Evaluation of 7-arylaminopyrazolo[1,5-a]pyrimidines as anti-Plasmodium falciparum, antimalarial, and Pf-dihydroorotate dehydrogenase inhibitors
Evaluation of 7-arylaminopyrazolo[1,5-a]pyrimidines as anti-Plasmodium falciparum, antimalarial, and Pf-dihydroorotate dehydrogenase inhibitors
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DOI：
10.1016/j.ejmech.2016.09.073
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发表时间：
2017-01-27
影响因子：
6.7
通讯作者：
Boechat, Nubia
中科院分区：
文献类型：
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作者：
Azeredo, Luis Felipe S. P.;Coutinho, Julia P.;Boechat, Nubia
疟疾仍然是全球最严重的传染病之一。抗疟化疗的一个重要靶标是来自恶性疟原虫的二氢乳清酸脱氢酶（PJDHODH），其负责在从头嘧啶生物合成途径中将二氢乳清酸转化为乳清酸。本研究以高活性的5-甲基-N-（萘-2-基）-2-（三氟甲基）-[1，2，4]三唑并[1，5-a]嘧啶-7-胺为基础，通过环的生物电子等排取代和功能基团的分子杂化，设计合成了1,5个7-芳基吡唑并[1，5-a]嘧啶衍生物。测试了化合物对恶性疟原虫的抗疟作用，在患有伯氏疟原虫的小鼠中作为抗疟药，以及作为PJDHODH的抑制剂。发现13种化合物对恶性疟原虫有活性，在抗HRP 2和次黄嘌呤测定中IC 50值范围为1.2 +/- 0.3至92 +/- 26 μ M。四个化合物显示出最高的选择性指数（SI），这是细胞毒性和体外活性之间的比率。抑制PJDHODH的实验表明，化合物30（R-2 = CH_3; R-5 = CF_3; Ar = 7-（β-萘基））表现出较高的选择性抑制活性，IC_（50）= 0.16 +/- 0.01 μ M，其次为25（R-2 = CH 3; R-5 = CH 3; Ar = 7-β-萘基）和19（R-2 = CF 3; R-5 = CF 3; Ar = 7-β-萘基），其中1050分别= 4 +/-1 μ M和6 +/-1 μ M。在吡唑并[1，5-a]嘧啶环的2-或5 -位的三氟甲基导致药物活性增加。对接结果与酶法测定值一致。(C)2016 Elsevier Masson SAS。All rights reserved.
Malaria remains one of the most serious global infectious diseases. An important target for antimalarial chemotherapy is the enzyme dihydroorotate dehydrogenase from Plasmodium falciparum (PJDHODH), which is responsible for the conversion of dihydroorotate to orotate in the de novo pyrimidine biosynthetic pathway. In this study, we have designed and synthesized fifteen 7-arylpyrazolo[1,5-alpha]pyrimidine derivatives using ring bioisosteric replacement and molecular hybridization of functional groups based on the highly active 5-methyl-N-(naphthalen-2-y1)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidin7-amine. The compounds were tested against Plasmodium falciparum, as antimalarials in mice with P. berghei, and as inhibitors of PJDHODH. Thirteen compounds were found to be active against P. falciparum, with IC50 values ranging from 1.2 +/- 0.3 to 92 +/- 26 mu M in the anti-HRP2 and hypoxanthine assays. Four compounds showed the highest selective index (SI), which is a ratio between cytotoxicity and activity in vitro. The inhibition of PJDHODH showed that compound 30 (R-2 = CH3; R-5 = CF3; Ar = 7-(beta-naphthyl) displayed higher and selective inhibitory activity, with IC50 = 0.16 +/- 0.01 mu M, followed by 25 (R-2 = CH3; R-5 = CH3; Ar = 7-beta-Naphthyl) and 19 (R-2 = CF3; R-5 = CF3; Ar = 7-beta-naphthyl), with 1050 = 4 +/- 1 mu M and 6 +/- 1 mu M, respectively. The trifluoromethyl group at the 2-or 5 -positions of the pyrazolo[1,5-a]pyrimidine ring led to increased drug activity. The docking results agreed with the values obtained from enzymatic assays. (C) 2016 Elsevier Masson SAS. All rights reserved.