Antimicrobial evaluation of neutral and cationic iridium(III) and rhodium(III) aminoquinoline-benzimidazole hybrid complexes

Nadia Baartzes; Audrey Jordaan; Digby F Warner; Jill Combrinck; Dale Taylor; Kelly Chibale; Gregory S Smith

doi:10.1016/j.ejmech.2020.112694

Antimicrobial evaluation of neutral and cationic iridium(III) and rhodium(III) aminoquinoline-benzimidazole hybrid complexes

Eur J Med Chem. 2020 Nov 15:206:112694. doi: 10.1016/j.ejmech.2020.112694. Epub 2020 Aug 5.

Authors

Nadia Baartzes¹, Audrey Jordaan², Digby F Warner³, Jill Combrinck⁴, Dale Taylor⁵, Kelly Chibale⁶, Gregory S Smith⁷

Affiliations

¹ Department of Chemistry, University of Cape Town, Rondebosch, 7701, Cape Town, South Africa.
² SAMRC/NHLS/UCT Molecular Mycobacteriology Research Unit, DST/NRF Centre of Excellence for Biomedical TB Research, Department of Clinical Laboratory Sciences, University of Cape Town, Rondebosch, 7701, Cape Town, South Africa.
³ SAMRC/NHLS/UCT Molecular Mycobacteriology Research Unit, DST/NRF Centre of Excellence for Biomedical TB Research, Department of Clinical Laboratory Sciences, University of Cape Town, Rondebosch, 7701, Cape Town, South Africa; Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town, Rondebosch, 7701, South Africa.
⁴ Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, 7925, Cape Town, South Africa.
⁵ Drug Discovery and Development Centre (H3D), Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory 7925, Cape Town, South Africa.
⁶ Department of Chemistry, University of Cape Town, Rondebosch, 7701, Cape Town, South Africa; South African Medical Research Council, Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa.
⁷ Department of Chemistry, University of Cape Town, Rondebosch, 7701, Cape Town, South Africa. Electronic address: gregory.smith@uct.ac.za.

PMID: 32861176
DOI: 10.1016/j.ejmech.2020.112694

Abstract

A series of neutral and cationic Ir(III) and Rh(III) aminoquinoline-benzimidazole hybrid complexes were synthesised and their inhibitory activities evaluated against Plasmodium falciparum and Mycobacterium tuberculosis. In general, the hybrid complexes display good activity against the chloroquine-sensitive NF54 strain of P. falciparum. The neutral Ir(III)- and Rh(III)-Cp∗ complexes were the most active (IC₅₀ = 0.488 μM for Ir^III), maintaining activity against the multidrug-resistant K1 strain. Low to no cytotoxicity against the Chinese hamster ovarian cell line was observed for the tested complexes. Selected active hybrid complexes demonstrated significant inhibition of β-haematin formation in a cell-free NP-40 assay, suggesting an effect on the host haemoglobin degradation pathway as a potential contributing mechanism of action. When tested against M. tuberculosis H37Rv, most hybrid complexes displayed moderate to good activity. Again, the neutral complexes outperformed the cationic complexes, with the neutral Ir(III)-Cp∗ complexes proving most active (MIC₉₀ = 0.488-1.490 μM).

Keywords: Aminoquinolines; Antimicrobial; Benzimidazoles; Bioorganometallic chemistry; Hybrids; Platinum group metals.

MeSH terms

Aminoquinolines / chemistry*
Animals
Anti-Infective Agents / chemistry
Anti-Infective Agents / pharmacology
Benzimidazoles / chemistry*
CHO Cells
Coordination Complexes / chemistry*
Coordination Complexes / pharmacology*
Cricetulus
Drug Resistance, Multiple / drug effects
Iridium / chemistry*
Mycobacterium tuberculosis / drug effects
Plasmodium falciparum / drug effects
Rhodium / chemistry*

Substances

Aminoquinolines
Anti-Infective Agents
Benzimidazoles
Coordination Complexes
Iridium
Rhodium
benzimidazole