Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa.
Department of Chemistry and Polymer Science, Stellenbosch University, Private Bag X1, Matieland, 7602, South Africa.
Eur J Med Chem. 2018 Nov 5;159:243-254. doi: 10.1016/j.ejmech.2018.09.060. Epub 2018 Sep 28.
The 2-phenylbenzimidazole scaffold has recently been discovered to inhibit β-hematin (synthetic hemozoin) formation by high throughput screening. Here, a library of 325,728 N-4-(1H-benzo[d]imidazol-2-yl)aryl)benzamides was enumerated, and Bayesian statistics used to predict β-hematin and Plasmodium falciparum growth inhibition. Filtering predicted inactives and compounds with negligible aqueous solubility reduced the library to 35,124. Further narrowing to compounds with terminal aryl ring substituents only, reduced the library to 18, 83% of which were found to inhibit β-hematin formation <100 μM and 50% parasite growth <2 μM. Four compounds showed nanomolar parasite growth inhibition activities, no cross-resistance in a chloroquine resistant strain and low cytotoxicity. QSAR analysis showed a strong association of parasite growth inhibition with inhibition of β-hematin formation and the most active compound inhibited hemozoin formation in P. falciparum, with consequent increasing exchangeable heme. Pioneering use of molecular docking for this system demonstrated predictive ability and could rationalize observed structure activity trends.
2-苯基苯并咪唑支架最近通过高通量筛选被发现可抑制β-血晶素（合成疟色素）的形成。在此，枚举了 325,728 个 N-4-(1H-苯并[d]咪唑-2-基)芳基)苯甲酰胺的库，并使用贝叶斯统计预测β-血晶素和疟原虫生长抑制。过滤预测的非活性化合物和水溶性可忽略的化合物，将库减少到 35,124 个。进一步缩小到仅具有末端芳基环取代基的化合物，将库减少到 18 个，其中 83%的化合物被发现抑制β-血晶素形成<100μM，50%的寄生虫生长<2μM。四种化合物表现出纳摩尔级别的寄生虫生长抑制活性，对氯喹耐药株无交叉耐药性，细胞毒性低。QSAR 分析表明，寄生虫生长抑制与β-血晶素形成抑制之间存在很强的相关性，最有效的化合物抑制疟原虫中的血晶素形成，导致可交换的血红素增加。该系统中开创性地使用分子对接证明了预测能力，并可以合理地解释观察到的结构活性趋势。
