Functionalized benzophenone, thiophene, pyridine, and fluorene thiosemicarbazone derivatives as inhibitors of cathepsin L

Synthesis and Biochemical Evaluation of Thiochromanone Thiosemicarbazone Analogues as Inhibitors of Cathepsin L

“…17,18 Previous research from our group has focused on inhibitors of the cysteine protease, cruzain, which has implications in the treatment of Chagas' disease. 19−21 As a preliminary assay to evaluate selectivity for cruzain inhibition, a series of compounds was also screened against the structurally similar human cysteine protease cathepsin L. Several compounds, based primarily on the benzophenone or thiochromanone thiosemicarbazone molecular structure, were identified as lead compound inhibitors of cathepsin L. 20,22−24 These original findings provided the foundational support for the current studies involving functionalized thiochromanone thiosemicarbazone inhibitors of cathepsin L. To the best of our knowledge, we are the first to report 20,24 thiochromanone thiosemicarbazones and their corresponding sulfone analogues as molecular scaffolds that inhibit cathepsin L. A sampling of previously reported inhibitors (Figure 2) containing the thiosemicarbazone moiety includes VI, 22 VII, 23 VIII, 22 and IX. 25 To incorporate structural diversity within the aryl portion of the target compounds, as shown in Scheme 1, 3-bromopropionic acid was reacted with various commercially available thiophenols appropriately functionalized on the aromatic ring.…”

Crystal structure of 2-(9H-fluoren-9-ylidene)hydrazine-1-carbothioamide, C14H11N3S

“…as (9H-uorene-9-ylidine)-thiosemicarbazide have biological activity such as antifungal [1], antitumor [2], inhibitors of cathepsin L [3] and antibacterial [4] that can be exploited for therapeutics applications. The thiosemicarbazone moiety was described as a major functional group in a wide variety of anticancer agents [5][6][7].…”

Synthesis and biochemical evaluation of benzoylbenzophenone thiosemicarbazone analogues as potent and selective inhibitors of cathepsin L

“…51 Previously, 45-46 incorporation of the 3-bromo functionality in benzophenone thiosemicarbazone analogues proved critical in providing analogues which displayed potent inhibitory activity against cathepsin L as demonstrated by the large differences in IC 50 values found for X and XI compared to the non-brominated analogues XIII and XIV , respectively (Figure 3). Additionally, the 4-bromo analogue XII displayed reduced activity towards cathepsin L compared to the 3-bromo analogue XI further emphasizing the importance of the 3-bromo functionality.…”

“…44 In addition to the inhibition of cathepsins, 45-51, 52 incorporation of the thiosemicarbazone moiety as an electrophilic warhead has proved useful in the identification of potent small-molecule inhibitors of cysteine proteases found in Trypanosoma cruzi and Trypanosoma brucei , 53-57 Plasmodium falciparum , 57-59 Leishmania Mexicana , 60 and Eimeria tenella . 61 In the investigation of thiosemicarbazone inhibitors in our group 45-50 several cathepsin L inhibitors based on the benzophenone, thiochromanone, thiochromanone sulfone, and dihydroquinoline scaffolds including (3-bromo-3′-hydroxybenzophenone) thiosemicarbazone X , 46-48 (3-bromo-2′-fluorobenzophenone) thiosemicarbazone XI , 45 and 6-nitrothio-4-chromanone thiosemicarbazone XVI 49 emerged as promising lead compounds (Figure 3). …”