5-Substituted tetrazoles as bioisosteres of carboxylic acids. Bioisosterism and mechanistic studies on glutathione reductase inhibitors as antimalarials
5-Substituted tetrazoles as bioisosteres of carboxylic acids. Bioisosterism and mechanistic studies on glutathione reductase inhibitors as antimalarials
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DOI：
10.1021/jm0497545
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发表时间：
2004-11-18
影响因子：
7.3
通讯作者：
Davioud-Charvet, E
中科院分区：
文献类型：
--
作者：
Biot, C;Bauer, H;Davioud-Charvet, E
疟原虫寄生虫在红细胞内生活期间暴露于高通量的活性氧。最重要的抗氧化系统基于疟疾寄生虫恶性疟原虫和宿主红细胞的谷胱甘肽还原酶。甲萘醌化学的发展导致选择羧酸6-[2'-(3'甲基)-1',4'-萘喹基]己酸M-5作为寄生酶的抑制剂。正如本文所报道的，重新审视 M-5 的作用机制揭示了对 NADPH 和二硫化谷胱甘肽的非竞争性抑制类型。通过酯或酰胺键掩盖 M-5 酸性功能的极性可提高抗疟原虫活性。用四唑生物等排取代羧基功能以增加生物利用度并保持相当的酸度也导致抗疟特性的改善，但仅限于氰乙基保护的四唑。使用从头计算的量子方法，对电子分布和分子特性的详细分析证明了 M-5 和生物等排四唑 T-4 的相似性。根据最近解析的恶性疟原虫酶的晶体结构讨论了这些分子的潜在结合位点。
Plasmodium parasites are exposed to elevated fluxes of reactive oxygen species during intraerythrocytic life. The most important antioxidative systems are based on the glutathione reductases of the malarial parasite Plasmodium falciparum and the host erythrocyte. The development of menadione chemistry has led to the selection of the carboxylic acid 6-[2'-(3'methyl)-1',4'-naphthoquinolyl] hexanoic acid M-5 as an inhibitor of the parasitic enzyme. As reported here, revisiting the mechanism of M-5 action revealed an uncompetitive inhibition type with respect to both NADPH and glutathione disulfide. Masking the polarity of the acidic function of M-5 by ester or amide bonds improved antiplasmodial activity. Bioisosteric replacement of the carboxylic function by tetrazole to increase bioavailability and to maintain comparable acidity led to improved antimalarial properties as well, but only with the cyanoethyl-protected tetrazoles. Using computed ab initio quantum methods, detailed analyses of the electronic profiles and the molecular properties evidenced the similarity of M-5 and the bioisoteric tetrazole T-4. The potential binding site of these molecules is discussed in light of the recently solved crystallographic structure of P. falciparum enzyme.