Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, U.P, India.
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.
Eur J Med Chem. 2023 Jun 5;254:115340. doi: 10.1016/j.ejmech.2023.115340. Epub 2023 Apr 5.
In the pursuance of novel scaffolds with promising antiplasmodial and anti-inflammatory activity, a series of twenty-one compounds embraced with most promising penta-substituted pyrrole and biodynamic hydroxybutenolide in single skeleton was designed and synthesized. These pyrrole-hydroxybutenolide hybrids were evaluated against Plasmodium falciparum parasite. Four hybrids 5b, 5d, 5t and 5u exhibited good activity with IC of 0.60, 0.88, 0.97 and 0.96 μM for chloroquine sensitive (Pf3D7) strain and 3.92, 4.31, 4.21 and 1.67 μM for chloroquine resistant (PfK1) strain, respectively. In vivo efficacy of 5b, 5d, 5t and 5u was studied against the P. yoelii nigeriensis N67 (a chloroquine-resistant) parasite in Swiss mice at a dose of 100 mg/kg/day for 4 days via oral route. 5u was found to show maximum 100% parasite inhibition with considerably increased mean survival time. Simultaneously, the series of compounds was screened for anti-inflammatory potential. In preliminary assays, nine compounds showed more than 85% inhibition in hu-TNFα cytokine levels in LPS stimulated THP-1 monocytes and seven compounds showed more than 40% decrease in fold induction in reporter gene activity analyzed via Luciferase assay. 5p and 5t were found to be most promising amongst the series, thus were taken up for further in vivo studies. Wherein, mice pre-treated with them showed a dose dependent inhibition in carrageenan induced paw swelling. Moreover, the results of in vitro and in vivo pharmacokinetic parameters indicated that the synthesized pyrrole-hydroxybutenolide conjugates abide by the required criteria for the development of orally active drug and thus this scaffold can be used as pharmacologically active framework that should be considered for the development of potential antiplasmodial and anti-inflammatory agents.
为了寻找具有抗疟和抗炎活性的新型支架，我们设计并合成了一系列 21 种化合物，这些化合物均由最有前途的五取代吡咯和生物动力羟丁烯内酯组成。这些吡咯-羟丁烯内酯杂种被评估对恶性疟原虫寄生虫的活性。四种杂种 5b、5d、5t 和 5u 表现出良好的活性，对氯喹敏感（Pf3D7）株的 IC 为 0.60、0.88、0.97 和 0.96 μM，对氯喹耐药（PfK1）株的 IC 为 3.92、4.31、4.21 和 1.67 μM。以 100mg/kg/天的剂量经口服途径在瑞士小鼠中对 5b、5d、5t 和 5u 的体内功效进行了针对恶性疟原虫 nigeriensis N67（氯喹耐药）寄生虫的研究，共 4 天。发现 5u 表现出最大的 100%寄生虫抑制作用，同时平均生存时间显著增加。同时，对该系列化合物进行了抗炎潜力的筛选。在初步试验中，有 9 种化合物在 LPS 刺激的 THP-1 单核细胞中显示出超过 85%的 hu-TNFα 细胞因子水平抑制作用，有 7 种化合物在报告基因活性分析的荧光素酶测定中显示出超过 40%的诱导倍数降低。在该系列中，发现 5p 和 5t 最有前途，因此被进一步用于体内研究。其中，用它们预处理的小鼠在角叉菜胶诱导的足肿胀中显示出剂量依赖性抑制。此外，体内和体外药代动力学参数的结果表明，合成的吡咯-羟丁烯内酯缀合物符合开发口服活性药物的要求标准，因此该支架可作为具有药理活性的框架，可考虑用于开发潜在的抗疟和抗炎药物。
