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

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±0.2μM), 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.

journal_name

Bioorg Med Chem

authors

Mundra S,Thakur V,Bello AM,Rathore S,Asad M,Wei L,Yang J,Chakka SK,Mahesh R,Malhotra P,Mohmmed A,Kotra LP

doi

10.1016/j.bmc.2017.08.049

subject

Has Abstract

pub_date

2017-10-15 00:00:00

pages

5662-5677

issue

20

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(17)31340-8

journal_volume

25

pub_type

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