新型喹唑啉类化合物的抑菌活性筛选及作用机理初步研究
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摘要
本论文采用室内生长速率法对本课题组新合成的数十个喹唑啉类化合物进行了抑菌活性的初步筛选，通过筛选发现含喹唑啉母环结构的化合物具有较好的抗真菌活性，如6-氟-4-乙硫基喹唑啉(q17)、6-氟-4-正丙硫基喹唑啉(q21)和6-氟-4-烯丙硫基喹唑啉(q25)等化合物。实验结果表明：化合物6-氟-4-乙硫基喹唑啉抑菌效果最好，对小麦赤霉病原菌(G．zeae)、辣椒枯萎病原菌(F．oxysporum)、苹果腐烂病原菌(C．mandshurica)、半夏立枯病原菌(R．solani)、水稻纹枯病原菌(T．cucumeris)、马铃薯晚疫病原菌(P．infestans)、油菜菌核病原菌(S．sclerotiorum)、黄瓜灰霉病原菌(B．cinerea)、苹果炭疽病原菌(C．gloeosporioides)九种植物病原真菌都有较好的生物活性，其EC_(50)分别为12.41μg／mL、18.19μg／mL、19.24μg／mL、24.91μg／mL、30.75μg／mL、26.77μg／mL、11.40μg／mL、8.31μg／mL、64.18μg／mL，对某些病原菌的生物活性甚至超过了商品药剂恶霉灵。
由于其较高的抑菌活性，本文选择抑菌活性最好的化合物6-氟-4-乙硫基喹唑啉(q17)为研究对象，以辣椒枯萎病原菌为作用靶标，并以商品药剂恶霉灵为对照，对其作用机理进行了初步研究。实验结果表明：化合物q17在100μg／mL时，强烈抑制辣椒枯萎病原菌小孢子的萌发；使菌丝细胞出现肿胀，细胞质凝缩，并能诱导细胞膜通透性的增加；同时降低病原菌菌体细胞内包括还原糖、N-乙酰葡萄糖胺在内的一系列生物分子的含量；并抑制几丁质酶的活性；影响细胞对培养基中葡萄糖的吸收；但对蛋白合成几乎没有影响。
The effect of new quinazoline derivatives were tested against pathogenic fungi by using the mycelial growth rate method in the laboratory. Preliminary bioassay tests showed that some compounds possessed good antifungal activities, such as 4-ethylthio-6-fluoroquinazoline(q17), 4-n-Propylthio-6-fluoroquinazoline(q21) and 4-allylthio-6-fluoroquinazoline(q25). Further bioassays disclosed that compounds q17, q21 and q25 showed remarkable inhibitory effect on all kinds of tested plant pathogenic fungi with q17 showing the best results. The EC50 of q17 on G. zeae, F. oxysporum, C. mandshurica, R. solani, T. cucumeris, P. infestans, S. sclerotiorum, B. cinerea, C. gloeosporioides were 12.41 g/mL, 18.19μg/mL, 19.24μg/mL, 24.91μg/mL, 30.75μg/mL, 26.77μg/mL, 11.40μg/mL, 8.31μg/mL, 64.18μg/mL, respectively. Compound q17 had more potent antifungal activities against most of the tested fungi, and showed a broad-spectrum bioactivity.
Action mechanisim of compound(q17) against F. oxysporum was studied, and hymexazol serving as the control. After treating F. oxysporum with compound q17 at 100μg/mL, only 6.5% of its spore bourgeoned. The permeability of the cell membrane increased along with the malformation of the hyphal and condensation of its endosome. After treatment with compound q17 at 100μg/mL within 12 h, the mycelial reducing sugar, D-GlcNAc content and chitinase activity declined, and the ability of sugar absorption by the cell from the culture medium was depressed, but the soluble protein content showed no obvious change.
