Preclinical Evaluation of the Antifolate QN254, 5-Chloro-N′6′-(2,5-Dimethoxy-Benzyl)-Quinazoline-2,4,6-Triamine, as an Antimalarial Drug Candidate
Preclinical Evaluation of the Antifolate QN254, 5-Chloro-N′6′-(2,5-Dimethoxy-Benzyl)-Quinazoline-2,4,6-Triamine, as an Antimalarial Drug Candidate
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DOI：
10.1128/aac.01526-09
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发表时间：
2010-06-01
影响因子：
4.9
通讯作者：
Diagana, Thierry T.
中科院分区：
文献类型：
--
作者：
Nzila, Alexis;Rottmann, Matthias;Diagana, Thierry T.
对二氢叶酸还原酶（DHFR）抑制剂（如乙胺嘧啶（PM））的耐药性现在已经蔓延到疟疾流行的几乎所有地区，使得基于抗叶酸的疟疾治疗非常无效。我们之前已经证明，二氨基喹唑啉QN254[5-氯- n '6'-（2,5-二甲氧基-苄基）-喹唑啉-2,4,6-三胺]对高度耐pm的恶性疟原虫V1S菌株具有活性，这表明QN254可用于治疗抗叶酸耐药高流行地区的疟疾。在这里，我们进一步证明了QN254对恶性疟原虫临床分离株具有高活性，表现出不同程度的抗叶酸药物耐药性，我们提供了生化和结构证据，证明QN254结合并抑制DHFR酶的野生型和四倍突变（V1S）形式的功能。此外，我们还评估了QN254的口服生物利用度、有效性和体内安全性。该化合物在啮齿类动物中口服后表现出良好的药代动力学特性。该药对伯氏疟原虫有显著的治疗效果，每日口服3次，剂量为30 mg/kg，可完全治愈感染小鼠。在这些功效研究的过程中，我们发现了在大鼠中证实的高剂量的一些剂量限制性毒性。因此，尽管QN254对疟原虫DHFR酶具有相对的体外选择性，但它并没有显示出足够的治疗指数来证明其作为单一药物的进一步开发是合理的。
Drug resistance against dihydrofolate reductase (DHFR) inhibitors-such as pyrimethamine (PM)-has now spread to almost all regions where malaria is endemic, rendering antifolate-based malaria treatments highly ineffective. We have previously shown that the di-amino quinazoline QN254 [5-chloro-N'6'-(2,5-dimethoxy-benzyl)-quinazoline-2,4,6-triamine] is active against the highly PM-resistant Plasmodium falciparum V1S strain, suggesting that QN254 could be used to treat malaria in regions with a high prevalence of antifolate resistance. Here, we further demonstrate that QN254 is highly active against Plasmodium falciparum clinical isolates, displaying various levels of antifolate drug resistance, and we provide biochemical and structural evidence that QN254 binds and inhibits the function of both the wild-type and the quadruple-mutant (V1S) forms of the DHFR enzyme. In addition, we have assessed QN254 oral bioavailability, efficacy, and safety in vivo. The compound displays favorable pharmacokinetic properties after oral administration in rodents. The drug was remarkably efficacious against Plasmodium berghei and could fully cure infected mice with three daily oral doses of 30 mg/kg. In the course of these efficacy studies, we have uncovered some dose limiting toxicity at higher doses that was confirmed in rats. Thus, despite its relative in vitro selectivity toward the Plasmodium DHFR enzyme, QN254 does not show the adequate therapeutic index to justify its further development as a single agent.