RESUMEN
In this communication we report a serendipitously discovered hybrid molecule 1, combining fragment of 3 (an in vivo active antileishmanial molecule) with H2S donor moiety (known for bimodal behavior of cytoprotection and apoptosis), as antileishmanial agent. Compound 1 suppresses 99.82% parasitemia of L. donovani infected macrophages at 12.5µg/ml without even deforming them (CC50>100µg/ml). This compound appears cytotoxic for intracellular amastigotes while cytoprotective to host macrophages. The concept can be utilized to develop high therapeutic index NCE (New Chemical Entities) for other macrophage mediated diseases like tuberculosis and cancer.
Asunto(s)
Antiprotozoarios/química , Indoles/química , Antiprotozoarios/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Humanos , Sulfuro de Hidrógeno/metabolismo , Indoles/farmacología , Leishmania donovani/efectos de los fármacos , Macrófagos/citología , Macrófagos/metabolismo , Macrófagos/parasitologíaRESUMEN
In an attempt to synthesize pentamidine-aplysinopsin hybrid molecule 25, a lead molecule 8 (containing Z-configured aplysinopsin moiety) was identified for antileishmanial activity. Optimization of lead 8 provided 24 (containing E-configured aplysinopsin) possessing 10 times more activity and 401-fold less toxicity than the drug pentamidine in cell based assays. Synthesis of 24 was possible, surprisingly, because of two innate reactivities of indole-3-carbaldehyde which provided it in diastereo- and regio-selectively pure form without recourse to the long reaction pathway.
