Vyas V K, Bhati S, Sharma M, Gehlot P, Patel N, Dalai S
Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad, India.
Institute of Science, Nirma University, Ahmedabad, India.
SAR QSAR Environ Res. 2023 Jul-Sep;34(8):639-659. doi: 10.1080/1062936X.2023.2247326.
2,4-Disubstituted quinoline derivatives were designed based on a 3D-QSAR study, synthesized and evaluated for antimalarial activity. A large dataset of 178 quinoline derivatives was used to perform a 3D-QSAR study using CoMFA and CoMSIA models. PLS analysis provided statistically validated results for CoMFA ( = 0.969, = 0.677, = 0.682) and CoMSIA ( = 0.962, = 0.741, = 0.683) models. Two series of a total of 40 2,4-disubstituted quinoline derivatives were designed with amide (quinoline-4-carboxamide) and secondary amine (4-aminoquinoline) linkers at the -C4 position of the quinoline ring. For the purpose of selecting better compounds for synthesis with good pEC values, activity prediction was carried out using CoMFA and CoMSIA models. Finally, a total of 10 2,4-disubstituted quinoline derivatives were synthesized, and screened for their antimalarial activity based on the reduction of parasitaemia. Compound #5 with amide linker and compound #19 with secondary amine linkers at the -C4 position of the quinoline ring showed maximum reductions of 64% and 57%, respectively, in the level of parasitaemia. In vivo screening assay confirmed and validated the findings of the 3D-QSAR study for the design of quinoline derivatives.
基于三维定量构效关系（3D-QSAR）研究设计了2,4-二取代喹啉衍生物，合成并评估了其抗疟活性。使用包含178种喹啉衍生物的大型数据集，通过比较分子场分析（CoMFA）和比较分子相似性指数分析（CoMSIA）模型进行3D-QSAR研究。偏最小二乘法（PLS）分析为CoMFA（R² = 0.969，q² = 0.677，r² = 0.682）和CoMSIA（R² = 0.962，q² = 0.741，r² = 0.683）模型提供了统计学上有效的结果。设计了总共40种2,4-二取代喹啉衍生物的两个系列，在喹啉环的-C4位置带有酰胺（喹啉-4-甲酰胺）和仲胺（4-氨基喹啉）连接基。为了选择具有良好pEC值的更好化合物进行合成，使用CoMFA和CoMSIA模型进行活性预测。最后，总共合成了10种2,4-二取代喹啉衍生物，并根据疟原虫血症的降低情况筛选其抗疟活性。在喹啉环-C4位置带有酰胺连接基的化合物#5和带有仲胺连接基的化合物#19分别使疟原虫血症水平最大降低了64%和57%。体内筛选试验证实并验证了3D-QSAR研究在喹啉衍生物设计方面的结果。
