Preliminary Evaluation of Artemisinin-Cholesterol Conjugates as Potential Drugs for the Treatment of Intractable Forms of Malaria and Tuberculosis.
ChemMedChem
; 13(1): 67-77, 2018 01 08.
Article
em En
| MEDLINE
| ID: mdl-29193799
ABSTRACT
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 inâ
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 0.02-1.7â
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 24â
h pretreatment of cultures with each of the compounds. Percentage inhibition ranged from 3-38 % and 18-52 % at 10 and 80â
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 inâ
vivo, and for TB, assays using an infected macrophage model and assessment of granuloma influx.
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1
Coleções:
01-internacional
Contexto em Saúde:
3_ND
Base de dados:
MEDLINE
Assunto principal:
Colesterol
/
Artemisininas
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Antimaláricos
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Antituberculosos
Limite:
Humans
Idioma:
En
Revista:
ChemMedChem
Ano de publicação:
2018
Tipo de documento:
Article