Synthesis, Characterization, and In Vivo Study of Some Novel 3,4,5-Trimethoxybenzylidene-hydrazinecarbothioamides and Thiadiazoles as Anti-Apoptotic Caspase-3 Inhibitors.

The present study aims to discover novel derivatives as antiapoptotic agents and their protective effects against renal ischemia/reperfusion. Therefore, a series of new thiadiazole analogues - was designed and synthesized through cyclization of the corresponding opened hydrazinecarbothioamides - followed by confirmation of the structure via spectroscopic tools (NMR, IR and mass spectra) and elemental analyses. The antiapoptotic activity showed alongside decreasing of tissue damage induced by I/R in the kidneys of rats using -acetylcysteine (NAC) as an antiapoptotic reference. Most of the cyclized thiadiazoles are better antiapoptotic agents than their corresponding opened precursors. Particularly, compounds and were the most active antiapoptotic compounds with significant biomarkers. A preliminary mechanistic study was performed through caspase-3 inhibition. Compound was selected along with its corresponding opened precursor . An assay of cytochrome revealed that there is an attenuation of cytochrome level of about 5.5-fold, which was better than with a level of 4.1-fold. In caspases-3, 8 and 9 assays, compound showed more potency and selectivity toward caspase-3 and 9 compared with . The renal histopathological investigation indicated normal renal tissue for most of the compounds, especially and relative to the control. Finally, a molecular docking study was conducted at the caspase-3 active site to suggest possible binding modes.