You Win Some, You Lose Some: Modifying the Molecular Periphery of Nitrofuran-Tagged Diazaspirooctane Reshapes Its Antibacterial Activity Profile

The use of the concept of privileged structures significantly accelerates the search for new leads and their optimization. 6-(methylsulfonyl)-8-(4-methyl-4<i>H</i>-1,2,4-triazol-3-yl)-2-(5-nitro-2-furoyl)-2,6-diazaspiro[3.4]octane <b>1</b> has been identified as a lead, with MICs of 0.0124-0.0441 μg/mL against <i>MTb</i> multiresistant strains. Several series of structural analogues have been synthesized, including variations in the periphery and simplifications of their scaffolds. All synthesized compounds were tested against the <i>MTb</i> H37Rv strain and ESKAPE panel of pathogens using serial broth dilutions. However, an attempt to optimize structure of <b>1</b> did not lead to the development of more active compounds which can work against <i>MTb</i>, but to substances with high activity against <i>S. aureus</i>. Induced-fit docking and MM-GBSA calculations determined a change in the likely biotarget from deazaflavin-dependent nitroreductase to azoreductases. The privileged nature of the scaffold was demonstrated by the detection of a different type of activity.