidinomethylbenzamide as new antibacterial agents: synthesis and bioactivity¹

Wen-yuan YU², Li-xia YANG², Jian-shu XIE³, Ling ZHOU², Xue-yuan JIANG⁴, De-xu ZHU⁴, Mutsumi MURAMATSU⁴, Ming-wei WANG^2,5

²The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; ³Shanghai East Best Biopharmaceutical Enterprises Co Ltd, Shanghai 200233, China; ⁴Department of Biochemistry, Nanjing University, Nanjing 210093, China

Aim: The aim of the present study was to design, synthesize, and evaluate novel antibacterial agents, derivatives of aryl-4-guanidinomethylbenzoate and N-aryl-4-guanidinomethylbenzamide.

Methods: A total of 44 derivatives of aryl-4-guanidin-omethylbenzoate (series A) and N-aryl-4-guanidinomethylbenzamide (series B) were synthesized and their antibacterial activities were assessed in vitro against a variety of Gram-positive and Gram-negative bacteria by an agar dilution method.

Results: Twelve compounds showed potent bactericidal effects against a panel of Gram-positive germs, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), vancomycin-intermediate Staphylococcus aureus (VISA), and methicillin-resistant coagulase-negative staphylococci (MRCNS), with minimum inhibitory concentrations (MIC) ranging between 0.5 and 8 µg/mL, which were comparable to the MIC values of several marketed antibiotics. They exhibited weak or no activity on the Gram-negative bacteria tested. In addition, these compounds displayed high inhibitory activities towards oligopeptidase B of bacterial origin.

Conclusion: In comparison with the previously reported MIC values of several known antibiotics, the derivatives of aryl-4-guanidinomethylbenzoate and N-aryl-4-guanidinomethylbenzamide showed comparable in vitro bactericidal activities against VRE and VISA as linezolid. Their growth inhibitory effects on MRSA were similar to vancomycin, but were less potent than linezolid and vancomycin against MRCNS. This class of compounds may have the potential to be developed into narrow spectrum antibacterial agents against certain drug-resistant strains of bacteria.

Keywords: antibacterial agents; drug-resistant bacteria; Gram-positive bacteria

¹Project supported in part by grants from the Ministry of Science and Technology of China (No 2004CB518902) and Shanghai Municipality Government (No 30219228 and 05dz22914).

⁵Correspondence to Dr Ming-wei WANG.
Phn 86-21-5080-1313.
Fax 86-21-5080-0721.
E-mail mwwang@mail.shcnc.ac.cn
Received 2007-05-30 Accepted 2007-07-23

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