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.

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Upregulation of cathepsin L in a variety of tumors and its ability to promote cancer cell invasion and migration through degradation of the extracellular matrix suggest that cathepsin L is a promising biological target for the development of anti-metastatic agents. Based on encouraging results from studies on benzophenone thiosemicarbazone cathepsin inhibitors, a series of fourteen benzoylbenzophenone thiosemicarbazone analogues were designed, synthesized, and evaluated for their inhibitory activity against cathepsins L and B. Thiosemicarbazone inhibitors 3-benzoylbenzophenone thiosemicarbazone 1, 1,3-bis(4-fluorobenzoyl)benzene thiosemicarbazone 8, and 1,3-bis(2-fluorobenzoyl)-5-bromobenzene thiosemicarbazone 32 displayed the greatest potency against cathepsin L with low IC50 values of 9.9 nM, 14.4 nM, and 8.1 nM, respectively. The benzoylbenzophenone thiosemicarbazone analogues evaluated were selective in their inhibition of cathepsin L compared to cathepsin B. Thiosemicarbazone analogue 32 inhibited invasion through Matrigel of MDA-MB-231 breast cancer cells by 70% at 10 μM. Thiosemicarbazone analogue 8 significantly inhibited the invasive potential of PC-3ML prostate cancer cells by 92% at 5 μM. The most active cathepsin L inhibitors from this benzoylbenzophenone thiosemicarbazone series (1, 8, and 32) displayed low cytotoxicity toward normal primary cells [in this case human umbilical vein endothelial cells (HUVECs)]. In an initial in vivo study, 3-benzoylbenzophenone thiosemicarbazone (1) was well-tolerated in a CDF1 mouse model bearing an implanted C3H mammary carcinoma, and showed efficacy in tumor growth delay. Low cytotoxicity, inhibition of cell invasion, and in vivo tolerability are desirable characteristics for anti-metastatic agents functioning through an inhibition of cathepsin L. Active members of this structurally diverse group of benzoylbenzophenone thiosemicarbazone cathepsin L inhibitors show promise as potential anti-metastatic, pre-clinical drug candidates.

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Flame retardants endow epoxy resins (EP) with flame retardance, however, their introduction often lead to the decrease in the glass transition temperature (Tg), which is an important property for EP. Therefore, it is significant to design and synthesize a high‐efficiency flame retardant that enhances flame retardance and Tg of EP. To achieve this goal, a hyperbranched polyamide oligomer containing DOPO (HPD) was successfully synthesized by A4 + B2 polymerization and its structure was confirmed by FTIR, 1H NMR, and 30P NMR spectra and GPC. HPD was used as an additive flame retardant in epoxy resin, and its effect on the flame retardance and thermal properties of epoxy resin was studied. The epoxy resin with 7.5 wt% HPD reached UL‐94V‐0 rating and a higher LOI value of 29.6%, and its Tg was 176.2°C, which is higher than the pure epoxy resin. Moreover, the results of cone calorimetry testing (CCT) and TG‐FTIR analysis suggested that the gas‐phase and condensed‐phase flame‐retarded roles of HPD delayed the time to ignition, and reduced the value of relevant combustion parameters, including the peak of heat release rate, average of heat release rate, total heat release, smoke production rate, and total smoke production. The analysis results of Py‐GC/MS test of HPD further confirmed that HPD was able to play the flame‐retarded role in the gaseous and condensed phases.