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(37)Rv strain of Mycobacterium tuberculosis as revealed by BACTEC, MABA and LORA assays.