Dipeptidyl nitroalkenes are potent reversible inhibitors of cysteine proteases. Inhibitor 11 resulted to be the most potent one with K i values of 0.49 and 0.44 nM against rhodesain and cruzain, respectively. According to enzymatic dilution and dialysis experiments, as well as computational and NMR studies, dipeptidyl nitroalkenes are tightly binding covalent reversible inhibitors.KEYWORDS: Rhodesain, cruzain, inhibitors, Chagas' disease, sleeping sickness T he target proteases of the presented study, rhodesain and cruzain, are parasite proteases, which belong to the papain-family of cysteine proteases.1,2 They are related to human cathepsins.1,2 Rhodesain is expressed by the protozoa Trypanosoma brucei rhodesiense, which causes the African sleeping sickness. 3,6,7 Cruzain is expressed by T. cruzi, the parasite causing Chagas' disease occurring in South and Central America.4,5 Both proteases are essential for the life cycles of the pathogens. Consequently, their inhibition is an important strategy for the treatment of these diseases. 8,9 K11777 (Figure 1a), a dipeptidyl vinyl sulfone, irreversibly inactivates cysteine proteases 10 by conjugate addition of the thiolate of the cysteine at the active site to the double bond. The resulting carbanion is subsequently protonated driving the process thermodynamically to the more stable enzyme− inhibitor complex (Figure 1b).Irreversible inhibitors can give rise to undesired side reactions. Turning dipeptidyl vinyl sulfones into compounds that reversibly react with thiols by introducing thioethers or halogen atoms into the structure has been reported. 11 In case of the halogenated vinylsulfones this leads to covalent reversible inhibition. 12We envisioned dipeptidyl nitroalkenes as inhibitors for cysteine proteases. Based upon the inhibition mechanism of

The diastereoselectivity of the nucleophilic epoxidation of 3-hydroxy-2-methylene esters has been studied. The 3-hydroxy-2-methylene esters were obtained through a Morita-Baylis-Hillman reaction. The resulting epoxyesters were treated with thiophenol for transformation into 2,3-dihydroxy-2-((phenylthio)methyl) which upon treatment with triphosgene afforded the corresponding cyclic carbonates.

Abstract-The mechanism of the dehydrosulfenylation of 2-arylsulfinyl esters was investigated. The reaction was found to follow a homolytic cleavage mechanism as verified by electrospray ionization tandem mass spectrometry and experimental work. Rearranged sulfoxides are obtained as by-products during the elimination reaction. _______________________________________________________________________________________________________________Elimination reactions of sulfoxides and sulfones are well known reactions in synthetic organic chemistry.

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A Darzens reaction between tert-butoxycarbonyl alaninal and chloromethyl phenyl sulfone afforded chlorohydrins, which were converted into epoxysulfones by reaction with sodium tert-butoxide. Epoxysulfone 10 and chloroketone 14 derived from chlorohydrins by oxidation proved to be inhibitors of cathepsins H, S, and C as determined by competitive activity-based protein profiling.