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.

Synthesis of silver nanoparticles using leaves of Catharanthus roseus Linn. G. Don and their antiplasmodial activities

“…These nanohybrid solids possessed distinct cell growth inhibitory activity. The IC 50 values of LCuCl 2 and LCu(CH 3 COO) 2 were found to be 0.025 and 0.032 lg/mL, respectively, almost the same potency as the standard drug chloroquine (IC 50 , 0.020 lg/mL) [63] .…”

Nanoparticles as potential new generation broad spectrum antimicrobial agents

“… The larvicidal effect was observed in the cobalt acetate solution and against the A. subpictus and A. aegypti ND [ 108 ] Copper(II) nanohybrid solids, LCu(CH 3 COO) 2 and LCuCl 2 TEM, dynamic light scattering, and IR spectroscopy 5–10 and 60–70 nm of LCu(CH 3 COO) 2 and LCuCl 2 Plasmodium falciparum (MRC 2). The two compounds showed significant antimalarial activities against the parasites The copper(II) nanohybrid solids were nontoxic to human hepatocellular carcinoma cells [ 109 ] …”

Copper nano composites functionalized by bis-benzimidazole diamide ligand: Effect of size, co-anion dependent conductivity and band gap studies

“…The splitting and shifting of the amide I and amide II bands has been assigned to the binding of the amide functionality to the Copper ions. Similarly, benzimidazole, n C ] NeC ] C vibrational band is shifted from 1441 cm À1 to 1455 cm À1 , while the benzene ring vibrations appear at 749 cm À1 [21,38].…”

“…The two micro emulsions were mixed together very slowly and stirred over night using a magnetic stirrer. This method has been reported earlier [21]. Green precipitate so obtained was separated from the apolar solvent and surfactant by centrifuging and was thoroughly washed with HPLC grade chloroform.…”

“…They also control nucleation of particles and thus act as particle growth terminators. Recently, a number of articles have appeared describing the synthesis of copper nano-particles by various methods [21].…”