Antimalarial Agents Targeting Plasmodium falciparum Carbonic Anhydrase: Towards Artesunate Hybrid Compounds with Dual Mechanism of Action.
ChemMedChem
; 18(21): e202300267, 2023 11 02.
Article
em En
| MEDLINE
| ID: mdl-37697903
Malaria continues to be a major public health challenge worldwide and, as part of the global effort toward malaria eradication, plasmodium carbonic anhydrases (CAs) have recently been proposed as potential targets for malaria treatment. In this study, a series of eight hybrid compounds combining the Artesunate core with a sulfonamide moiety were synthesized and evaluated for their inhibition potency against the widely expressed human (h) CAs I, II and the isoform from P.â
falciparum (PfCA). All derivatives demonstrated high inhibition potency against PfCA, achieving a KI value in the sub-nanomolar range (0.35â
nM). Two Compounds showed a selectivity index of 4.1 and 3.1, respectively, against this protozoan isoform compared to hCAâ
II. Three Derivatives showed no cytotoxic effects on human gingival fibroblasts at 50â
µM with a high killing rate against both P.â
falciparum and P.â
knowlesi strains with IC50 in the sub-nanomolar range, providing a wide therapeutic window. Our findings suggest that these compounds may serve as promising leads for developing new antimalarial drugs and warrant further investigation, including activity against antimalarial-resistant strains, mode of action studies, and inâ
vivo efficacy assessment in preclinical mouse models of malaria.
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Base de dados:
MEDLINE
Assunto principal:
Malária Falciparum
/
Anidrases Carbônicas
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Malária
/
Antimaláricos
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article