Exploring the Chemical Space Around N-(5-nitrothiazol-2-yl)-1,2,3-thiadiazole-4-carboxamide, a Hit Compound with Serine Acetyltransferase (SAT) Inhibitory Properties

The development of the so-called antibiotic adjuvants as inhibitors of non-essential targets represents an innovative and attractive approach to counteract antimicrobial resistance (AMR). Most bacteria rely on the reductive sulfate assimilation pathway (RSAP) to synthesize cysteine, which is a building block for many important biomolecules. Cysteine biosynthetic enzymes are colonization factors that are dispensable during growth in rich media but might become indispensable during host colonization. Being this pathway absent in mammals, it might represent a promising target for drug intervention. We have focused our attention on compounds targeting serine acetyltransferase (SAT), which is one of the key enzymes involved in the L-cysteine biosynthesis, catalyzing the rate-limiting step of the whole process. In a previous communication, we have reported the discovery through a virtual screening of a new compound (1) with promising SAT inhibitory activity. The capability of this compound to interfere with bacterial growth in the cell assays prompted us to carry out a medicinal chemistry campaign to further investigate its potential. We herein report the synthesis of compound 1 analogues to define the structure-activity relationships (SAR) of this series of potential SAT inhibitors regarding the target binding and general toxicity. Despite the improvement in the inhibitory activity of some molecules, the toxicity profile needs to be fine-tuned, and these findings will be used to drive the synthesis of new analogues.