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-4H-1,2,4-triazol-3-yl)-2-(5-nitro-2-furoyl)-2,6-diazaspiro[3.4]octane 1 has been identified as a lead, with MICs of 0.0124–0.0441 μg/mL against MTb 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 MTb H37Rv strain and ESKAPE panel of pathogens using serial broth dilutions. However, an attempt to optimize structure of 1 did not lead to the development of more active compounds which can work against MTb, but to substances with high activity against S. aureus. 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.