Viktor Krchnak

Evolution of natural product scaffolds by acyl- and arylnitroso hetero-diels-alder reactions: new chemistry on piperine.

Piperine, a natural product containing a conjugated diene, was reacted with polymer-supported acyl- and arylnitroso dienophiles. The reactions with arylnitroso dienophiles were also carried out in solution. The oxazine rings formed by the corresponding hetero-Diels-Alder reactions were further transformed and novel acyclic as well as heterocyclic derivatives including pyrroles and quinoxalinones were prepared.

Solid-Phase Synthesis of Biologically Interesting Compounds Containing Hydroxamic Acid Moiety

Chemical strategies developed for the solid-phase synthesis of hydroxamates are divided into four groups: (i) the traditional synthesis of hydroxamates via cleavage of resin-bound esters by hydroxylamine and its derivatives, (ii) introduction of hydroxamic acid moiety on the resin-bound precursor, (iii) transformation of polymer-supported hydroxylamine, attached to a solid supported linker either by oxygen (O-linking strategy) or by nitrogen (N-linking strategy), and (iv) synthesis of N-alkyl hydroxamates. The scope and limitation of individual approaches are discussed.

In Vivo Dearomatization of the Potent Antituberculosis Agent BTZ043 via Meisenheimer Complex Formation

Nitrobenzothiazinones are among the most potent antituberculosis agents. Herein, we disclose an unprecedented in vivo reduction process that affords Meisenheimer complexes of the clinical candidates BTZ043 and PBTZ169. The reduction is reversible, occurs in all mammalian species investigated, has a profound influence on the in vivo ADME characteristics, and has considerable implications for the design and implementation of clinical studies. The reduction was confirmed by chemical studies that enabled the complete characterization of the Meisenheimer complex and its subsequent chemistry. Combination of the in vivo and chemical studies with LC-MS characterization and assay development also provides a basis for rational lead optimization of this very promising class of antituberculosis agents.

Unprecedented Rearrangement of 2-(2-Aminoethyl)-1-aryl-3,4-dihydropyrazino[1,2-b]indazole-2-ium 6-oxides to 2,3-Dihydro-1H-imidazo[1,2-b]indazoles

Easily accessible 2-(2-aminoethyl)-1-aryl-3,4-dihydropyrazino[1,2-b]indazole-2-ium 6-oxides rearranged to 2,3-dihydro-1H-imidazo[1,2-b]indazoles under mild conditions. The rearrangement appeared to be general, tolerated a wide range of functional groups, and provided access to an as yet unexplored class of heterocycles. Herein we report the characterization of these heterocycles.