Synthesis of new 4-[2-(alkylamino)ethylthio]pyrrolo[1,2-a]quinoxaline and 5-[2-(alkylamino)ethylthio]pyrrolo[1,2-a]thieno[3,2-e]pyrazine derivatives, as potential bacterial multidrug resistance pump inhibitors
Synthesis of new 4-[2-(alkylamino)ethylthio]pyrrolo[1,2-a]quinoxaline and 5-[2-(alkylamino)ethylthio]pyrrolo[1,2-a]thieno[3,2-e]pyrazine derivatives, as potential bacterial multidrug resistance pump inhibitors
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DOI：
10.1080/14756360701485406
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发表时间：
2007-01-01
影响因子：
5.6
通讯作者：
Jarry, Christian
中科院分区：
文献类型：
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作者：
Vidaillac, Celine;Guillon, Jean;Jarry, Christian
以各种取代的硝基苯胺2a-e为起始原料，经五步或六步合成了新的4-[2-（烷氨基）乙硫基]吡咯并[1，2-a]喹喔啉衍生物1a-1。合成了生物电子等排体5-[2-（烷氨基）乙硫基]吡咯并[1，2-a]噻吩并[3，2-e]吡嗪1 m。在靶向金黄色葡萄球菌的诺拉系统的模型中，评价了新衍生物作为外排泵抑制剂（EPI）。通过琼脂扩散法和MIC测定，与利血平和奥美拉唑作为参比EPI相比，测定了两种过量产生诺拉A的菌株SA-1199 B和SA-1单独和与新合成化合物组合的抗生素敏感性。初步的构效关系研究首先允许澄清在位置7和/或8的吡咯并[1，2-a]喹喔啉核的取代基的影响。甲氧基取代的化合物1b和1g比未取代的化合物（1a和1f）更有效，其次是氯化衍生物（1c-d和1h）。此外，用生物电子等排体如吡咯烷（化合物1f-h）取代N，N-二乙基氨基（化合物1a-e）增强了EPI活性，这与用哌啶部分取代（化合物1 i-k）相反。最后，吡咯并[1，2-a]噻吩并[3，2-e]吡嗪化合物1 m显示出比其吡咯并[1，2-a]喹喔啉类似物1a更高的EPI活性，为进一步的药物调节开辟了道路。
The synthesis of new 4-[2-(alkylamino)ethylthio] pyrrolo[1,2-a]quinoxaline derivatives 1a-1 is described in five or six steps starting from various substituted nitroanilines 2a-e. The bioisostere 5-[2-(alkylamino)ethylthio] pyrrolo[1,2-a]thieno[3,2-e]pyrazine 1m was also prepared. The new derivatives were evaluated as efflux pump inhibitors (EPIs) in a model targeting the NorA system of Staphylococcus aureus. The antibiotic susceptibility of two strains overproducing NorA, SA-1199B and SA-1, was determined alone and in combination with the neo-synthesised compounds by the agar diffusion method and MIC determination, in comparison with reserpine and omeprazole taken as reference EPIs. A preliminary structure-activity relationship study firstly allowed to clarify the influence of the substituents at positions 7 and/or 8 of the pyrrolo[1,2-a]quinoxaline nucleus. Methoxy substituted compounds, 1b and 1g, were more potent EPIs than the unsubstituted compounds (1a and 1f), followed by chlorinated derivatives (1c-d and 1h). Moreover, the replacement of the N,N-diethylamino group (compounds 1a-e) by a bioisostere such as pyrrolidine (compounds 1f-h) enhanced the EPI activity, in contrast with the replacement by a piperidine moiety (compounds 1i-k). Finally, the pyrrolo[1,2-a]thieno[3,2-e]pyrazine compound 1m exhibited a higher EPI activity than its pyrrolo[1,2-a]quinoxaline analogue 1a, opening the way to further pharmacomodulation.