Spirofused tetrahydroisoquinoline-oxindole hybrids as a novel class of fast acting antimalarial agents with multiple modes of action
Autor: | Lawrence Ayong, Noella M. Efange, Simon M. N. Efange, Rodrigue Keumoe, Maloba M. M. Lobe |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Phenotypic screening Plasmodium falciparum 030106 microbiology Drug Evaluation Preclinical lcsh:Medicine Diseases Biochemistry Article Antimalarials Hemoglobins Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Tetrahydroisoquinolines Oxindole Antimalarial Agent lcsh:Science Mode of action Multidisciplinary Drug discovery Tetrahydroisoquinoline lcsh:R Biological activity Lipid Metabolism In vitro Multiple drug resistance Chemistry 030104 developmental biology chemistry lcsh:Q |
Zdroj: | Scientific Reports Scientific Reports, Vol 10, Iss 1, Pp 1-12 (2020) |
ISSN: | 2045-2322 |
DOI: | 10.1038/s41598-020-74824-0 |
Popis: | Molecular hybridization of privileged scaffolds may generate novel antiplasmodial chemotypes that display superior biological activity and delay drug resistance. In the present study, we describe the in vitro activities and mode of action of 3′,4′-dihydro-2′H-spiro[indoline-3,1′-isoquinolin]-2-ones, a novel class of spirofused tetrahydroisoquinoline–oxindole hybrids, as novel antimalarial agents. Whole cell phenotypic screening of these compounds identified (14b), subsequently named (±)-moxiquindole, as the most potent compound in the current series with equipotent antiplasmodial activity against both chloroquine sensitive and multidrug resistant parasite strains with good selectivity. The compound was active against all asexual stages of the parasite including inhibition of merozoite egress. Additionally, (±)-moxiquindole exhibited significant inhibitory effects on hemoglobin degradation, and disrupted vacuolar lipid dynamics. Taken together, our data confirm the antiplasmodial activity of (±)-moxiquindole, and identify 3′4′-dihydro-2′H-spiro[indoline-3,1′-isoquinolin]-2-ones as a novel class of antimalarial agents with multiple modes of action. |
Databáze: | OpenAIRE |
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