Pentamethylcyclopentadienyl-rhodium and iridium complexes containing (N^N and N^O) bound chloroquine analogue ligands: synthesis, characterization and antimalarial properties.

Erik Ekengard,Peter J Smith,Carmen De Kock,Matti Haukka,Thibault Fogeron,Magda Monari,Ebbe Nordlander,Kamlesh Kumar

doi:10.1039/c5dt03739e

Abstract

The synthesis and characterization of twenty new pentamethylcyclopentadienyl-rhodium and iridium complexes containing N^N and N^O-chelating chloroquine analogue ligands are described. The in vitro antimalarial activity of the new ligands as well as the complexes was evaluated against the chloroquine sensitive (CQS) NF54 and the chloroquine resistant (CQR) Dd2 strains of Plasmodium falciparum. The antimalarial activity was found to be good to moderate; although all complexes are less active than artesunate, some of the ligands and complexes showed better activity than chloroquine (CQ). In particular, rhodium complexes were found to be considerably more active than iridium complexes against the CQS NF54 strain. Salicylaldimine Schiff base ligands having electron-withdrawing groups (F, Cl, Br, I and NO2) in para position of the salicyl moiety and their rhodium complexes showed good antiplasmodial activity against both the CQS-NF54 and the CQR-Dd2 strains. The crystal structures of (η(5)-pentamethylcyclopentadienyl){N(1)-(7-chloroquinolin-4-yl)-N(2)-(pyridin-2-ylmethyl)ethane-1,2-diamine)} chlororhodium(III) chloride and (η(5)-pentamethylcyclopentadienyl){(4-chloro-2-(((2-((7-chloroquinolin-4-yl)amino)ethyl)imino)methyl)phenolate)}chlororhodium(III) chloride are reported. The crystallization of the amino-pyridyl complex (η(5)-pentamethylcyclopentadienyl){(N(1)-(7-chloroquinolin-4-yl)-N(2)-(pyridin-2-ylmethyl)ethane-1,2-diamine)}chloroiridium(III) chloride in acetone resulted in the formation of the imino-pyridyl derivative (η(5)-pentamethylcyclopentadienyl){(N1-(7-chloroquinolin-4-yl)-N2-(pyridin-2-ylmethylene)ethane-1,2-diamine)}chloroiridium(III) chloride, the crystal structure of which is also reported.

Highlights

Malaria is a parasitic disease and constitutes a serious societal problem in many countries in the tropical and sub-tropical regions of Africa, Asia and Latin America
The rhodium complexes 3a–10a and their iridium analogues 3b–10b were synthesized by deprotonating the ligands HL3–10 with triethylamine followed by reaction with [Cp*MCl2]2 (M = Rh and Ir) (Scheme 1)
The anti-malarial activity of all rhodium (1a–10a) and iridium (1b–10b) complexes has been evaluated against the chloroquine-sensitive (CQS) NF54 and the chloroquine-resistant (CQR) Dd2 strains of Plasmodium falciparum

Summary

Introduction

Malaria is a parasitic disease and constitutes a serious societal problem in many countries in the tropical and sub-tropical regions of Africa, Asia and Latin America. We have synthesized and characterized twenty new rhodium and iridium-Cp* complexes containing (N^N and N^O)-bound chloroquine analogue ligands. More, the molecular structures of complexes 1a and 5a have been authenticated by single crystal X-ray diffraction analysis.

Results

Conclusion