【作者】 许良忠；

【导师】 焦奎；

【作者基本信息】 中国海洋大学 ， 海洋化学， 2004， 博士

【摘要】 三唑类化合物因具有广泛的生物活性而备受重视，已有许多品种作为杀菌剂、植物生长调节剂和药物得到开发和应用，其中一些品种每年在国际上销售额超过1亿美元，如用于农业的杀菌剂丙环唑，每年销售额超过2亿美元，作为药物使用的氟康唑每年的销售额达15亿美元，成为N—杂环化合物中最重要、品种最多的杀菌剂类型。结构不同的三唑化合物具有不同的生物活性，研究开发新结构类型的三唑类化合物已成为该类化合物的研究热点。 本论文对三唑类化合物的结构、合成、应用、作用机制、构效关系及生物活性研究进展进行了综述，利用生物电子等排原理，将不同作用机制的活性基团引入三唑类化合物中，设计合成了15种结构类型共106个新三唑衍生物。通过~1HNMR、IR、MS、EA及部分化合物的晶体结构测定，确证了化合物的结构，探索了化合物的波谱性质及生物活性，发现部分化合物具有良好的杀菌和植物生长调节活性。具体研究内容及创新研究成果如下： 1) 首次将嘧啶环、1，3—二噻茂环、噻吩环、1，3—噻唑环、噻二唑环引入1，2，4—三唑类化合物结构中，研究了其合成方法、结构特点及生物活性，测定了部分化合物的晶体结构，对化合物的波谱性质及生物活性进行了分析。 2) 通过晶体结构测定，发现了噻吩环新的成环方式，首次合成出三唑环连噻吩环的新三唑化合物。生测结果表明，三唑环周围较多的杂环或芳环对生物活性有不利影响。 3) 首次合成出含丙硫酰胺结构类型的新三唑化合物，晶体结构测定表明，三唑环与芳环不共平面，但硫原子的裸露可能产生竞争性抑制，导致生物活性不三哇类P450一14DM抑制剂的合成、表征及生物活性研究高。 4)探索出实验室制备2一哇基芳乙酮或烷基乙酮的新方法，此法产物收率高，纯度好。 5)首次设计合成出含N，N一二烷基二硫代氨基甲酸酷的新三哇化合物，并测定了晶体结构，生测结果表明，该类化合物的综合抑菌效果好于商品三哇酮，具有商品化的潜力。 6)利用生物等排原理，设计合成了含芳硫基的新三哇化合物。生物活性主要受R基团的影响。R为叔丁基时，所合成的化合物在供试浓度下对小麦锈病菌的抑菌率达100%。 7)首次用3一氯一1，2一丙二醇替代丁二醇或戊二醇合成出含1，3一二氧戊环的新三哇化合物，生测结果表明，该类结构的三哇化合物属高活性结构类型。当苯环为2，4一二氯取代时，综合抑菌效果达A级(>90%)。 8)首次设计合成出含嗯醚哇类似物结构的新三哇化合物，生测结果表明，苯环上亚甲基的存在破坏了芳环间的共辘，生物活性降低。 9)利用有机磷化合物与三哇化合物不同作用机制的特点，设计合成了含0，0一二烷基二硫代磷酸醋的新三哇类化合物。IHNMR证明，与磷原子相联的基团旋转部分受阻，该类化合物稳定性不好导致活性一般。 10)首次采用量子化学Hartree一Fock等方法进行化合物结构与活性关系研究。所选两种化合物的总能量和偶极矩不同是导致其杀菌活性不同的主要原因。更多还原

【Abstract】 Triazole compounds have been found to show wide spread biological activities, many of them have been developed and used as fungicides, plant growth regulators and medicine. Some of them have more than 100 million dollars sale a year, propiconazole is one of them , used as agricultural fungicide, its total sale per year surpasses 200 million dollars. Another one is fluconazole, used as medicine, the total sale reaches 1500 million dollars per year. Triazole compounds have been the most important of types of fungicides in nitrogen heterocyclic compounds. Different structures of triazole compounds have different biological activities, developing novel structural triazole compounds is the research focus at present.In this thesis, We have reviewed the recent advances in the studies on the structures, synthesis, action mechanism, structure-activity relationship and biological activities of triazo’les, different active groups of action mechanism were inducted into the triazole compounds according to the concept of bioisosterism. One hundred and six novel triazole compounds in fifteen types of structure were designed and synthesized and their structures were confirmed by means of 1HNMR, IR, MS, EA and crystal structure determination. Spectral properties and biological activities were also researched and some of them were found to show good fungicidal activities and plant growth regulation activities. The contents and the primary contributions of the research are summarized as follows:1) Pyrimidine ring, 1,3-dithiolan ring, thiophene ring, 1,3-thiazolidine ring and thiadi -zole ring were inducted into structures of triazoles for the first time. Theirsynthesis methods, crystal structures and spectral properties were researched, respectively. The results of bioactivity test show that their fungicidal activities are not good except of triazoles bearing thiadizole ring.2) New manner of cyclization of thiophene ring was found by crystal structure determination, novel triazole compounds of triazole ring attached thiophene ring were synthesized for the first time. Bioactivity test shows that so many heterocycles or phenyl rings arrounding the triazole ring is not good for the biological activities.3) Novel tiazole compounds containing pentanethiomide group were synthesized for the first time. The crystal structure determination shows that triazole ring and phenyl ring is not planar, but the exposed sulphur atom might compete with nitrogen atom of triazole ring in inhibiting center iron atom of P-450, leading to the fungicidal activities are not high.4) New method for preparing intermediates 2-(l,2,4-triazole-l-yl)-aryl (or alkyl) ethanone was achieved, the yield and purity are both higher.5) Novel triazole compounds containing N, A/-dialkyldithiocarbamate were desi -gned and synthesized for the first time, the crystal structure of one of them was determined, the results of their biological tests show that the synthesized compounds have better comprehensive inhibiting efficiency towards tested fungus than triadimefon. Some of them possess the potency of commercialization.6) Novel triazole compounds containing arylsulphur group were designed and synthesized according to the concept of bioisosterism. Their bioactivities are mainly effected by R group. When R is t-Bu, corresponding compounds synthesized have the inhibiting rate of 100% towards wheat rust fungus at 50ug/mL.7) Novel triazole compounds containing 1,3-dioxiolane were synthesized by utilizing 3-chloro-l, 2-propanediol instead of butanedial or pentanediol. This type of the structure belongs to the one’s of high activities. When R is 2,4-Cl2C6H3, thecomprehensive inhibiting rate towards tested fungus reaches A grade ( > 90%).8) Novel triazole compounds as the analogues of difenoconazole were designed and synthesized for the first time. The result of bioactivity test shows that the existence of the methylene on the phenyl group destroys the conjugation system of the molecular, leading to the lower fungicidal activities.9) Novel更多还原