本文選題：大環(huán)內(nèi)酯 + 抗菌活性��； 參考：《山東大學(xué)》2016年博士論文

【摘要】：大環(huán)內(nèi)酯是治療細(xì)菌感染的重要藥物,活性主要來自化合物的大環(huán)。阿奇霉素和克拉霉素為第二代大環(huán)內(nèi)酯,它們比第一代大環(huán)內(nèi)酯紅霉素的藥代動力學(xué)性質(zhì)更好,穩(wěn)定性更強(qiáng)。然而,細(xì)菌耐藥性的出現(xiàn)促使研究出對耐藥菌活性更好的新型大環(huán)內(nèi)酯類藥物成為一項(xiàng)亟待完成的任務(wù)。在核糖體的50S亞基上,從肽酰轉(zhuǎn)移酶的中心到肽釋放通道有三個(gè)可能結(jié)合位置。大環(huán)內(nèi)酯通過和50S亞基結(jié)合以及堵塞肽通道出口,阻止蛋白質(zhì)合成。據(jù)報(bào)道紅霉素的2'位羥基能夠與23SrRNA上結(jié)構(gòu)域V的A2058結(jié)合(這是第一個(gè)結(jié)合位點(diǎn))。第二個(gè)位點(diǎn)是酮內(nèi)酯的11,12位氨基甲酸酯側(cè)鏈與A752結(jié)合,能保證酮內(nèi)酯類對耐藥性菌種的優(yōu)良活性。第三個(gè)結(jié)合位點(diǎn)是CP-544372的4"-O-芳烷基基團(tuán)能和50S亞基的A位和P位的核苷酸發(fā)生作用。最近幾年,耐藥性愈加惡化,新的大環(huán)內(nèi)酯抗生素研發(fā)的需求十分迫切。耐藥性主要是erm編碼的核糖體甲基化和mefA編碼的外排泵耐藥。由erm表達(dá)的甲基化酶讓A2058甲基化,造成了主要的大環(huán)內(nèi)酯耐藥。由mef基因表達(dá)的外排泵會把藥物泵到胞外造成中等水平的耐藥。因此,迫切需要研發(fā)出能夠克服肺炎鏈球菌耐藥性的大環(huán)內(nèi)酯抗生素,科學(xué)家也希望新的結(jié)構(gòu)能夠保持優(yōu)良的藥代動力學(xué)性質(zhì)同時(shí)對酸穩(wěn)定。綜上所述,我們以肽酰轉(zhuǎn)移酶中心區(qū)域(peptidyl transferase center, PTC)的核苷酸為靶點(diǎn),設(shè)計(jì)了3-O-芳烷基氨基甲酸酯一脫克拉定糖阿奇霉素11,12環(huán)碳酸酯A。我們希望3-0-芳烷基氨基甲酸酯側(cè)鏈能夠與PTC區(qū)域的核苷酸G2505,C2610和U2586等通過氫鍵、π鍵堆積和靜電作用結(jié)合。在此基礎(chǔ)上,我們以肽酰轉(zhuǎn)移酶中心區(qū)域和結(jié)構(gòu)域II的A752為靶點(diǎn),設(shè)計(jì)3-O-芳烷基氨基甲酸酯-11-O-芳烷基氨基甲酸酯阿奇霉素B,同時(shí)進(jìn)行了活性測定。它的11位側(cè)鏈可以與A752作用,產(chǎn)生核糖體親和力。同時(shí),我們設(shè)計(jì)了以erm介導(dǎo)的甲基化的核糖體為靶點(diǎn)的2'-O-芳烷基氨基甲酸酯-11,12-環(huán)碳酸酯脫糖阿奇霉素C-E。C-E是我們合成的3個(gè)系列的未見文獻(xiàn)報(bào)道的全新的化合物,2'-O-側(cè)鏈可以與A2058(在耐輻射球菌中是A2041)和其周圍核苷酸通過疏水鍵、氫鍵和π鍵作用結(jié)合。我們合成了71個(gè)新型氮雜內(nèi)酯類,它們的結(jié)構(gòu)已通過幾種譜進(jìn)行了確證。之后,我們采用肉湯稀釋法進(jìn)行目標(biāo)化合物的體外活性測定,以最小抑菌濃度(MIC, minimum inhibitory concentrations)表示�？咕钚钥偨Y(jié)如下：1.對陰性菌活性：化合物C6、D1和D2對大腸桿菌活性最強(qiáng),MIC值是32μg/mL,與對照藥克拉霉素相當(dāng)(32μg/mL)。活性最好化合物對銅綠假單胞菌的MIC值是4μg/mL,比對照藥顯著提高。2.對敏感菌活性：化合物B7對敏感性金黃色葡萄球菌、敏感性化膿球菌活性最強(qiáng),MIC值分別為1和0.03μg/mL。令人鼓舞的是,化合物B8(0.5μg/mL)對枯草芽孢桿菌活性比對照藥阿奇霉素提高了兩倍(1 μg/mL)。3.對耐藥菌活性：對表皮葡萄球菌活性最好的為B8 (0.125 μg/mL),比對照的阿奇霉素(0.25μg/mL)和克拉霉素(0.25μg/mL)提高了兩倍。化合物A3、B7、C15、C16和D8對耐藥金葡菌的MIC是32μ8/mL,與對照藥物克拉霉素相等(32μg/mL)�；衔顰1對紅霉素耐藥的化膿球菌有強(qiáng)的活性,MIC是8 μg/mL,活性比對照藥物提高了32倍(256μg/mL)。E3對耐藥化膿菌的MIC為16 μg/mL,活性比對照藥強(qiáng)16倍。化合物2, A3, A8, A15, B4, B6, B8, C13, D8, E2, E4, E8和E9也表現(xiàn)出了對耐藥性化膿球菌中等水平的活性(32μg/mL)。