title: Correlation of the antimicrobial activity of salicylaldehydes with broadening of the NMR signal of the hydroxyl proton. Possible involvement of proton exchange processes in the antimicrobial activity.
abstract: Certain substituted salicylaldehydes are potent antibacterial and antifungal agents and some of them merit consideration as potential chemotherapeutic agents against Candida infections, but their mechanism of action has remained obscure. We report here a distinct correlation between broadening of the NMR signal of the hydroxyl proton of salicylaldehydes and their activity against several types of bacteria and fungi. When proton NMR spectra of the compounds were determined using hexadeuterodimethylsulfoxide as solvent and the height of the OH proton signal was measured, using the signal of the aldehyde proton as an internal standard, it was discovered that a prerequisite of potent antimicrobial activity is that the proton signal is either unobservable or relatively very low, i.e. that it is extremely broadened. Thus, none of the congeners whose OH proton signal was high were potent antimicrobial agents. Some congeners that gave a very low OH signal were, however, essentially inactive against the microbes, indicating that although drastic broadening of the OH signal appears to be a prerequisite, also other (so far unknown) factors are needed for high antimicrobial activity. Because broadening of the hydroxyl proton signal is related to the speed of the proton exchange process(es) involving that proton, proton exchange may be involved in the mechanism of action of the compounds. Further studies are needed to analyze the relative importance of different factors (such as electronic effects, strength of the internal hydrogen bond, co-planarity of the ring and the formyl group) that determine the rates of those processes.
authors.affiliation: Division of Pharmaceutical Biosciences, Faculty of Pharmacy, P.O. Box 56 (Biocenter 1), FIN-00014, University of Helsinki, Finland. Electronic address: hannu.elo@helsinki.fi.
authors.forename: Hannu
authors.initials: H
authors.lastname: Elo
authors.affiliation: Division of Pharmaceutical Biosciences, Faculty of Pharmacy, P.O. Box 56 (Biocenter 1), FIN-00014, University of Helsinki, Finland. Electronic address: matti_kuure@hotmail.com.
authors.forename: Matti
authors.initials: M
authors.lastname: Kuure
authors.affiliation: Division of Pharmaceutical Biosciences, Faculty of Pharmacy, P.O. Box 56 (Biocenter 1), FIN-00014, University of Helsinki, Finland. Electronic address: eila.pelttari@helsinki.fi.
authors.forename: Eila
authors.initials: E
authors.lastname: Pelttari
mesh_terms: D000447:Aldehydes / Q000737:chemistry / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005658:Fungi / Q000187:drug effects*; D006878:Hydroxides / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011522:Protons; D013329:Structure-Activity Relationship
chemical_list: D000447:Aldehydes; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D006878:Hydroxides; D011522:Protons; C013243:salicylaldehyde; C031356:hydroxide ion
keywords: Antimicrobial activity of 2-hydroxybenzaldehydes; Phenolic hydroxyl; Proton NMR; Proton exchange; Rate processes; Structure–activity relationships