gThe pressing need for better drugs against Chagas disease, African sleeping sickness, and schistosomiasis motivates the search for inhibitors of cruzain, rhodesain, and Schistosoma mansoni CB1 (SmCB1), the major cysteine proteases from Trypanosoma cruzi, Trypanosoma brucei, and S. mansoni, respectively. Thiosemicarbazones and heterocyclic analogues have been shown to be both antitrypanocidal and inhibitory against parasite cysteine proteases. A series of compounds was synthesized and evaluated against cruzain, rhodesain, and SmCB1 through biochemical assays to determine their potency and structure-activity relationships (SAR). This approach led to the discovery of 6 rhodesain, 4 cruzain, and 5 SmCB1 inhibitors with 50% inhibitory concentrations (IC 50 s) of <10 M. Among the compounds tested, the thiosemicarbazone derivative of peracetylated galactoside (compound 4i) was discovered to be a potent rhodesain inhibitor (IC 50 ‫؍‬ 1.2 ؎ 1.0 M). The impact of a range of modifications was determined; removal of thiosemicarbazone or its replacement by semicarbazone resulted in virtually inactive compounds, and modifications in the sugar also diminished potency. Compounds were also evaluated in vitro against the parasites T. cruzi, T. brucei, and S. mansoni, revealing active compounds among this series. N ew drugs for parasitic diseases are urgently needed, but these globally important infections are often "neglected" because they most commonly afflict poor and marginalized communities. Current therapies are limited by poor efficacy, toxicity, high costs, and parasite resistance. Chagas disease, African sleeping sickness, and schistosomiasis are examples of diseases for which new therapies are needed (1, 2). Among the most studied and exploited molecular targets for these diseases are cysteine proteases. These enzymes have essential roles in parasite nutrition, immune evasion, host cell invasion, and metacyclogenesis (3-6). Indeed, the cysteine proteases cruzain, rhodesain, and Schistosoma mansoni CB1 (SmCB1) from Trypanosoma cruzi, Trypanosoma brucei, and S. mansoni, respectively, are validated molecular targets and have been the subject of numerous medicinal chemistry projects (7-17) that have yielded trypanocidal inhibitors, both in parasite culture and in animal models of infection (13,15,(18)(19)(20)(21).The diverse inhibitors of these enzymes comprise compound classes which bind noncovalently (11, 12) and scaffolds containing a "warhead" that binds covalently to the catalytic cysteine. Within the latter category, vinylsulfones (8,(22)(23)(24)(25), oxy-methyl ketones (7, 26), nitriles (16), epoxides, and thiosemicarbazones (13-15, 27-29) have been described previously. Thiosemicarbazones present as advantages their low molecular weight, low cost of synthesis, and nonpeptidic nature (27). Greenbaum and coworkers synthesized and evaluated the cysteine protease inhibitory and antiparasitic activities of a library of thiosemicarbazones, with promising results (13). According to those authors, the thiosemicarbazones are...

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Background The increasing incidence of invasive forms of candidiasis and resistance to antifungal therapy leads us to seek new and more effective antifungal compounds. Objectives Investigate the antifungal activity and toxicity as well as to evaluate the potential targets of 2-cyclohexylidenhydrazo-4-phenyl-thiazole (CPT) in Candida albicans. Methods The antifungal activity of CPT against the survival of C. albicans was investigated in Caenorhabditis elegans. Additionally, we determined the effect of CPT on the inhibition of C. albicans adhesion capacity to buccal epithelial cells (BECs), the toxicity of CPT in mammalian cells, and the potential targets of CPT in C. albicans. Results CPT exhibited a minimum inhibitory concentration (MIC) value of 0.4-1.9 µg/mL. Furthermore, CPT at high concentrations (>60 x MIC) showed no or low toxicity in HepG2 cells and <1% haemolysis in human erythrocytes. In addition, CPT decreased the adhesion capacity of yeasts to the BECs and prolonged the survival of C. elegans infected with C. albicans. Analysis of CPT-treated the cells showed that their cell wall was thinner than that of untreated cells, especially the glucan layer. We found that there was a significantly lower quantity of 1,3-β-D-glucan present in CPT-treated cells than that in untreated cells. Assays performed on several mutant strains showed that the MIC value of CPT was high for its antifungal activity on yeasts with defective 1,3-β-glucan synthase. Conclusions In conclusion, CPT appears to target the cell wall of C. albicans, exhibits low toxicity in mammalian cells, and prolongs the survival of C. elegans infected with C. albicans.

The aims of this study were to synthesize a series of thiosemicarbazones and their thiazole derivatives, to investigate their cytotoxic activity against three human cancers and normal (Vero cells) cell lines, and to evaluate the pro-apoptotic potential of the most active compounds. Materials and Methods: The thiosemicarbazones were obtained by reacting an aromatic aldehyde with thiosemicarbazide (yield 71-96%), which were subjected to a cyclization with α-bromoacetophenone to yield the required thiazole heterocycles (yield 63-100%). All the synthesized compounds were screened at 50 µM concentration against three cell lines representing HL60 (promyelocytic leukemia), Jurkat (acute lymphoblastic leukemia), and MCF-7 (breast cancer). The pro-apoptotic effect was measured by flow cytometry as the percentage of cells with hypodiploid DNA. Results: Three thiazole compounds showed activity against at least one tumor cell line (IC 50 = 43-76 µM) and low cytotoxicity against Vero cells (IC 50 > 100 µM). The most active compound of this series induced 91% and 51% DNA fragmentation in HL60 and MCF-7 cell lines, respectively, suggesting that this compound triggered apoptosis in these cells. Conclusion: Among the synthesized compounds, one in particular was found to exert antiproliferative and pro-apoptotic activity on tumor cells and can be considered promising as a lead molecule for the design of new analogues with improved activity.Uniterms: Thiosemicarbazones/synthesis. Thiosemicarbazones/cytotoxic activity. Thiazoles/derivatives/ synthesis. Thiazoles/derivatives/cytotoxic activity. O estudo teve como objetivo a síntese de uma série de tiossemicarbazonas e seus derivados tiazólicos e a avaliação da atividade citotóxica contra três linhagens de células tumorais humanas e células normais (Vero), a fim de se avaliar o potencial pró-apoptótico dos compostos mais ativos. As tiossemicarbazonas foram obtidas por reação entre um aldeído aromático e tiossemicarbazida (rend. 71-96%), as quais foram submetidas à ciclização com α-bromoacetofenona, fornecendo os heterociclos tiazólicos desejados (rend. 63-100%). Todos os compostos sintetizados foram testados na concentração de 50 µM contra três linhagens de células tumorais: HL60 (leucemia promielocítica), Jurkat (leucemia linfoblástica aguda) e MCF-7 (câncer de mama). O efeito pró-apoptótico foi avaliado por citometria de fluxo como porcentagem de células com DNA hipodiplóide. Três compostos tiazólicos foram ativos contra, pelo menos, uma linhagem tumoral (CI 50 =43-76 µM), com baixa citotoxicidade contra células Vero (CI 50 > 100 µM). O composto mais ativo dessa série induziu fragmentação do DNA de 91% e 51% nas linhagens HL60 e MCF-7, respectivamente, sugerindo que este composto ativou a apoptose nessas células. Dentre os compostos sintetizados, um em particular apresentou atividade antiproliferativa e pró-apoptótica em células tumorais e pode ser considerado composto protótipo promissor na busca por novos análogos com atividade melhorada.