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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Design, synthesis and structure-activity relationships of novel macrolones: Hybrids of 2-fluoro 9-oxime ketolides and carbamoyl quinolones with highly improved activity against resistant pathogens
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Design, synthesis and structure-activity relationships of novel macrolones: Hybrids of 2-fluoro 9-oxime ketolides and carbamoyl quinolones with highly improved activity against resistant pathogens

机译：新型大镰刀醇的设计，合成和结构 - 活性关系：2-氟9-肟酮酮和碳酰氧酰喹诺酮的杂交物，具有高度改善的抗性病原体的活性

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摘要

Constitutively erythromycin-resistant apathogens are more difficult to address than inducibly resistant and efflux-resistant strains. Three series of the 4th generation 2-fluoro 9-oxime erythromycin ketolides were synthesized and evaluated. Incorporation of substituted heteroaryl groups (a - m), in contrast to previously reported the unsubstituted heteroaryl groups, proved to the beneficial for enhancement of the activities of the 9-propgargyl ketolide 8 series and the 9-allyl ketolide 14 series. But these aryl groups (a - m) cannot supply the resulting compounds 8 and 14, unlike corresponding the 6-allyl ketolide 20 series, with activity against constitutively resistant Streptococcus pneumoniae. However, hybrids of macrolides and quinolones (8, 14 and 20, Ar = n - t) exhibited not only high activities against susceptible, inducibly erm-mediated resistant, and efflux-mediated resistant strains, but also significantly improved potencies against constitutively resistant Streptococcus pneumoniae and Streptococcus pyogenes. The capacity was highlighted by introduction of newly designed carbamoyl quinolones (q, r, s and t) rather than commonly seen carboxy quinolones (o and p) as the pharmacophores. Structure-activity relationships and molecular modelling indicated that 8r, 14r and 20q may have different binding sites compared to current erythromycins. Moreover, 8r, 14r and 20q have 2.5-3.6 times prolonged half-life and 2.3- to 2.6-fold longer mean residence time in vivo over telithromycin. These findings pave the way for rational design of novel non-telithromycin macrolides that target new binding sites within bacterial ribosomes. (C) 2019 Elsevier Masson SAS. All rights reserved.
机译：组成型红霉素抗性的过热度比诱导耐心和流出的抗性菌株更难以解决。合成并评价第4代第4代2-氟9-肟红霉素酮霉素酮霉素。与先前报道的未取代的杂芳基相反，掺入取代的杂芳基（A-M）被证明是有益于增强9-支撑酮酮8系和9-烯丙基酮胺14系列的活性的有益。但是这些芳基（A-M）不能提供所得化合物8和14，与相应的6-烯丙基酮酮20系列不同，具有针对组成抗性链球菌肺炎料的活性。然而，大环内酯和喹诺酮类（8,14和20，AR = N-T）的杂种不仅表现出对抗易感，诱导的ERM介导的抗性和流出介导的抗性菌株的高活性，而且显着改善了对组成抗性链球菌的型效力肺炎和链球菌的活性。通过引入新设计的氨基甲酰喹啉酮（Q，R，S和T）而不是常见的羧基喹诺酮（O和P）作为药物的能力突出了容量。结构 - 活性关系和分子建模表明，与电流红霉素相比，8R，14R和20Q可以具有不同的结合位点。此外，8R，14R和20Q延长了2.5-3.6倍的半衰期，在Telitroomycin的体内体内延长了2.3至2.6倍。这些发现为靶向细菌核糖体内的新结合位点的新型非致铬霉素大环内酯的理性设计铺平了道路。 （c）2019年Elsevier Masson SAS。版权所有。

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