甲氟喹衍生物的設(shè)計(jì)、合成及抗血吸蟲(chóng)活性研究以及泛酸合成酶抑制劑的設(shè)計(jì)、合成及活性研究
發(fā)布時(shí)間：2018-12-06 13:29
【摘要】：本文包含兩個(gè)部分。本文第一部分是甲氟喹衍生物的設(shè)計(jì)、合成及抗血吸蟲(chóng)活性研究血吸蟲(chóng)病是由血吸蟲(chóng)引起的一種急性與慢性寄生蟲(chóng)病。寄生人體的主要蟲(chóng)種有日本血吸蟲(chóng)、曼氏血吸蟲(chóng)和埃氏血吸蟲(chóng)。目前吡喹酮(PZQ)是用于治療日本血吸蟲(chóng)病的唯一特效藥物。過(guò)分依賴吡喹酮必然存在潛在的危險(xiǎn)�？汞懰幖追话l(fā)現(xiàn)對(duì)血吸蟲(chóng)童蟲(chóng)和成蟲(chóng)均有很高的殺滅作用,但臨床研究發(fā)現(xiàn)其單獨(dú)使用時(shí)對(duì)血吸蟲(chóng)病治療效果不佳。本文將甲氟喹作為先導(dǎo)物,為了減小甲氟喹的中樞神經(jīng)副作用,參考β受體抑制劑的設(shè)計(jì)原理,構(gòu)建了新的結(jié)構(gòu)骨架,在甲氟喹的側(cè)鏈中插入一個(gè)氧亞甲基,通過(guò)變換不同的氨基和芳環(huán)來(lái)進(jìn)行構(gòu)效關(guān)系研究。全文共合成了52個(gè)新化合物,24個(gè)化合物體外對(duì)日本血吸蟲(chóng)童蟲(chóng)的LD50小于10μM,其中有10個(gè)化合物抗童蟲(chóng)活性與甲氟喹相當(dāng)或者更好。7個(gè)化合物體外對(duì)日本血吸蟲(chóng)成蟲(chóng)的LD50小于10μM。其中化合物QC010105與甲氟喹體外抗血吸蟲(chóng)童蟲(chóng)和成蟲(chóng)活性相當(dāng)。雖然該類化合物在體內(nèi)實(shí)驗(yàn)中表現(xiàn)不佳,但證明了該類化合物是一類值得進(jìn)一步研究的抗血吸蟲(chóng)化合物。下一步研究可以針對(duì)二三氟甲基喹啉這個(gè)基團(tuán)進(jìn)行改造,期待獲得活性更好的抗血吸蟲(chóng)新藥。本文第二部分是泛酸合成酶抑制劑的設(shè)計(jì)、合成和活性研究。耐藥結(jié)核病例的不斷增長(zhǎng),和艾滋病的流行,使得研發(fā)抗結(jié)核藥物是新藥研發(fā)的熱點(diǎn)之一,雖然近3年有兩個(gè)抗耐藥結(jié)核的藥物被批準(zhǔn)上市,但治療耐藥結(jié)核的形式卻依然嚴(yán)峻,不斷有新的耐藥菌被發(fā)現(xiàn),并且XDR-TB目前依然無(wú)藥可治。由pan C基因編碼的泛酸合成酶是一個(gè)可能的抗結(jié)核藥物作用靶點(diǎn),它與目前廣泛運(yùn)用的一線抗結(jié)核藥物的作用靶點(diǎn)完全不同,從而不會(huì)導(dǎo)致交叉耐藥。目前發(fā)現(xiàn)的泛酸合成酶抑制劑的數(shù)量很有限,而且所有抑制劑幾乎都對(duì)結(jié)核桿菌無(wú)效。本文以模擬泛酸合成酶催化反應(yīng)的中間體的方式合成了10個(gè)新的泛酸合成酶抑制劑。所有抑制劑都在C2位保持了與泛酸合成酶催化的反應(yīng)中間體相同的手性構(gòu)象,并分別對(duì)Pantioc acid部分,糖環(huán)部分以及堿基部分進(jìn)行改造獲得了不同的抑制劑。我們將抑制劑4-8進(jìn)行了抑酶活性的測(cè)定,得到其抑制常數(shù),并利用計(jì)算機(jī)輔助設(shè)計(jì)對(duì)其結(jié)果進(jìn)行了解釋。最后對(duì)其進(jìn)行了抗結(jié)核桿菌的活性評(píng)價(jià)。所有抑制劑是都是底物pantoate的競(jìng)爭(zhēng)性抑制劑,活性最好的抑制劑4相對(duì)于pantoate的Ki為0.27±0.04μM,與文獻(xiàn)報(bào)道的差向異構(gòu)體混合物3j相當(dāng)(Ki為0.3μM)。雖然測(cè)定Ki的方法不同,但也說(shuō)明pantioc acid片段的C2位的手性對(duì)活性影響不大。通過(guò)計(jì)算機(jī)模擬對(duì)接試驗(yàn),我們發(fā)現(xiàn)抑制劑4與蛋白質(zhì)共有9處氫鍵相互作用,作用很強(qiáng),這也解釋了抑制劑的較高活性。其余抑制劑的結(jié)構(gòu)改變都會(huì)使氫鍵的減少或減弱,導(dǎo)致抑酶活性下降。抑制劑4-8雖然體現(xiàn)出較好的抑酶活性,但是對(duì)結(jié)核桿菌卻是無(wú)效的�；衔锟赡軣o(wú)法在細(xì)胞內(nèi)部積累,化合物可能無(wú)法進(jìn)入到結(jié)核菌內(nèi)部或者被主動(dòng)外排,造成活性喪失。到目前為止,所有泛酸合成酶抑制劑的報(bào)道都局限于對(duì)酶的抑制。而那些抑酶活性很好的泛酸合成酶抑制劑卻很少有報(bào)道其抗結(jié)核活性,這也從另一個(gè)方面說(shuō)明目前泛酸合成酶可能不是一個(gè)抗結(jié)核的理想靶點(diǎn)。
[Abstract]:This article contains two parts. The first part of this paper is the design, synthesis and anti-schistosome activity in the first part of this paper, which is an acute and chronic parasitic disease caused by the schistosome. The main insect species of the parasitic human body are Schistosoma japonicum, Schistosoma mansoni and Schistosoma japonicum. PZQ is the only special drug used for the treatment of schistosomiasis in Japan. It is inevitable that the excessive dependence on the oxycodone is a potential hazard. The antimalarial drug was found to have a high killing effect on the worm and the adult, but the clinical study found that it was not good for the treatment of schistosomiasis. In order to reduce the central nervous side effect of the alpha-fluorobenzene, a new structural framework is constructed, and an oxygen methylene group is inserted into the side chain of the methyl fluoride. The structure-effect relationship was studied by transforming different amino and aromatic rings. A total of 52 new compounds were synthesized, and the LD50 of 24 compounds in vitro was less than 10. m The LD50 of the compound QC010105 was less than 10. m u.M. The activity of the compound QC010105 was comparable to that of the anti-schistosome and the adult in vitro. Although