多數(shù)化合物對erm耐藥鏈球菌有比對照提高許多的活性�；钚宰罴训腂8對ermB鏈球菌的活性比對照(256 μg/m L)提高256倍,它的MIC值是1μg/mL�；衔顱6、B7、A7、A8對mefA耐藥菌的MIC分別為0.5μg/mL,0.25 μg/mL,1 μg/mL,1μg//mL,比對照藥物阿奇霉素顯著提高(4μg/mL)�；衔顰3 (1 μg/mL), B8 (1 μg/mL), B2 (2 μg/mL), B7 (2 μg/mL), C15 (2 μg/mL),表現(xiàn)出了優(yōu)異的抗mefA+ermB型耐藥肺炎鏈球菌活性,抗菌活性分別比阿奇霉素(256 μg/mL)提高了256倍,256倍,128倍,128倍,128倍。對71個(gè)化合物的MIC分析而得出的構(gòu)效關(guān)系：1.B8對枯草芽孢桿菌(0.5 μg/mL).表皮(0.125 μg/mL).erm型耐藥的肺炎鏈球菌(1μg/mL)和ermB+mefA鏈球菌(1μg/mL)的活性都為最佳,可能是B8的11位側(cè)鏈和A752作用,而且3-O-芳烷基氨基甲酸酯基團(tuán)與PTC區(qū)域的核苷酸結(jié)合位點(diǎn)結(jié)合。這能提高化合物對敏感和耐藥菌活性,尤其是對erm和erm+mef鏈球菌。結(jié)合方式包括氫鍵、靜電力和π鍵堆積等。2.對于敏感的金葡菌、芽孢桿菌、表皮葡萄球菌、erm+mef鏈球菌和耐藥的化膿菌,3-O-正己基D8的活性比3-O-正戊基D7更好。具有3-O-正己基的B8也表現(xiàn)出對這4種細(xì)菌強(qiáng)的活性。所以C-3位側(cè)鏈末端的正己基基團(tuán)對抗菌活性的提高是有利的。我們推測3-O-正己基氨基甲酸酯側(cè)鏈具有適宜的長度和空間構(gòu)象,所以能夠到達(dá)PTC區(qū)域并與核苷酸發(fā)生作用。3.經(jīng)過體外抗菌活性測試發(fā)現(xiàn),化合物C3,C6-C7,C11-C13,D7-D8, E2-E4, E7-E9對ermB型耐藥性肺炎鏈球菌的活性是16-64 μg/mL,是對照藥物(MIC為256 μg/mL)的4-16倍。我們猜測被測化合物的2’OH可能通過氫鍵和范德華力與甲基化的A2058(A2041)或其附近核苷酸結(jié)合。總而言之,我合成71個(gè)3-0-脫克拉定糖阿奇霉素并測了活性。在此基礎(chǔ)上,本文中進(jìn)行了構(gòu)效關(guān)系分析和總結(jié)。
[Abstract]:Macrolides are the important drugs for treatment of bacterial infections, mainly due to the activity of macrocyclic compounds. Azithromycin and clarithromycin for second generation macrolides, they better pharmacokinetic properties first generation macrolide erythromycin is more stable. However, the emergence of resistant bacteria to research on drug resistant bacteria and better activity of the new high macrolides has become an urgent task. In the ribosomal 50S subunit of the enzyme, transfer from the center to the peptidyl peptide release channel has three possible binding sites of macrolides. Through 50S subunit binding and blocking peptide exit, prevent protein synthesis. According to reports of erythromycin 2'can 23SrRNA and hydroxyl A2058 binding domain of V (this is the first binding site). Second sites are 11,12 carbamate side chains and A752 ketolide combination, can guarantee the ketolides on Excellent activity of antibiotic resistant bacteria. The third binding sites are CP-544372 4 -O- aralkyl group and 50S subunits A and P nucleotides occurred. In recent years, drug resistance worse, new macrolide antibiotic research is urgently needed. Drug resistance is mainly ERM encoding ribosomal methylation and mefA encoding efflux pump resistance methylase. By the expression of ERM for A2058 methylation, resulting in macrolide resistance mainly by