Preliminary Evaluation of Artemisinin–Cholesterol Conjugates as Potential Drugs for the Treatment of Intractable Forms of Malaria and Tuberculosis

To evaluate the feasibility of developing drugs that may be active against both malaria and tuberculosis (TB) by using in part putative cholesterol transporters in the causative pathogens and through enhancement of passive diffusion in granulomatous TB, artemisinin–cholesterol conjugates were synthe...

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Published in:ChemMedChem 2018-01, Vol.13 (1), p.67-77
Main Authors: Morake, Mokhitli, Coertzen, Dina, Ngwane, Andile, Wentzel, Johannes F., Wong, Ho Ning, Smit, Frans J., Birkholtz, Lyn‐Marie, Pietersen, Ray‐Dean, Baker, Bienyameen, Wiid, Ian, N'Da, David D., Haynes, Richard K.
Format: Article
Language:English
Subjects:
Artemether
Artemisinin
artemisinins
Assaying
Chemical synthesis
Cholesterol
Conjugates
Drug resistance
Drugs
Feasibility studies
Granuloma
Macrophages
Malaria
Plasmodium falciparum
Pretreatment
Tuberculosis
Vector-borne diseases
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Summary:To evaluate the feasibility of developing drugs that may be active against both malaria and tuberculosis (TB) by using in part putative cholesterol transporters in the causative pathogens and through enhancement of passive diffusion in granulomatous TB, artemisinin–cholesterol conjugates were synthesized by connecting the component molecules through various linkers. The compounds were screened in vitro against Plasmodium falciparum (Pf) and Mycobacterium tuberculosis (Mtb). Antimalarial activities (IC50) against Pf drug‐sensitive NF54, and drug‐resistant K1 and W2 strains ranged from 0.03–2.6, 0.03–1.9, and 0.02–1.7 μm. Although the compounds are less active than the precursor artemisinin derivatives, the cholesterol moiety renders the compounds relatively insoluble in the culture medium, and variation in solubilities among the different compounds may reflect in the range of efficacies observed. Activities against Mtb H37Rv were assessed using a standardized colony‐forming unit (CFU) assay after 24 h pretreatment of cultures with each of the compounds. Percentage inhibition ranged from 3–38 % and 18–52 % at 10 and 80 μm, respectively. Thus, in contrast to the comparator drug artemether, the conjugates display enhanced activities. The immediate aims include the preparation of conjugates with enhanced aqueous solubilities, assays against malaria and TB in vivo, and for TB, assays using an infected macrophage model and assessment of granuloma influx. Teaming up: Because of the potential for initiating active transport of substrates containing a peroxide pharmacophore by way of a putative cholesterol transporter, a series of artemisinin–cholesterol conjugates were prepared. Although they are less active than the parent artemisinin against P. falciparum, they were found to be appreciably more active against M. tuberculosis in vitro. Poor solubility appears to limit activity of the conjugates.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.201700579