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Title: | A novel class of Plasmodial ClpP protease inhibitors as potential antimalarial agents |
Authors: | Mahesh, R. |
Keywords: | Pharmacy ATP-dependent ClpP protease Plasmodial ClpP Apicoplast |
Issue Date: | Oct-2017 |
Publisher: | Elsevier |
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. Compound 33 exhibited potent antiparasitic activity (EC₅₀ 9.0 ± 0.2 μM), 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. |
URI: | https://www.sciencedirect.com/science/article/abs/pii/S0968089617313408 http://dspace.bits-pilani.ac.in:8080/xmlui/handle/123456789/13180 |
Appears in Collections: | Department of Pharmacy |
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