MEF gene. The expression of the efflux pump to pump drugs to the extracellular resistance caused by the medium level. Therefore, an urgent need to develop to overcome macrolide antibiotics for pneumonia antimicrobial resistance of Streptococcus, scientists also hope that the new structure can maintain excellent pharmacokinetic properties of acid stable. In summary, our region to the peptidyl transferase center (peptidyl transferase, center, PTC) nuclear glucoside Acid as the target, the design of 3-O- aryl alkyl carbamate a descladinosylation azithromycin 11,12 cyclocarbonate A. we want 3-0- aralkyl carbamic acid ester side chain with nucleotide G2505 PTC region, C2610 and U2586 by hydrogen bonding, with pi bond stacking and electrostatic interaction. On this basis, we transferase the central area and the II domain to the peptidyl A752 as the target, the design of 3-O- aryl alkyl carbamate -11-O- aryl alkyl carbamate and azithromycin B activity. The 11 side chain which can interact with A752 ribosome affinity. At the same time, we design the methylation mediated by ERM ribosome targeting 2'-O- aryl alkyl carbamate -11,12- cyclocarbonate desugarization azithromycin C-E.C-E is the new 3 series compounds we synthesized has not been reported in the literature, 2'-O- and A2058 in the side chain (radiation resistant ball Bacteria is A2041) and its surrounding nucleotides through hydrophobic binding, hydrogen bonds and pi bond. We synthesized 71 novel azalides, their structure has been through several spectra were confirmed. Then, we use the in vitro activity of target compounds by broth dilution method, the minimum inhibitory concentration (MIC, minimum inhibitory concentrations). The antibacterial activity are summarized as follows: 1. of negative bacteria activity: compounds C6, D1 and D2 of Escherichia coli was the strongest, MIC value is 32 g/mL, and the control drug is clarithromycin (32 g/mL). The best activity of compounds of Pseudomonas aeruginosa MIC value is 4 g/mL, compared with the control improve.2. on sensitive bacteria activity: compound B7 on the sensitivity of Staphylococcus aureus, sensitivity pyococcus activity, MIC values were 1 and 0.03 g/mL. encouragingly, compound B8 (0.5 g/ mL) of Bacillus subtilis rod 鑿屾椿鎬ф瘮瀵圭収鑽樋濂囬湁绱犳彁楂樹簡涓ゅ，

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