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Eur J Med Chem. 2019 Jun 26;180:121-133. doi: 10.1016/j.ejmech.2019.06.069. [Epub ahead of print]

Bioisosteric ferrocenyl aminoquinoline-benzimidazole hybrids: Antimicrobial evaluation and mechanistic insights.

Author information

1
Department of Chemistry, University of Cape Town, Rondebosch, 7701, Cape Town, South Africa.
2
Drug Discovery and Development Centre (H3D), Institute of Infectious Disease and Molecular Medicine, 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
H3D, Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, 7925, Cape Town, South Africa.
5
Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002, Basel, Switzerland; University of Basel, 4003, Basel, Switzerland.
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.

Abstract

Phenyl- and bioisosteric ferrocenyl-derived aminoquinoline-benzimidazole hybrid compounds were synthesised and evaluated for their in vitro antiplasmodial activity against the chloroquine-sensitive NF54 and multi-drug resistant K1 strains of the human malaria parasite, Plasmodium falciparum. All compounds were active against the two strains, generally showing enhanced activity in the K1 strain, with resistance indices less than 1. Cytotoxicity studies using Chinese hamster ovarian cells revealed that the hybrids were relatively non-cytotoxic and demonstrated selective killing of the parasite. Based on favourable in vitro antiplasmodial and cytotoxicity data, the most active phenyl (4c) and ferrocenyl (5b) hybrids were tested in vivo against the rodent Plasmodium berghei mouse model. Both compounds caused a reduction in parasitemia relative to the control, with 5c displaying superior activity (92% reduction in parasitemia at 4 × 50 mg/kg oral doses). The most active phenyl and ferrocenyl derivatives showed inhibition of β-haematin formation in a NP-40 detergent-mediated assay, indicating a possible contributing mechanism of antiplasmodial action. The most active ferrocenyl hybrid did not display appreciable reactive oxygen species (ROS) generation in a ROS-induced DNA cleavage gel electrophoresis study. The compounds were also screened for their in vitro activity against Mycobacterium tuberculosis. The hybrids containing a more hydrophobic substituent had enhanced activity (<32.7 μM) compared to those with a less hydrophobic substituent (>62.5 μM).

KEYWORDS:

Aminoquinolines; Antiplasmodial; Benzimidazoles; Bioorganometallic chemistry; Ferrocene; Hybrids

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