Sulfondiimines: synthesis, derivatisation and application.

Sulfondiimines are aza-analogues of sulfones and sulfoximines. In contrast to the latter two compound classes, sulfondiimines are rare in the chemical literature. Although a full understanding of the stability and reactivity of sulfondiimines is wanting, sulfondiimines have recently been recognized as novel bioisosteres for carbonyl moieties enabling expansion of the well-known portfolio of pharmaceutically relevant compounds. In this review, we briefly summarize the structure and stability of sulfondiimines and then focus on syntheses and derivatisations of these interesting compounds with sulfur-nitrogen core units. Furthermore, their use in heterocyclic chemistry and recent applications as bioactive compounds are presented.

Synthesis of trifluoromethyl-substituted 1,2,6-thiadiazine 1-oxides from sulfonimidamides under mechanochemical conditions.

TBS-protected or NH-sulfonimidamides react with ß-alkoxyvinyl trifluoromethylketones under solvent-free mechanochemical conditions to give 3-trifluoromethyl-substituted three-dimensional 1,2,6-thiadiazine 1-oxides. C4-Functionalized products can be obtained by starting from cyclic enones and brominations of the initially formed heterocycles. The stability of the products was investigated by varying the pH value and storage under aerobic conditions.

Mechanochemical Synthesis of 1,2,6-Thiadiazine 1-Oxides from Sulfonimidamides and the Fluorescence Properties of the Products.

A solvent-free mechanochemical synthesis for 1,2,6-thiadiazine 1-oxides starting from NH-sulfonimidamides and propargyl ketones has been developed. Lewis acids affect these one-pot aza-Michael-addition/cyclization/dehydration reaction sequences. The photophysical properties of the resulting heterocyclic sulfonimidamide derivatives were characterized.

Evaluation of Chiral Organosulfur Compounds on Their Activity against the Malaria Parasite Plasmodium falciparum.

Malaria is one of the deadliest tropical diseases, especially causing havoc in children under the age of five in Africa. Although the disease is treatable, the rapid development of drug resistant parasites against frontline drugs requires the search for novel antimalarials. In this study, we tested a series of organosulfur compounds from our internal library for their antiplasmodial effect against Plasmodium falciparum asexual and sexual blood stages. Some active compounds were also obtained in enantiomerically pure form and tested individually against asexual blood stages of the parasite to compare their activity. Out of the 23 tested compounds, 7 compounds (1, 2, 5, 9, 15, 16, and 17) exhibited high antimalarial activity, with IC50 values in the range from 2.2 ± 0.64 to 5.2 ± 1.95 µM, while the other compounds showed moderate to very low activity. The most active compounds also exhibited high activity against the chloroquine-resistant strain, reduced gametocyte development and were not toxic to non-infected red blood cells and Hela cells, as well as the hematopoietic HEL cell line at concentrations below 50 µM. To determine if the enantiomers of the active compounds display different antimalarial activity, enantiomers of two of the active compounds were separated and their antimalarial activity compared. The results show a higher activity of the (-) enantiomers as compared to their (+) counterparts. Our combined data indicate that organosulfur compounds could be exploited as antimalarial drugs and enantiomers of the active compounds may represent a good starting point for the design of novel drugs to target malaria.

Chiral Analogues of PFI-1 as BET Inhibitors and Their Functional Role in Myeloid Malignancies.

Structural analogues of PFI-1 varying at the sulfur core were prepared, and their activities as BET inhibitors in myeloid cell lines and primary cells from patients with acute myeloid leukemia were studied. Docking calculations followed by molecular dynamics simulations revealed the binding mode of the newly prepared inhibitors, suggesting explanations for the observed high enantiospecificity of the inhibitory activity.

1,2,6-Thiadiazine 1-Oxides: Unsaturated Three-Dimensional S,N-Heterocycles from Sulfonimidamides.

Unprecedented three-dimensional 1,2,6-thiadiazine 1-oxides have been prepared by an aza-Michael-addition/cyclization/condensation reaction sequence starting from sulfonimidamides and propargyl ketones. The products have been further functionalized by standard cross-coupling reactions, selective bromination of the heterocyclic ring, and conversion into a ß-hydroxy substituted derivative. A representative product was characterized by single-crystal X-ray structure analysis.