Mechanisms of antibacterial formaldehyde delivery from noxythiolin and other ‘masked-formaldehyde’ compounds

Abstract

Abstract Formaldehyde release in aqueous solutions of noxythiolin (N-methyl-N'-hydroxymethyl thiourea) has been monitored by nuclear magnetic resonance (n.m.r.) spectroscopy. The results suggest that antibacterial activity in such solutions resides mainly in the free formaldehyde. N.m.r. spectroscopy also demonstrated slow C-N bond rotation in noxythiolin and N-methylthiourea, with ΔG‡ of ca 15 kcal mol−1 (63 kJ mol−1)-N-Hydroxymethyl imidazole is marginally more effective than corresponding hydrated formaldehyde solutions, an effect which is attributed to more rapid turnover of unhydrated formaldehyde as detected by saturation transfer n.m.r. spectroscopy. These observations are combined with the known delivery of lethal iminium ions, R2N+=CH2, by compounds of the form R2NCH2X (X = OH, NR2; R is alkyl) to suggest a single consistent explanation of the antibacterial properties of a wide range of masked formaldehyde compounds.