Synthesis and Structure−Activity Relationships of Parasiticidal Thiosemicarbazone Cysteine Protease Inhibitors against Plasmodium falciparum, Trypanosoma brucei, and Trypanosoma cruzi

Abstract

We have synthesized a library of thiosemicarbazones and screened them against three parasitic cysteine proteases, cruzain, falcipain-2, and rhodesain, and against the respective parasite sources of these three proteases, Trypanosoma cruzi, Plasmodium falciparum, and Trypanosoma brucei. The screens identified compounds that were effective against the enzymes and the parasites but also some compounds that were parasiticidal despite a lack of activity against the proteases. Several compounds were effective in killing all tested parasites. These promising lead compounds were tested for general toxicity in mice, and only one produced observable toxicity after 62 h. Our results suggest that thiosemicarbazones represent validated drug leads that kill several species of protozoan parasites through the inhibition of cysteine proteases as well as other novel targets.

5-Nitroisatin-derived thiosemicarbazones: potential antileishmanial agents

“…The chelation of Fe from intracellular Fe pools results in the inhibition of RDR. The tridentate chelating thiosemicarbazones have been proposed to act by inhibiting RDR 13,[38][39][40] . Such compounds have also been proposed to act by inhibiting dihydrofolate reductase 41,42 .…”

“…Thiosemicarbazones are an important class of organic compounds, which possesses a number of medicinal properties, including antibacterial, antifungal, antiprotozoal, antitumoral, antiviral and more particularly, the antileishmanial activities [8][9][10][11][12][13][14][15][16][17][18][19][20][21] . Isatin-derived thiosemicarbazones have also been found to possess a variety of biological activities, such as antimicrobial, antineoplastic, antiplasmodial and antiviral [22][23][24][25][26][27][28][29][30][31][32][33][34] .…”

“…7,8,[10][11][12][13][15][16][17][18][19]21,23,24,26,28 and 30 exhibited good to excellent antileishmanial activities with IC 50 values ranging from 0.44 AE 0.02 to 32.38 AE 0.66 mg/mL. Of these, 5, 7, 19 and 28 proved to be the most active antileishmanial agents, displaying activities with IC 50 values 1.78 AE 0.35, 0.44 AE 0.02, 1.91 AE 0.04 and 4.28 AE 0.75 mg/mL, respectively, which were even better than the standard drug, pentamidine (IC 50 ¼ 5.09 AE 0.04 mg/mL).…”

Synthesis, spectroscopic studies and characterizations of some new bis thiosemicarbazones and their cyclization reactions

“…[1][2][3][4] In a previous study, the bis(thiosemicarbazone) complexes of copper have shown special promise as radiopharmaceuticals, as illustrated by the per fusion imaging agent. [5][6][7][8][9] Thiosemicarbazones have been reported to exhibit antituberculosis activity.…”

Antileishmanial Thioureas: Synthesis, Biological Activity and <i>in Silico</i> Evaluations of New Promising Derivatives

“…8) Thiourea derivatives have already been identified as potential antiprotozoal agents. Several works demonstrate their activity against Plasmodium falciparum, 11,16) Trichomonas vaginalis, 17) Trypanosoma cruzi 16,18) and Leishmania infantum, 18) and some examples of these compounds are given in Fig. 1.…”