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Novel Terminal Bipheny-Based Diapophytoene Desaturases (CrtN) Inhibitors as Anti-MRSA/VISR/LRSA Agents with Reduced hERG Activity
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-12-28 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01300 Baoli Li 1 , Shuaishuai Ni 1 , Fei Mao 1 , Feifei Chen 2 , Yifu Liu 1 , Hanwen Wei 1 , Wenhua Chen 1 , Jin Zhu 1 , Lefu Lan 2 , Jian Li 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-12-28 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01300 Baoli Li 1 , Shuaishuai Ni 1 , Fei Mao 1 , Feifei Chen 2 , Yifu Liu 1 , Hanwen Wei 1 , Wenhua Chen 1 , Jin Zhu 1 , Lefu Lan 2 , Jian Li 1
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CrtN has been identified as an attractive and druggable target for treating pigmented Staphylococcus aureus infections. More than 100 new compounds were synthesized, which target the overwhelming the defects of the CrtN inhibitor 1. Analogues 23a and 23b demonstrated a significant activity against pigmented S. aureus Newman and 13 MRSA strains (IC50 = 0.02–10.5 nM), along with lower hERG inhibition (IC50 > 30 μM, ∼10-fold decrease in comparison with 1). Furthermore, 23a and 23b were confirmed to reduce the staphylococcal load in the kidney and heart in a mouse model with normal treatment deeper than pretreatment ones, comparable even with vancomycin and linezolid. Remarkably, 23a could strongly block the pigment biosynthesis of these nine multidrug-resistant MRSA strains, including excellent activity against LRSA strains and VISA strains in vivo, and all of which demonstrated that 23a has a huge potential against intractable MRSA, VISA, and LRSA issues as a therapeutic drug.
中文翻译：
新型终端基于Bipheny-基的番茄红素去饱和酶（CrtN）抑制剂作为具有降低的hERG活性的抗MRSA / VISR / LRSA药物
CrtN已被确定为治疗色素沉着的金黄色葡萄球菌感染的有吸引力且可药物治疗的靶标。合成了100多种新化合物，这些化合物针对的是CrtN抑制剂1的绝大多数缺陷。类似物23a和23b证明对有色的金黄色葡萄球菌Newman和13个MRSA菌株具有显着活性（IC 50 = 0.02-10.5 nM），同时具有较低的hERG抑制作用（IC 50 > 30μM，与1相比降低约10倍） 。此外，23a和23b在正常治疗下比正常治疗更深的小鼠模型中，已证实可以减轻肾脏和心脏中的葡萄球菌负荷，即使与万古霉素和利奈唑胺也无可比拟。值得注意的是，23a可能强烈阻断这9种具有多重耐药性的MRSA菌株的色素生物合成，包括在体内对LRSA菌株和VISA菌株的优异活性，所有这些都表明23a具有解决棘手的MRSA，VISA和LRSA问题的巨大潜力作为治疗药物。
更新日期：2017-12-28
中文翻译：
新型终端基于Bipheny-基的番茄红素去饱和酶（CrtN）抑制剂作为具有降低的hERG活性的抗MRSA / VISR / LRSA药物
CrtN已被确定为治疗色素沉着的金黄色葡萄球菌感染的有吸引力且可药物治疗的靶标。合成了100多种新化合物，这些化合物针对的是CrtN抑制剂1的绝大多数缺陷。类似物23a和23b证明对有色的金黄色葡萄球菌Newman和13个MRSA菌株具有显着活性（IC 50 = 0.02-10.5 nM），同时具有较低的hERG抑制作用（IC 50 > 30μM，与1相比降低约10倍） 。此外，23a和23b在正常治疗下比正常治疗更深的小鼠模型中，已证实可以减轻肾脏和心脏中的葡萄球菌负荷，即使与万古霉素和利奈唑胺也无可比拟。值得注意的是，23a可能强烈阻断这9种具有多重耐药性的MRSA菌株的色素生物合成，包括在体内对LRSA菌株和VISA菌株的优异活性，所有这些都表明23a具有解决棘手的MRSA，VISA和LRSA问题的巨大潜力作为治疗药物。
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