Baartzes Nadia, Jordaan Audrey, Warner Digby F, Combrinck Jill, Taylor Dale, Chibale Kelly, Smith Gregory S
Department of Chemistry, University of Cape Town, Rondebosch, 7701, Cape Town, South Africa.
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.
Eur J Med Chem. 2020 Nov 15;206:112694. doi: 10.1016/j.ejmech.2020.112694. Epub 2020 Aug 5.
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 (IC = 0.488 μM for Ir), 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 (MIC = 0.488-1.490 μM).
合成了一系列中性和阳离子型铱（III）和铑（III）氨基喹啉 - 苯并咪唑杂化配合物，并评估了它们对恶性疟原虫和结核分枝杆菌的抑制活性。总体而言，杂化配合物对氯喹敏感的恶性疟原虫NF54菌株表现出良好的活性。中性铱（III）和铑（III）-Cp∗配合物活性最高（铱的IC = 0.488 μM），对多药耐药的K1菌株保持活性。测试的配合物对中国仓鼠卵巢细胞系的细胞毒性较低或无细胞毒性。在无细胞NP - 40试验中，选定的活性杂化配合物对β-血红素的形成有显著抑制作用，表明对宿主血红蛋白降解途径有影响，这可能是潜在的作用机制。当针对结核分枝杆菌H37Rv进行测试时，大多数杂化配合物表现出中度至良好的活性。同样，中性配合物优于阳离子配合物，中性铱（III）-Cp∗配合物活性最高（MIC = 0.488 - 1.490 μM）。
