Synthesis and antimalarial activity of sixteen dispiro-1,2,4, 5-tetraoxanes: alkyl-substituted 7,8,15,16-tetraoxadispiro[5.2.5. 2]hexadecanes.
Synthesis and antimalarial activity of sixteen dispiro-1,2,4, 5-tetraoxanes: alkyl-substituted 7,8,15,16-tetraoxadispiro[5.2.5. 2]hexadecanes.
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十六种二螺-1,2,4,5-四恶烷的合成和抗疟活性：烷基取代的7,8,15,16-四氧二螺[5.2.5。
DOI：
10.1021/jm0000766
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发表时间：
2000
影响因子：
7.3
通讯作者：
Milhous,WK
中科院分区：
文献类型：
--
作者：
Vennerstrom,JL;Dong,Y;Andersen,SL;AgerJr,AL;Fu,H;Miller,RE;Wesche,DL;Kyle,DE;Gerena,L;Walters,SM;Wood,JK;Edwards,G;Holme,AD;McLean,WG;Milhous,WK
合成了16种烷基取代的二螺-1，2，4，5-四氧杂环己烷（7，8，15，16-四氧杂二螺[5.2.5.2]十六烷），以探索二螺-1，2，4，5-四氧杂环己烷SAR并鉴定四氧杂环己烷的口服抗疟活性优于原型四氧杂环己烷1（WR 148999）。四氧杂环己烷的制备要么通过相应的环己酮衍生物在H_2SO_4/CH_3CN中的过氧化反应，或通过相应的环己酮甲基肟的臭氧分解。在1和10位具有烷基取代基的那些四恶烷形成为单一立体异构体，而在没有由1和10位的烷基提供的立体化学控制的情况下形成的五种四恶烷分离为非对映异构体的混合物。16种四氧杂环己烷中有3种无活性（IC 50> 1000 nM），但5种（2、6、10、11、12）对氯喹敏感的D 6和氯喹抗性的W2恶性疟原虫克隆的IC 50在10和30 nM之间，而对青蒿素的相应IC 50分别为55和32 nM以及8.4和7.3 nM。我们认为，tetraoxanes 13，16和17是无活性的，tetraoxanes 4和7是弱活性的，由于空间效应防止或阻碍过氧化物键进入寄生血红素。Tetraoxane 1、10、11和14，沿着与青蒿素和蒿乙醚作为对照，经口给药，每日两次。(128 mg/kg/天）至P.在感染后第3、4和5天感染Berghei的小鼠。在这个剂量下，四氧杂环己烷10、11和14治愈了40%到60%的感染动物。相比之下，青蒿素和四氧杂环己烷1没有治愈效果，而蒿乙醚治愈了100%的感染动物。四氧杂环己烷结构与体外神经毒性之间没有明显的关系，这17个四氧杂环己烷的抗疟活性与神经毒性之间也没有任何相关性。
Sixteen alkyl-substituted dispiro-1,2,4,5-tetraoxanes (7,8,15,16-tetraoxadispiro[5.2.5.2]hexadecanes) were synthesized to explore dispiro-1,2,4,5-tetraoxane SAR and to identify tetraoxanes with better oral antimalarial activity than prototype tetraoxane1(WR 148999). The tetraoxanes were prepared either by peroxidation of the corresponding cyclohexanone derivatives in H2SO4/CH3CN or by ozonolysis of the corresponding cyclohexanone methyl oximes. Those tetraoxanes with alkyl substituents at the 1 and 10 positions were formed as single stereoisomers, whereas the five tetraoxanes formed without the stereochemical control provided by alkyl groups at the 1 and 10 positions were isolated as mixtures of diastereomers. Three of the sixteen tetraoxanes were inactive (IC50's > 1000 nM), but five (2,6,10,11,12) had IC50's between 10 and 30 nM against the chloroquine-sensitive D6 and chloroquine-resistant W2 clones ofPlasmodium falciparumcompared to corresponding IC50's of 55 and 32 nM for1and 8.4 and 7.3 nM for artemisinin. We suggest that tetraoxanes13,16, and17were inactive and tetraoxanes4and7were weakly active due to steric effects preventing or hindering peroxide bond access to parasite heme. Tetraoxanes1,10,11, and14, along with artemisinin and arteether as controls, were administered po b.i.d. (128 mg/kg/day) toP. berghei-infected mice on days 3, 4, and 5 post-infection. At this dose, tetraoxanes10,11, and14cured between 40% and 60% of the infected animals. In comparison, artemisinin and tetraoxane1produced no cures, whereas arteether cured 100% of the infected animals. There was no apparent relationship between tetraoxane structure and in vitro neurotoxicity, nor was there any correlation between antimalarial activity and neurotoxicity for these seventeen tetraoxanes.