Twenty eight new N²,N⁴-diphenylpyrimidine-2,4-diamines have been prepared in order to expand our understanding of the anti-malarial SAR of the scaffold. The aim of the study was to make structural modifications to improve the overall potency, selectivity and solubility of the series by varying the anilino groups attached to the 2- and 4-position. We evaluated the activity of the compounds against Plasmodium falciparum (Pf) 3D7, cytotoxicity against HepG2, % inhibition at a panel of 10 human kinases, solubility, permeability and lipophilicity, and human and rat in vitro clearance. 11 was identified as a potent anti-malarial with an IC₅₀ of 0.66 µM at the 3D7 strain and a selectivity (SI) of ∼40 in terms of cytotoxicity against the HepG2 cell line. It also displayed low experimental logD_7.4 (2.27), reasonable solubility (124 µg/ml), good metabolic stability, but low permeability. A proteo-chemometric workflow was employed to identify putative Pf targets of the most promising compounds. Ligand-based similarity searching of the ChEMBL database led to the identification of most probable human targets. These were then used as input for sequence-based searching of the Pf proteome. Homology modelling and molecular docking were used to evaluate whether compounds could indeed bind to these targets with valid binding modes. In vitro biological testing against close human analogs of these targets was subsequently undertaken. This allowed us to identify potential Pf targets and human anti-targets that could be exploited in future development.

已经制备了 28 种新的N ² , N ⁴ -二苯基嘧啶-2,4-二胺，以扩大我们对支架抗疟疾 SAR 的理解。该研究的目的是通过改变连接到 2 位和 4 位的苯胺基团来进行结构修饰，以提高该系列的整体效力、选择性和溶解度。我们评估了化合物对恶性疟原虫( Pf ) 3D7 的活性、对 HepG2 的细胞毒性、对一组 10 种人激酶的抑制百分比、溶解度、渗透性和亲脂性，以及人和大鼠的体外清除率。11被确定为具有 IC _{50的强效抗疟药}在 3D7 菌株中为 0.66 µM，就对 HepG2 细胞系的细胞毒性而言，选择性 (SI) 约为 40。它还表现出低实验 logD _7.4 (2.27)、合理的溶解度 (124 µg/ml)、良好的代谢稳定性，但渗透性低。采用蛋白质化学计量工作流程来确定最有希望的化合物的推定Pf目标。对 ChEMBL 数据库的基于配体的相似性搜索导致识别最可能的人类目标。然后将这些用作基于序列的Pf搜索的输入蛋白质组。同源建模和分子对接用于评估化合物是否确实可以以有效的结合模式与这些靶标结合。随后进行了针对这些目标的接近人类类似物的体外生物测试。这使我们能够识别可在未来开发中利用的潜在Pf目标和人类反目标。