A novel class of Plasmodial ClpP protease inhibitors as potential antimalarial agents

作者：Mundra Sourabh; Thakur Vandana; Bello Angelica M; Rathore Sumit; Asad Mohd; Wei Lianhu; Yang Jane; Chakka Sai Kumar; Mahesh Radhakrishnan; Malhotra Pawan; Mohmmed Asif^*; Kotra Lakshmi P^*

来源：Bioorganic & Medicinal Chemistry, 2017, 25(20): 5662-5677.

DOI：10.1016/j.bmc.2017.08.049

• Malaria
• ClpP protease
• In silico docking
• Apicoplast
• Antimalarial agents

The prokaryotic ATP-dependent ClpP protease, localized in the relict plastid of malaria parasite, represents a potential drug target. In the present study, we utilized in silico structure-based screening and medicinal chemistry approaches to identify a novel pyrimidine series of compounds inhibiting P. falciparum ClpP protease activity and evaluated their antiparasitic activities. Structure-activity relationship indicated that morpholine moiety at C2, an aromatic substitution at N3 and a 4-oxo moiety on the pyrimidine are important for potent inhibition of ClpP enzyme along with antiparasiticidal activity. Compound 33 exhibited potent antiparasitic activity (EC50 9.0 +/- 0.2 mu M), a 9-fold improvement over the antiparasitic activity of the hit molecule 6. Treatment of blood stage P. falciparum cultures with compound 33 caused morphological and developmental abnormalities in the parasites; further, compound 33 treatment hindered apicoplast development indicating the targeting of apicoplast.

• 出版日期2017-10-15
• 单位河北医科大学