biostudies-otherUnknown3(6)Song JACS medicinal chemistry letters450-3https://www.ebi.ac.uk/biostudies/studies/S-EPMC4025852A series of 36 thiosemicarbazone analogues containing the thiochromanone molecular scaffold functionalized primarily at the C-6 position were prepared by chemical synthesis and evaluated as inhibitors of cathepsins L and B. The most promising inhibitors from this group are selective for cathepsin L and demonstrate IC50 values in the low nanomolar range. In nearly all cases, the thiochromanone sulfide analogues show superior inhibition of cathepsin L as compared to their corresponding thiochromanone sulfone derivatives. Without exception, the compounds evaluated were inactive (IC50 > 10000 nM) against cathepsin B. The most potent inhibitor (IC50 = 46 nM) of cathepsin L proved to be the 6,7-difluoro analogue 4. This small library of compounds significantly expands the structure-activity relationship known for small molecule, nonpeptidic inhibitors of cathepsin L.biostudies-otherPMC4025852Europe PMCBayeh LConner ESChavarria GECharlton-Sevcik AKKumar GDPinney KGJones LMTrawick MLSong JChaplin DJChen SEfalseSynthesis and biochemical evaluation of thiochromanone thiosemicarbazone analogues as inhibitors of cathepsin L.A series of 36 thiosemicarbazone analogues containing the thiochromanone molecular scaffold functionalized primarily at the C-6 position were prepared by chemical synthesis and evaluated as inhibitors of cathepsins L and B. The most promising inhibitors from this group are selective for cathepsin L and demonstrate IC50 values in the low nanomolar range. In nearly all cases, the thiochromanone sulfide analogues show superior inhibition of cathepsin L as compared to their corresponding thiochromanone sulfone derivatives. Without exception, the compounds evaluated were inactive (IC50 > 10000 nM) against cathepsin B. The most potent inhibitor (IC50 = 46 nM) of cathepsin L proved to be the 6,7-difluoro analogue 4. This small library of compounds significantly expands the structure-activity relationship known for small molecule, nonpeptidic inhibitors of cathepsin L.2012-01-01T00:00:00Z2012 Jun2019-03-27T01:28:30Z2019-03-27T01:28:30ZS-EPMC40258522490049410.1021/ml200299g