title: Synthesis and biochemical evaluation of thiochromanone thiosemicarbazone analogues as inhibitors of cathepsin L.
abstract: 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.
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University , One Bear Place #97348, Waco, Texas, 76798-7348 United States.
authors.forename: Jiangli
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University , One Bear Place #97348, Waco, Texas, 76798-7348 United States.
authors.forename: Lindsay M
authors.initials: LM
authors.lastname: Jones
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University , One Bear Place #97348, Waco, Texas, 76798-7348 United States.
authors.forename: G D Kishore
authors.initials: GD
authors.lastname: Kumar
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University , One Bear Place #97348, Waco, Texas, 76798-7348 United States.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Conner
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University , One Bear Place #97348, Waco, Texas, 76798-7348 United States.
authors.forename: Liela
authors.initials: L
authors.lastname: Bayeh
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University , One Bear Place #97348, Waco, Texas, 76798-7348 United States.
authors.forename: Gustavo E
authors.initials: GE
authors.lastname: Chavarria
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University , One Bear Place #97348, Waco, Texas, 76798-7348 United States.
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Charlton-Sevcik
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University , One Bear Place #97348, Waco, Texas, 76798-7348 United States.
authors.forename: Shen-En
authors.initials: SE
authors.lastname: Chen
authors.affiliation: OXiGENE Inc. , 701 Gateway Boulevard, Suite 210, South San Francisco, California, 94080, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: Chaplin
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University , One Bear Place #97348, Waco, Texas, 76798-7348 United States.
authors.forename: Mary Lynn
authors.initials: ML
authors.lastname: Trawick
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University , One Bear Place #97348, Waco, Texas, 76798-7348 United States.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Pinney
keywords: cathepsin B; cathepsin L; inhibitor; thiochromanone; thiosemicarbazone