Jarvest Richard L, Armstrong Sula A, Berge John M, Brown Pamela, Elder John S, Brown Murray J, Copley Royston C B, Forrest Andrew K, Hamprecht Dieter W, O'Hanlon Peter J, Mitchell Darren J, Rittenhouse Stephen, Witty David R
GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.
Bioorg Med Chem Lett. 2004 Aug 2;14(15):3937-41. doi: 10.1016/j.bmcl.2004.05.070.
Potent inhibitors of bacterial methionyl tRNA synthetase (MRS) have previously been reported. Through SAR of the quinolone moiety, the right hand side pharmacophore for MRS inhibition has now been defined as an NH-C-NH functionality in the context of a bicyclic heteroaromatic system. Potent antibacterial fused-pyrimidone and fused-imidazole analogues have been obtained and enantioselective activity demonstrated. Compound 46 demonstrated very good antibacterial activity against panels of antibiotic-resistant staphylococci and enterococci.
此前已有关于细菌甲硫氨酰-tRNA合成酶（MRS）强效抑制剂的报道。通过喹诺酮部分的构效关系研究，现已确定在双环杂芳环体系中，MRS抑制的右侧药效团为NH-C-NH官能团。已获得强效抗菌的稠合嘧啶酮和稠合咪唑类似物，并证明了其对映选择性活性。化合物46对一系列耐抗生素葡萄球菌和肠球菌表现出非常好的抗菌活性。
