Robenidine Analogues as Gram-Positive Antibacterial Agents
Robenidine Analogues as Gram-Positive Antibacterial Agents
复制标题
DOI：
10.1021/acs.jmedchem.5b01797
复制
发表时间：
2016-03-10
影响因子：
7.3
通讯作者：
Trott, Darren J.
中科院分区：
文献类型：
--
作者：
Abraham, Rebecca J.;Stevens, Andrew J.;Trott, Darren J.
Robenidine，1（2，2 '-双[（4-氯苯基）亚甲基]碳亚胺二酰肼），对MRSA和VRE有活性，MIC分别为8.1和4.7 μ M。SAR显示4-Cl电子等排体与4-F（8）、3-F（9）、3-CH 3（22）和4-C（CH 3）（3）（27）（23.7-71 μ M）以及与3-Cl（3）、4-CH 3（21）和4-CH（CH 3）（2）（26）（8.1-13.0 μ M）的耐受性。亚胺碳烷基化鉴定了甲基/乙基结合口袋，其也容纳CH 2 OH部分（75; 2，2 '-双[1-（4-氯苯基）-2-羟基亚乙基]碳亚胺基二酰肼）。类似物1、27（2，2 '-双{[4-（1，1-二甲基乙基）苯基]亚甲基}碳亚胺基二酰肼）和69（2，2'-双[1-（4-氯苯基）亚乙基]碳亚胺基二酰肼盐酸盐）对24种临床MRSA和MSSA分离株具有活性。在>= 2x MIC时未观察到剂量限制性细胞毒性或在>= 8x MIC时未观察到溶血。多粘菌素B的加入产生大肠杆菌和铜绿假单胞菌革兰氏阴性活性MIC为4.2-21.6 μ M。1和75显示出优异的微粒体稳定性、固有清除率和肝提取率，其中1在人和小鼠脂质体中以及75在人脂质体中的T-1/2 > 247 min，克林特< 7 μ L/min/mg蛋白，并且E-H < 0.22。
Robenidine, 1 (2,2'-bis[(4-chlorophenyl)methylene]carbonimidic dihydrazide), was active against MRSA and VRE with MIC's of 8.1 and 4.7 mu M, respectively. SAR revealed tolerance for 4-Cl isosteres with 4-F (8), 3-F (9), 3-CH3 (22), and 4-C(CH3)(3) (27) (23.7-71 mu M) and with 3-Cl (3), 4-CH3 (21), and 4-CH(CH3)(2) (26) (8.1-13.0 mu M). Imine carbon alkylation identified a methyl/ethyl binding pocket that also accommodated a CH2OH moiety (75; 2,2'-bis[1-(4-chlorophenyl)-2-hydroxyethylidene] carbonimidic dihydrazide). Analogues 1, 27 (2,2'-bis{[4-(1,1-dimethylethyl)phenyl]methylene}carbonimidic dihydrazide), and 69 (2,2'-bis[1-(4-chlorophenyl)ethylidene]carbonimidic dihydrazide hydrochloride) were active against 24 clinical MRSA and MSSA isolates. No dose-limiting cytotoxicity at >= 2x MIC or hemolysis at >= 8x MIC was observed. Polymyxin B addition engendered Escherichia coli and Pseudomonas aeruginosa Gram-negative activity MIC's of 4.2-21.6 mu M. 1 and 75 displayed excellent microsomal stability, intrinsic clearance, and hepatic extraction ratios with T-1/2 > 247 min, CLint < 7 mu L/min/mg protein, and E-H < 0.22 in both human and mouse liposomes for 1 and in human liposomes for 75.