the compounds are not good in in vivo experiments, it is proved that the compounds are a class of anti-schistosome compounds that are worthy of further study. The next study can be carried out for the modification of the group of ditrifluoromethyl and the like, and is expected to obtain a new anti-schistosome new drug with better activity. The second part of this paper is the design, synthesis and activity of pantothenic acid synthetase inhibitor. The increasing number of drug-resistant tuberculosis cases and the prevalence of AIDS have led to the development of anti-tuberculosis drugs as one of the hot spots in the research and development of new drugs. Although two anti-drug-resistant tuberculosis drugs have been approved for listing in the last three years, the form of the treatment of drug-resistant tuberculosis is still serious, and new drug-resistant bacteria have been found, and XDR-TB is still not available for treatment. The pantothenic acid synthetase encoded by the pan C gene is a potential target for anti-tuberculosis drugs, which is completely different from the target target of the first-line anti-tuberculosis drugs which are widely used at present, so that the cross resistance can not be caused. The amount of pantothenic acid synthetase inhibitor currently found is limited and all the inhibitors are almost ineffective for tubercle bacillus. In this paper, 10 new inhibitors of pantothenic acid synthase were synthesized in the form of an intermediate of the catalytic reaction of pantothenic acid synthase. All the inhibitors maintained the same chiral conformation as the reaction intermediate catalyzed by the pantothenic acid synthase at the C2 position, and different inhibitors were obtained for the transformation of the Pantic acid portion, the sugar ring portion, and the base portion, respectively. The inhibitor 4-8 was determined to inhibit the activity of the enzyme, and the inhibition constant was obtained, and the results were explained using the computer-aided design. and then the activity of the anti-tubercle bacillus is evaluated. All of the inhibitors are competitive inhibitors of the substrate pantate, and the activity of the best inhibitor 4 relative to pantate is 0.27 to 0.04. m u.M, and the difference reported in the literature is comparable to the heterogeneous mixture 3j (Ki is 0.3. mu.M). Although the method of determining Ki is different, it is also indicated that the chiral effect of the C2-position of the pantic acid fragment is not large. By computer simulation of the docking test, we found that the inhibitor 4 interacts with a total of 9 hydrogen bonds in the protein, and the effect is strong, which also explains the higher activity of the inhibitor. The structural changes of the rest of the inhibitor will decrease or decrease the hydrogen bond, resulting in a decrease in the enzyme-inhibiting activity. Although the inhibitor 4-8 shows a better enzyme-inhibiting activity, it is not effective for the tubercle bacillus. The compound may not accumulate inside the cell, and the compound may not be able to enter or be actively discharged into the tubercle bacillus, resulting in loss of activity. So far, the reports of all pantothenic acid synthetase inhibitors are limited to the inhibition of the enzyme. However, the anti-tuberculosis activity of the pantothenic acid synthetase inhibitor which is very good in the enzyme-inhibiting activity is rarely reported, which also shows that the present pantothenic acid synthetase may not be an ideal target for anti-tuberculosis.
