Synthesis and biological activity of certain alkyl 5-(alkoxycarbonyl)-1H-benzimidazole-2-carbamates and related derivatives: a new class of potential antineoplastic and antifilarial agents.
Synthesis and biological activity of certain alkyl 5-(alkoxycarbonyl)-1H-benzimidazole-2-carbamates and related derivatives: a new class of potential antineoplastic and antifilarial agents.
复制标题
某些烷基5-（烷氧基羰基）-1H-苯并咪唑-2-氨基甲酸酯及相关衍生物的合成和生物活性：一类新的潜在抗肿瘤和抗丝虫剂。
DOI：
10.1021/jm00081a016
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发表时间：
1992
影响因子：
7.3
通讯作者：
Townsend,LB
中科院分区：
文献类型：
--
作者：
Ram,S;Wise,DS;Wotring,LL;McCall,JW;Townsend,LB
通过适当的醇或胺与酰氯衍生物6a或6 b在室温下反应，合成了一系列5-（烷氧羰基）-1H-苯并咪唑-2-氨基甲酸甲酯和乙酯（7-19）和5-氨甲酰基-1H-苯并咪唑-2-氨基甲酸甲酯（24-34）。醇与酰氯6a在回流温度下反应，以良好的产率得到酯交换产物20 -23。用取代的苯甲酰氯处理5-氨基-IH-苯并咪唑-2-氨基甲酸甲酯，得到5-苯甲酰氨基-IH-苯并咪唑-2-氨基甲酸甲酯（36-38）。化合物9、16、20和22在L1210细胞中表现出显著的生长抑制，ICgg < 1 µ。这一系列化合物的生长抑制似乎与有丝分裂纺锤体中毒有关。所有测试的化合物9、10、19、20、22和23在有丝分裂中引起L1210细胞的显著积累。化合物7、9、19、25、26、27和36对实验感染的沙鼠体内的帕杭丝虫、卡氏矶丝虫和马铃薯刺螯线丝虫成虫表现出显着的体内抗丝虫活性。寄生虫病丝虫病仍然是世界卫生的一个主要问题，影响着超过2.5亿人。人类丝虫病，即班氏吴策线虫、马来丝虫和盘尾丝虫是造成包括毁容和失明在内的大量残疾的原因。2.这些肠外线虫，特别是O.由于丝虫成虫（巨丝虫）和它们的早期幼虫（微丝蚴）栖息在宿主的体腔、血管、消化道和皮下组织中，因此已证明难以治疗。尽管大环内酯抗生素伊维菌素最近已成功地用于治疗疾病的微丝蚴阶段，但尚未发现任何药物对成虫有效。因此，寻找一种广谱的杀微丝蚴剂仍然是迫切的。
A series of methyl and ethyl 5-(alkoxycarbonyl)-lH-benzimidazole-2-carbamates (7-19) and methyl 5-car bamoyl-lH-benzimidazole-2-carbamates (24-34) have been synthesized via the reaction of an appropriate alcohol or amine with the acid chloride derivatives 6a or 6b at room temperature. Reaction of an alcohol with acid chloride 6a at reflux temperature afforded transesterified products20-23 in good yield. Treatment of methyl 5-amino-lH-benzimidazole-2-carbamate with substituted benzoyl chlorides furnished the methyl 5-benzamido-lif-benz-imidazole-2-carbamates (36-38). Compounds 9, 16, 20, and 22 demonstrated significant growth inhibition in L1210 cells with ICgg’s< 1 µ. Growth inhibition by this series of compounds appears to be associated with mitotic spindle poisoning. All the compounds tested, 9, 10, 19, 20, 22, and 23, caused significant accumulation of L1210 cells in mitosis. Compounds 7, 9, 19, 25, 26, 27, and 36 showed significantin vivo antifilarial activity against adult worms of Brugia pahangi, Litomosoides carinii, and Acanthocheilonema viteae in experimentally infected jirds.The parasitic disease filariasis remains a major problem for world health, affecting over 250 million people. Human filarial diseases, ie, Wuchereria bancrofti, Brugia malayi, and Onchocerca volvulus are responsible for a large num-ber of disabilities including disfigurement and blindness. 2 These extraintestinal nematodes, especially O. volvulus, have proved difficult to treat since the adult filarial nem-atodes (macrofilariae) and their early larval stages (microfilariae) inhabit the body cavities, blood vessels, lymphatics, and subcutaneoustissues of the host. Al-though the macrocyclic lactone antibiotic ivermectin has recently been used successfully to treat the microfilarial stage of the disease, 3, 4 no drug has been found to be ef-fective against the adult worm. Thus, the search for a broad-range macrofilaricidal agent remains urgent.