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The lack of efficacy of current antibacterials to treat multidrug resistant bacteria poses a life-threatening alarm. In order to develop enhancers of the antibacterial activity, we carried out a medicinal chemistry campaign aiming to develop inhibitors of enzymes that synthesise cysteine and belong to the reductive sulphur assimilation pathway, absent in mammals. Previous studies have provided a novel series of inhibitors for O-acetylsulfhydrylase – a key enzyme involved in cysteine biosynthesis. Despite displaying nanomolar affinity, the most active representative of the series was not able to interfere with bacterial growth, likely due to poor permeability. Therefore, we rationally modified the structure of the hit compound with the aim of promoting their passage through the outer cell membrane porins. The new series was evaluated on the recombinant enzyme from Salmonella enterica serovar Typhimurium, with several compounds able to keep nanomolar binding affinity despite the extent of chemical manipulation.

The synthetic approaches towards unique asparagusic acid and its analogues as well as its chemical use, the breadth of its biological properties and their relevant applications have been explored. The significance of the 1,2‐dithiolane ring tension in dithiol‐mediated uptake and its use for the intracellular transport of molecular cargoes is discussed alongside some of the challenges that arise from the fast thiolate‐disulfide interchange. The short overview with the indication of the available literature on natural 1,2‐dithiolanes synthesis and biological activities is also included. The general review structure is based on the time‐line perspective of the application of asparagusic acid moiety as well as its primitive derivatives (4‐amino‐1,2‐dithiolane‐4‐carboxylic acid and 4‐methyl‐1,2‐dithiolane‐4‐carboxilic acid) used in clinics/cosmetics, focusing on the recent research in this area and including international patents applications.

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