Divergent synthesis and MoA investigation of antibacterial alkylguanidino ureas

The ever-faster rise of antimicrobial resistance (AMR) represents still nowadays a major Public Health issue to concern. Hence, new chemical entities with innovative Modes of Action (MoAs) are required. In this work is reported the extension of an already existing library of AlkylGuanidino Ureas (AGUs), endowed with broad-spectrum bactericidal activity, and a deeper insight is given concerning their mechanisms of action towards bacterial membranes. In fact, most promising derivatives of the series were submitted to model or simulated membrane-based investigations by means of LUVs interaction experiments, a modified PAMPA and MD simulations. The reliability of both analytical and in silico protocols was confirmed by performing cell-based permeabilization assays with non-permeable dyes SYTO9 and PI. Hemolytic activity of selected compounds revealed a promising and further optimizable selectivity profile. Moreover, the effect of the counterion was assessed, being AGUs trifluoroacetate salts. To this concern, a hydrochloride derivative and a free-base one of the series hit compound were synthesized and their biological profiles were compared to that of the corresponding trifluoroacetate salt. The second part of this work is focused on the merger of a HAT-mediated photochemical process with a palladium-catalyzed strategy in the Tsuji-Trost allylation. Briefly, findings and results of a cooperative HAT-mediated C(sp3)-H activation in a traditional palladium-catalyzed approach are herein reported and discussed.