Kannan Murugan, Raichurkar Anandkumar V, Khan Fazlur Rahman Nawaz, Iyer Pravin S
Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India; Organic and Medicinal Chemistry Research Laboratory, Organic Chemistry Division, School of Advanced Sciences, VIT University, Vellore 632014, Tamil Nadu, India.
Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
Bioorg Med Chem Lett. 2015 Mar 1;25(5):1100-3. doi: 10.1016/j.bmcl.2015.01.003. Epub 2015 Jan 9.
In the search of novel chemotherapeutic agents for emerging drug resistant parasites, the hybridization approaches have successfully emerged as an efficient tool in malarial chemotherapy. Herein, a rational design and synthesis of novel 8-aminoquinoline and pyrazolopyrimidine hybrids and their antimalarial activity against wild type Plasmodium falciparum (Pf_NF54) and resistant strain (Pf_K1) is reported. The medicinal chemistry approach to expand the scope of this series resulted in an identification of potent compounds with nanomolar potency (best IC50 5-10nM). Systematic structure activity relationship (SAR) studies revealed that pyrazolopyrimidine and 8-aminoquinoline ring are essential for achieving good P. falciparum potency. The docking study revealed that the compound 6 can retain some of the critical interactions within pfDHODH drug target.
在寻找针对新出现的耐药寄生虫的新型化疗药物时，杂交方法已成功成为疟疾化疗中的一种有效工具。在此，报道了新型8-氨基喹啉和吡唑并嘧啶杂化物的合理设计与合成及其对野生型恶性疟原虫（Pf_NF54）和耐药菌株（Pf_K1）的抗疟活性。扩展该系列范围的药物化学方法导致鉴定出具有纳摩尔效力的强效化合物（最佳IC50为5-10nM）。系统的构效关系（SAR）研究表明，吡唑并嘧啶和8-氨基喹啉环对于实现良好的恶性疟原虫效力至关重要。对接研究表明，化合物6可以在pfDHODH药物靶点内保留一些关键相互作用。
