title: Antimalarial evaluation of copper(II) nanohybrid solids: inhibition of plasmepsin II, a hemoglobin-degrading malarial aspartic protease from Plasmodium falciparum.
abstract: A new class of copper(II) nanohybrid solids, LCu(CH(3)COO)(2) and LCuCl(2), have been synthesized and characterized by transmission electron microscopy, dynamic light scattering, and IR spectroscopy, and have been found to be capped by a bis(benzimidazole) diamide ligand (L). The particle sizes of these nanohybrid solids were found to be in the ranges 5-10 and 60-70 nm, respectively. These nanohybrid solids were evaluated for their in vitro antimalarial activity against a chloroquine-sensitive isolate of Plasmodium falciparum (MRC 2). The interactions between these nanohybrid solids and plasmepsin II (an aspartic protease and a plausible novel target for antimalarial drug development), which is believed to be essential for hemoglobin degradation by the parasite, have been assayed by UV-vis spectroscopy and inhibition kinetics using Lineweaver-Burk plots. Our results suggest that these two compounds have antimalarial activities, and the IC(50) values (0.025-0.032 microg/ml) are similar to the IC(50) value of the standard drug chloroquine used in the bioassay. Lineweaver-Burk plots for inhibition of plasmepsin II by LCu(CH(3)COO)(2) and LCuCl(2) show that the inhibition is competitive with respect to the substrate. The inhibition constants of LCu(CH(3)COO)(2) and LCuCl(2) were found to be 10 and 13 microM, respectively. The IC(50) values for inhibition of plasmepsin II by LCu(CH(3)COO)(2) and LCuCl(2) were found to be 14 and 17 microM, respectively. Copper(II) metal capped by a benzimidazole group, which resembles the histidine group of copper proteins (galactose oxidase, beta-hydroxylase), could provide a suitable anchoring site on the nanosurface and thus could be useful for inhibition of target enzymes via binding to the S1/S3 pocket of the enzyme hydrophobically. Both copper(II) nanohybrid solids were found to be nontoxic against human hepatocellular carcinoma cells and were highly selective for plasmepsin II versus human cathepsin D. The pivotal mechanism of antimalarial activity of these compounds via plasmepsin II inhibition in the P. falciparum malaria parasite is demonstrated.
authors: Department of Chemistry, University of Delhi, Delhi, 110007, India. subashcm@gmail.com
authors: Subash Chandra
authors: SC
authors: Mohapatra
authors: Hemandra Kumar
authors: HK
authors: Tiwari
authors: Manisha
authors: M
authors: Singla
authors: Brijesh
authors: B
authors: Rathi
authors: Arun
authors: A
authors: Sharma
authors: Kuldeep
authors: K
authors: Mahiya
authors: Mukesh
authors: M
authors: Kumar
authors: Saket
authors: S
authors: Sinha
authors: Shyam Singh
authors: SS
authors: Chauhan
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002402:Cathepsin D / Q000378:metabolism; D003300:Copper / Q000737:chemistry* / Q000494:pharmacology*; D004912:Erythrocytes / Q000469:parasitology; D006454:Hemoglobins / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy*; D049329:Nanostructures / Q000737:chemistry / Q000648:ultrastructure; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013057:Spectrum Analysis
chemical_list: D000962:Antimalarials; D006454:Hemoglobins; D009942:Organometallic Compounds; D015800:Protozoan Proteins; D003300:Copper; D016282:Aspartic Acid Endopeptidases; C100637:plasmepsin II; D002402:Cathepsin D