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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New Mannich base-type eugenol derivatives were synthesized and evaluated for their anticandidal activity using a broth microdilution assay. Among the synthesized compounds, 4-allyl-2-methoxy-6-(morpholin-4-ylmethyl) phenyl benzoate (7) and 4-{5-allyl-2-[(4-chlorobenzoyl)oxy]-3-methoxybenzyl}morpholin-4-ium chloride (8) were found to be the most effective antifungal compounds with low IC50 values, some of them well below those of reference drug fluconazole. The most significant IC50 values were those of 7 against C. glabrata (1.23 μm), C. albicans and C. krusei (both 0.63 μm). Additionally, the synthesized compounds were evaluated for their in vitro cytotoxic effects on human mononuclear cells. As result, the cytotoxic activity of eugenol in eukaryotic cells decreased with the introduction of the morpholinyl group. Given these findings, we point out compounds 7 and 8 as the most promising derivatives because they showed potency values greater than those of eugenol and fluconazole and they also presented high selectivity indexes.

Piplartine (piperlongumine) is a plant-derived compound found in some Piper species that became a novel potential antineoplastic agent. In the present study, we synthesized a novel platinum complex containing a piplartine derivative cis-[PtCl(PIP-OH)(PPh3)2]PF6 (where, PIP-OH = piplartine demethylated derivative; and PPh3 = triphenylphosphine) with enhanced cytotoxicity in different cancer cells, and investigated its apoptotic action in human promyelocytic leukemia HL-60 cells. The structure of PIP-OH ligand was characterized by X-ray crystallographic analysis and the resulting platinum complex was characterized by infrared, molar conductance measurements, elemental analysis and NMR experiments. We found that the complex is more potent than piplartine in a panel of cancer cell lines. Apoptotic cell morphology, increased internucleosomal DNA fragmentation, without cell membrane permeability, loss of the mitochondrial transmembrane potential, increased phosphatidylserine externalization and caspase-3 activation were observed in complex-treated HL-60 cells. Treatment with the complex also caused a marked increase in the production of reactive oxygen species (ROS), and the pretreatment with N-acetyl-L-cysteine, an antioxidant, reduced the complex-induced apoptosis, indicating activation of ROS-mediated apoptosis pathway. Important, pretreatment with a p38 MAPK inhibitor (PD 169316) and MEK inhibitor (U-0126), known to inhibit ERK1/2 activation, also prevented the complex-induced apoptosis. The complex did not induce DNA intercalation in cell-free DNA assays. In conclusion, the complex exhibits more potent cytotoxicity than piplartine in a panel of different cancer cells and triggers ROS/ERK/p38-mediated apoptosis in HL-60 cells.

Seventeen new synthetic derivatives of eugenol (6, 8-15 and 8'-15') were planned following literature reports on antifungal activities of nitroeugenol and eugenol glucoside. The anti-Candida activity of these compounds was investigated by in vitro assay, and the cytotoxicity evaluation was performed with the most active compounds. The peracetylated glucosides presented better biological results than their hydroxylated analogues. The glucoside 11, a 4-nitrobenzamide, showed the best potency (MIC range 11.0-151.84 μm), the wider spectrum of action, and overall the best selectivity indexes, especially against C. tropicalis (~30) and C. krusei (~15). To investigate its possible mechanism of action, glucoside 11 was subjected to molecular docking studies with Candida sp. enzymes involved in ergosterol biosynthesis. Results have shown that the peracetyl glucosyl moiety and the 4-nitrobenzamide group in 11 are effectively involved in its high affinity with the active site of squalene epoxidase.