title: Structure-activity relationship of 2-hydroxy-2-aryl-2,3-dihydro-imidazo[1,2-a]pyrimidinium salts and 2N-substituted 4(5)-aryl-2-amino-1H-imidazoles as inhibitors of biofilm formation by Salmonella Typhimurium and Pseudomonas aeruginosa.
abstract: A library of 80 1-substituted 2-hydroxy-2-aryl-2,3-dihydro-imidazo[1,2-a]pyrimidinium salts and 54 2N-substituted 4(5)-aryl-2-amino-1H-imidazoles was synthesized and tested for the antagonistic effect against biofilm formation by Salmonella Typhimurium and Pseudomonas aeruginosa. The nature of the substituent at the 1-position of the salts was found to have a major effect on their biofilm inhibitory activity. Salts with an intermediate length n-alkyl or cyclo-alkyl chain (C7-C10) substituted at the 1-position in general prevented the biofilm formation of both species at low micromolar concentrations, while salts with a shorter n-alkyl or cyclo-alkyl chain (C1-C5) or longer n-alkyl chain (C11-C14) were much less potent. Salts with a long cyclo-alkyl chain however were found to be strong biofilm inhibitors. Furthermore, we demonstrated the biofilm inhibitory potential of salts with certain aromatic substituents at the 1-position, such as piperonyl or 3-methoxyphenetyl. The activity of the 2-aminomidazoles was found to be dependent on the nature of the 2N-substituent. Compounds with a n-butyl, iso-butyl, n-pentyl, cyclo-pentyl or n-hexyl chain at the 2N-position have an improved activity as compared to their unsubstituted counterparts, whereas compounds with shorter 2N-alkyl chains do have a reduced activity and compounds with longer 2N-alkyl chains do have an effect that is dependent on the nature of the substitution pattern of the 4(5)-phenyl ring. Finally, we demonstrated that introduction of a 3-methoxyphenethyl or piperonyl group at the 2N-position of the imidazoles could also result in an enhanced biofilm inhibition.
authors.affiliation: Centre of Microbial and Plant Genetics, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Hans P L
authors.initials: HP
authors.lastname: Steenackers
authors.forename: Denis S
authors.initials: DS
authors.lastname: Ermolat'ev
authors.forename: Bharat
authors.initials: B
authors.lastname: Savaliya
authors.forename: Ami De
authors.initials: AD
authors.lastname: Weerdt
authors.forename: David De
authors.initials: DD
authors.lastname: Coster
authors.forename: Anamik
authors.initials: A
authors.lastname: Shah
authors.forename: Erik V
authors.initials: EV
authors.lastname: Van der Eycken
authors.forename: Dirk E
authors.initials: DE
authors.lastname: De Vos
authors.forename: Jozef
authors.initials: J
authors.lastname: Vanderleyden
authors.forename: Sigrid C J
authors.initials: SC
authors.lastname: De Keersmaecker
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018441:Biofilms / Q000187:drug effects; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012486:Salmonella typhimurium / Q000187:drug effects*; D012492:Salts / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D007093:Imidazoles; D011743:Pyrimidines; D012492:Salts