Malarial aspartic protease, plasmepsin (Plm), is perspective antimalarial drug target. Following up our previosly identified 2-aminoquinazolin-4(3H)-one-based inhibitors, 2-aminopyrido[2,3-d]-, -[3,2-d]-, and -[4,3-d]pyrimidin-4(3H)-ones bearing subpocket-specific substituents at position 7 were prepared and tested for their Plm I, II, IV inhibition potency. The position of the nitrogen atom in 2-aminopyridopyrimidinones plays significant role in the inhibitory potency against Plms. Pyrido[2,3-d]pyrimidin-4(3H)-one derivatives showed poor inhibitory potency against Plms I, II, IV irrespectively of the substituent at position 7. However, pyrido[4,3-d]pyrimidin-4(3H)-ones and pyrido[3,2-d]pyrimidin-4(3H)-ones were more appropriate scaffolds for Plm inhibitor development. Particularly, 2-amino-7-[4-(3-phenylpropyl)phenyl]-3-[(tetrahydrofuran-2-yl)methyl]pyrido[3,2-d]pyrimidin-4(3H)-one showed very high potency against Plm IV subtype and high selectivity against human aspartic protease, cathepsin D.

中文翻译：

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2-氨基吡啶并嘧啶酮的合成及其纤溶酶I，II，IV抑制力

疟疾天冬氨酸蛋白酶，纤溶酶（Plm）是抗疟疾药物的靶标。跟进我们以前确定的基于2-氨基喹唑啉-4（3 H）-one的抑制剂，2-氨基吡啶[2,3- d ]-，-[3,2- d ]-和-[4,3- d制备在位置7带有亚口袋特异性取代基的]嘧啶-4（3 H）-并测试其对Plm I，II，IV的抑制能力。2-氨基吡啶并嘧啶酮中氮原子的位置在对Plms的抑制效力中起重要作用。吡咯并[2,3- d ]嘧啶-4（3 H）-one衍生物显示对Plms I，II，IV的抑制作用较弱，而与位置7处的取代基无关。但是，吡啶并[4,3-d ] pyrimidin-4（3 H）-ones和吡啶并[3,2- d ] pyrimidin-4（3 H）-ones更适合用于Plm抑制剂的开发。特别地，2-氨基-7- [4-（3-苯基丙基）苯基] -3-[（四氢呋喃-2-基）甲基]吡啶基[3,2 - d ]嘧啶-4（3 H）-显示非常好。对Plm IV亚型具有高效力，对人天冬氨酸蛋白酶组织蛋白酶D具有高选择性。