Disulfiram and dithiocarbamate analogues demonstrate promising antischistosomal effects

From dithiocarbamates to branched dithiocarbazates: Compounds with potent antischistosomal activity

“…The second series focussed on N ‐aminopiperazine derivatives, since the piperazine moiety increased the antischistosomal activity within the dithiocarbamate substance class. [ 7 ] Substituents in the 4‐position should primarily be sulfonamides, sulfuric acid diamides, and ureas, as these had proved to be particularly active in our previous work. [ 7 ] Commercially available 4‐methylpiperazin‐1‐amine, piperidin‐1‐amine, and morpholin‐4‐amine were converted into the corresponding dithiocarbazates 6a–c using reaction conditions a (from Scheme 1, syntheses of 6a–c not shown).…”

“…Previously, disulfiram ( 1 )‐derived dithiocarbamates ( 2 ) demonstrated antischistosomal activity in the low micromolar range. [ 7 ] Therefore, we investigated the antiparasitic activity of the structurally related dithiocarbazates 4 (Scheme 1). In general, there is only limited information on dithiocarbazates from a medicinal chemistry point of view.…”

“…This moiety significantly increased the antischistosomal activity of our dithiocarbamates, while having no major cytotoxic effects in two human cancer cell lines. [ 7 ] In this study, three different series of dithiocarbazates will be presented. The first series 5a–k deals with a broad spectrum of dithiocarbazate derivatives to obtain an overview of the antischistosomal potential of differently substituted dithiocarbazates.…”

“…The second series 6a–o focuses on N ‐aminopiperazine derivatives since the piperazine entity increased the antischistosomal efficacy of the dithiocarbamate substance class. [ 7 ] In the third series 7a–m , the results of the second series were combined with the possibility of further branching through the additional nitrogen of the dithiocarbazate moiety. The fourth series 8a–m deals with 4‐aminopiperidine derivatives, which are structural analogs of the N ‐aminopiperazine but much more accessible, as discussed later.…”

“…Both parameters were distinctly optimized leading to compound 3 with an antischistosomal activity at 10 µM while being not cytotoxic up to 100 µM. [ 7 ] Driven by this trend, the structurally related dithiocarbazates ( 5a–k to 7a–m ) were examined in the present study. In addition, 4‐amino piperidine derivatives ( 8a–m ) are discussed, which represent dithiocarbamates and are synthetically more easily accessible.…”