由于其较高的抑菌活性，本文选择抑菌活性最好的化合物6-氟-4-乙硫基喹唑啉(q17)为研究对象，以辣椒枯萎病原菌为作用靶标，并以商品药剂恶霉灵为对照，对其作用机理进行了初步研究。实验结果表明：化合物q17在100μg／mL时，强烈抑制辣椒枯萎病原菌小孢子的萌发；使菌丝细胞出现肿胀，细胞质凝缩，并能诱导细胞膜通透性的增加；同时降低病原菌菌体细胞内包括还原糖、N-乙酰葡萄糖胺在内的一系列生物分子的含量；并抑制几丁质酶的活性；影响细胞对培养基中葡萄糖的吸收；但对蛋白合成几乎没有影响。
The effect of new quinazoline derivatives were tested against pathogenic fungi by using the mycelial growth rate method in the laboratory. Preliminary bioassay tests showed that some compounds possessed good antifungal activities, such as 4-ethylthio-6-fluoroquinazoline(q17), 4-n-Propylthio-6-fluoroquinazoline(q21) and 4-allylthio-6-fluoroquinazoline(q25). Further bioassays disclosed that compounds q17, q21 and q25 showed remarkable inhibitory effect on all kinds of tested plant pathogenic fungi with q17 showing the best results. The EC50 of q17 on G. zeae, F. oxysporum, C. mandshurica, R. solani, T. cucumeris, P. infestans, S. sclerotiorum, B. cinerea, C. gloeosporioides were 12.41 g/mL, 18.19μg/mL, 19.24μg/mL, 24.91μg/mL, 30.75μg/mL, 26.77μg/mL, 11.40μg/mL, 8.31μg/mL, 64.18μg/mL, respectively. Compound q17 had more potent antifungal activities against most of the tested fungi, and showed a broad-spectrum bioactivity.
Action mechanisim of compound(q17) against F. oxysporum was studied, and hymexazol serving as the control. After treating F. oxysporum with compound q17 at 100μg/mL, only 6.5% of its spore bourgeoned. The permeability of the cell membrane increased along with the malformation of the hyphal and condensation of its endosome. After treatment with compound q17 at 100μg/mL within 12 h, the mycelial reducing sugar, D-GlcNAc content and chitinase activity declined, and the ability of sugar absorption by the cell from the culture medium was depressed, but the soluble protein content showed no obvious change.
引文
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[3] 万琴，徐尚成．新杀虫剂R-768[J]．世界农药，1999，21(6)：57-59．
[4] 刘昕，黄润秋，李慧英，杨昭．O-(4-喹唑啉)羟肟酸硫代酯(酰胺)类化合物的合成及生物活性[J]，应用化学，1999，16(2)：23-26．
[5] 刘进前，徐小岗，陈秀华，余爱珍，戴祖瑞，张秀平．2，4-二氨基-5-氯6-取代苄氨基喹唑啉的合成及其抗疟、抗肿瘤和抗菌活性[J]，药学学报，1991，26(11)：821-828．
[6] 刘云海，秦国伟，丁水平，吴晓云．板蓝根化学成分的研究(Ⅲ)[J]．中草药，2002，33(2)：97-99．
[7] 刘刚，宋宝安，桑维均，杨松，金林红，丁雄．N-取代芳环4-氨基喹唑啉类化合物的合成及生物活性研究[J]．有机化学，2004，23(10)：1296-1299．
[8] 刘庆，周伟澄，余爱珍，张庆文，张秀平．7-[4-(2，4-二氨基喹唑啉-6-基)哌嗪-1-基]-6-氟喹诺酮类化合物的合成和抗菌作用[J]．中国医药工业杂志，1996，27(3)：104-107．
[9] 李合生．植物生理生化实验原理和技术[M]．北京：高等教育出版社．2000，197-199．
[10] 张一宾．近几年新开发的化学农药品种[J]．现代农药，2003，2(4)：31-36．
[11] 张建华．6-氨基藜芦腈和呋喃锂(钠)在哌唑嗪及其他喹唑啉类降压药物合成中的应用[J]．北京医药，1994，28(2)：22-31．
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