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 IC 50 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 (IC 50 > 10000 nM) against cathepsin B. The most potent inhibitor (IC 50 = 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.

Nickel-Catalyzed Direct Thiolation of C(sp3)–H Bonds in Aliphatic Amides

“…5 Almeida et al noted that thiacycloalkynes (C) are promising new reagents for click chemistry. 6 Furthermore, thiosemicarbazone analogues (D) were found to be potent inhibitors of cathepsin L, 7 whereas in the synthesis of bryostatin, which is used in the treatment of lymphoma, sulfones (E) serve as central glycal intermediates. 8 In addition, 2,6,7-trioxabicyclo-[2.2.2]octane sulfone (F) is a new reagent that enables the rapid assembly of pyranone intermediates.…”

Hydrazone Derivatives Enhance Antileishmanial Activity of Thiochroman-4-ones

“…In fact, the thiosemicarbazide itself was inactive against Leishmania parasites. Therefore, despite the available information, it cannot be deduced that acylhydrazone derivatives always act as prodrugs [28,29], since it has been shown that several hydrazones are inhibitors of cysteine proteases [16,20,21].…”

“…Structures of thiochroman-4-ones ( [1][2][3][4][5] and hydrazone derivatives (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). …”

“…In addition, numerous hydrazones have been reported to possess interesting biological activities such as antitumoral, antiviral and antiparasitic effects [8][9][10]; some hydrazones also exhibit activity against the parasites that cause malaria, leishmaniasis and Chagas disease [3,[11][12][13][14][15][16][17][18], where the inhibition of proteases and represent the most common mechanism of action for the hydrazones [16,[19][20][21].…”

Ionic liquid-molecularly imprinted polymers for pipette tip solid-phase extraction of (Z)-3-(chloromethylene)-6-flourothiochroman-4-one in urine

“…Some 3-substituted thiochromanones have an antifungal effect on many fungi in vitro such as Trichophyton rubrum, Machaeranthera gypsum, Cryptococcus neoformans, Candida krusei, Epidermophyton floccosum and S. schenekn, and show a similar or higher level of activity when compared with fluconazole [4,5]. In recent years, it has been reported that some thiochromanones have anticancer activities, because they can act as potent inhibitors of cathepsin L which is a unique biomolecular target in anticancer drug development [6,7]. (Z)-3-(chloromethylene)-6-flourothiochroman-4-one (CFO) is one of thiochromanone derivatives that exhibits noticeable antitumor activities due to inducing apoptosis of tumor cells by triggering caspase cascade and increasing expression of death receptor 3 (DR3) [8].…”