【學(xué)位授予單位】：蘇州大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R914;R96
本文編號(hào)：2366101
[Abstract]:This article contains two parts. The first part of this paper is the design, synthesis and anti-schistosome activity in the first part of this paper, which is an acute and chronic parasitic disease caused by the schistosome. The main insect species of the parasitic human body are Schistosoma japonicum, Schistosoma mansoni and Schistosoma japonicum. PZQ is the only special drug used for the treatment of schistosomiasis in Japan. It is inevitable that the excessive dependence on the oxycodone is a potential hazard. The antimalarial drug was found to have a high killing effect on the worm and the adult, but the clinical study found that it was not good for the treatment of schistosomiasis. In order to reduce the central nervous side effect of the alpha-fluorobenzene, a new structural framework is constructed, and an oxygen methylene group is inserted into the side chain of the methyl fluoride. The structure-effect relationship was studied by transforming different amino and aromatic rings. A total of 52 new compounds were synthesized, and the LD50 of 24 compounds in vitro was less than 10. m The LD50 of the compound QC010105 was less than 10. m u.M. The activity of the compound QC010105 was comparable to that of the anti-schistosome and the adult in vitro. Although the compounds are not good in in vivo experiments, it is proved that the compounds are a class of anti-schistosome compounds that are worthy of further study. The next study can be carried out for the modification of the group of ditrifluoromethyl and the like, and is expected to obtain a new anti-schistosome new drug with better activity. The second part of this paper is the design, synthesis and activity of pantothenic acid synthetase inhibitor. The increasing number of drug-resistant tuberculosis cases and the prevalence of AIDS have led to the development of anti-tuberculosis drugs as one of the hot spots in the research and development of new drugs. Although two anti-drug-resistant tuberculosis drugs have been approved for listing in the last three years, the form of the treatment of drug-resistant tuberculosis is still serious, and new drug-resistant bacteria have been found, and XDR-TB is still not available for treatment. The pantothenic acid synthetase encoded by the pan C gene is a potential target for anti-tuberculosis drugs, which is completely different from the target target of the first-line anti-tuberculosis drugs which are widely used at present, so that the cross resistance can not be caused. The amount of pantothenic acid synthetase inhibitor currently found is limited and all the inhibitors are almost ineffective for tubercle bacillus. In this paper, 10 new inhibitors of pantothenic acid synthase were synthesized in the form of an intermediate of the catalytic reaction of pantothenic acid synthase. All the inhibitors maintained the same chiral conformation as the reaction intermediate catalyzed by the pantothenic acid synthase at the C2 position, and different inhibitors were obtained for the transformation of the Pantic acid portion, the sugar ring portion, and the base portion, respectively. The inhibitor 4-8 was determined to inhibit the activity of the enzyme, and the inhibition constant was obtained, and the results were explained using the computer-aided design. and then the activity of the anti-tubercle bacillus is evaluated. All of the inhibitors are competitive inhibitors of the substrate pantate, and the activity of the best inhibitor 4 relative to pantate is 0.27 to 0.04. m u.M, and the difference reported in the literature is comparable to the heterogeneous mixture 3j (Ki is 0.3. mu.M). Although the method of determining Ki is different, it is also indicated that the chiral effect of the C2-position of the pantic acid fragment is not large. By computer simulation of the docking test, we found that the inhibitor 4 interacts with a total of 9 hydrogen bonds in the protein, and the effect is strong, which also explains the higher activity of the inhibitor. The structural changes of the rest of the inhibitor will decrease or decrease the hydrogen bond, resulting in a decrease in the enzyme-inhibiting activity. Although the inhibitor 4-8 shows a better enzyme-inhibiting activity, it is not effective for the tubercle bacillus. The compound may not accumulate inside the cell, and the compound may not be able to enter or be actively discharged into the tubercle bacillus, resulting in loss of activity. So far, the reports of all pantothenic acid synthetase inhibitors are limited to the inhibition of the enzyme. However, the anti-tuberculosis activity of the pantothenic acid synthetase inhibitor which is very good in the enzyme-inhibiting activity is rarely reported, which also shows that the present pantothenic acid synthetase may not be an ideal target for anti-tuberculosis.
【學(xué)位授予單位】：蘇州大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R914;R96
【參考文獻(xiàn)】
相關(guān)碩士學(xué)位論文 前1條
1 龔立康;以泛酸合成酶為靶點(diǎn)的抗結(jié)核藥物篩選模型的建立和應(yīng)用[D];中國(guó)協(xié)和醫(yī)科大學(xué);2006年
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