A novel class of Plasmodial ClpP protease inhibitors as potential antimalarial agents. Issue 20 (15th October 2017)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 20(2017)
• Page Start: 5662
• Page End: 5677
• Publication Date: 2017-10-15
• Subjects: Malaria -- ClpP protease -- In silico docking -- Apicoplast -- Antimalarial agents; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.08.049
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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. Compound33 exhibited potent antiparasitic activity (EC₅₀ 9.0 ± 0.2 μM), a 9-fold improvement over the antiparasitic activity of the hit molecule6 . Treatment of blood stage P. falciparum cultures with compound33 caused morphological and developmental abnormalities in the parasites; further, compound33 treatment hindered apicoplast development indicating the targeting of apicoplast.