Novel thiolactone–isatin hybrids as potential antimalarial and antitubercular agents

The biological evaluation of novel thiolactone–isatin hybrids are described. Structure–activity relationships are explored and the activity profile of these derivatives revealed. The synthesis of a novel series of thiolactone–isatin hybrids led to the discovery of tetracyclic by-products which displ...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2011-04, Vol.21 (7), p.2055-2058
Main Authors: Hans, Renate H., Wiid, Ian J.F., van Helden, Paul D., Wan, Baojie, Franzblau, Scott G., Gut, Jiri, Rosenthal, Philip J., Chibale, Kelly
Format: Article
Language:English
Subjects:
Animals
Antibacterial agents
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antimalaria
antimalarials
Antimalarials - chemistry
Antimalarials - pharmacology
Antiparasitic agents
Antitubercular
Antitubercular Agents - chemistry
Antitubercular Agents - pharmacology
Biological and medical sciences
byproducts
Hybrids
inhibitory concentration 50
Isatin
Isatin - chemistry
Isatin - pharmacology
Lactones - chemistry
Lactones - pharmacology
Medical sciences
Mycobacterium tuberculosis
Mycobacterium tuberculosis - drug effects
Pharmacology. Drug treatments
Plasmodium falciparum
Plasmodium falciparum - drug effects
Structure-Activity Relationship
Thiolactone
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Summary:The biological evaluation of novel thiolactone–isatin hybrids are described. Structure–activity relationships are explored and the activity profile of these derivatives revealed. The synthesis of a novel series of thiolactone–isatin hybrids led to the discovery of tetracyclic by-products which displayed superior antiplasmodial activity. The tetracycles thus formed the basis of a more focused SAR study. Identified from this series is a compound with an IC 50 of 6.92 μM against the chloroquine-resistant (W2) strain of Plasmodium falciparum. Useful antimalarial SARs delineated include the need for substitution at C-5 of the isatin scaffold and the enhancement of activity by increasing the linker length. In contrast to their antimalarial activity, the tetracycles were devoid of antitubercular activity whereas the advanced intermediates displayed growth inhibitory activity against the H 37Rv strain of Mycobacterium tuberculosis as revealed by BACTEC, MABA and LORA assays.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.02.008