Enhancing the anti-biofilm activity of 5-aryl-2-aminoimidazoles through nature inspired dimerisation.

The increased tolerance of biofilms against disinfectants and antibiotics has stimulated research into new methods of biofilm prevention and eradication. In our previous work, we have identified the 5-aryl-2-aminoimidazole core as a scaffold that demonstrates preventive activity against biofilm formation of a broad range of bacterial and fungal species. Inspired by the dimeric nature of natural 2-aminoimidazoles of the oroidin family, we investigated the potential of dimers of our decorated 5-aryl-2-aminoimidazoles as biofilm inhibitors. A synthetic approach towards 2-aminoimidazole dimers linked by an alkyl chain was developed and a total of 48 dimers were synthesized. The linkers were introduced at two different positions, the N1-position or the N2-position, and the linker length and the substitution of the 5-phenyl ring (H, F, Cl, Br) were varied. Although, no clear correlation between linker length and biofilm inhibition was observed, a strong increase in anti-biofilm activity for almost all N1,N1'-linked dimers was obtained, compared to the respective monomers against Salmonella Typhimurium, Escherichia coli and Staphylococcus aureus. The N2,N2'-linked dimers, having a H- or F-substitution, were also found to show a strong increase in anti-biofilm activity compared to the respective monomers against these three bacterial species and against Pseudomonas aeruginosa. In addition, the obtained growth measurements suggest a broad concentration range with specific biofilm inhibition and no effect on the planktonic growth against Salmonella Typhimurium and Pseudomonas aeruginosa.

Synthesis of differentially substituted 2-aminoimidazolidines via a microwave-assisted tandem Staudinger/aza-Wittig cyclization.

A new route for the construction of 2-aminoimidazolidines including analogues of the α2 adrenergic agonist drug clonidine is elaborated. The key step is an intramolecular microwave-assisted Staudinger/aza-Wittig cyclization of an in situ generated urea intermediate (formed by the reaction of ß-amino azide and isocyanate) upon treatment with Bu3P or polymer-supported phosphine reagent, allowing the introduction of various substituents at the N1 and the 2-amino function. Furthermore, a useful one-pot Staudinger/aza-Wittig/Buchwald-Hartwig protocol leading to bicyclic guanidines has been elaborated.

Synthesis of symmetric 1,4-diamino-2-butynes via a Cu(I)-catalyzed one-pot A3-coupling/decarboxylative coupling of a propiolic acid, an aldehyde, and an amine.

A novel microwave-assisted approach for the one-pot Cu(I)-catalyzed A(3)-coupling/decarboxylative coupling (PA(2)-coupling) of a propiolic acid, an aldehyde, and an amine, resulting in the formation of diversely substituted 1,4-diamino-2-butynes,is described. It is noteworthy that this new multicomponent coupling provides an efficient access to introduce alkyl and aryl group at the 1,4-position of the 1,4-diamino-2-butynes.

Regioselective Cu(I)-catalyzed tandem A3-coupling/decarboxylative coupling to 3-amino-1,4-enynes.

An efficient and novel copper-mediated protocol for the synthesis of 3-amino-1,4-enynes from glyoxylic acid, an amine, and an alkyne was developed. This new reaction involving two sequential C-C bond formations is air and moisture tolerant and proceeds via a tandem A(3)-coupling and a selective decarboxylative coupling.

Microwave-assisted decarboxylative three-component coupling of a 2-oxoacetic acid, an amine, and an alkyne.

A novel and efficient microwave-assisted decarboxylative three-component coupling of a 2-oxoacetic acid, an amine, and an alkyne (OA(2)-coulpling) has been developed. This new multicomponent coupling constitutes an efficient approach for the synthesis of polysubstituted propargylamines in the presence of a catalytic amount of copper(I) catalyst.

Tetrasubstituted 2-imidazolones via Ag(I)-catalyzed cycloisomerization of propargylic ureas.

A one-pot protocol based on a Ag(I)-catalyzed cycloisomerization of propargylic ureas, derived from secondary propargylamines and isocyanates, was developed for the generation of the 2-imidazolone core.

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.

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.

An expeditious route toward pyrazine-containing nucleoside analogues.

An improved and convenient methodology for the synthesis of asymmetrically substituted pyrazines starting from 3,5-dichloropyrazin-2(1H)-ones has been elaborated. Several nucleoside analogues have been synthesized containing the pyrazine core as the organic base coupled with the sugar via a triazole linkage. The beneficial effect of microwave irradiation throughout the sequence has been demonstrated.

Structure-activity relationship of 4(5)-aryl-2-amino-1H-imidazoles, N1-substituted 2-aminoimidazoles and imidazo[1,2-a]pyrimidinium salts as inhibitors of biofilm formation by Salmonella typhimurium and Pseudomonas aeruginosa.

A library of 112 4(5)-aryl-2-amino-1H-imidazoles, 4,5-diphenyl-2-amino-1H-imidazoles, and N1-substituted 4(5)-phenyl-2-aminoimidazoles was synthesized and tested for the antagonistic effect against biofilm formation by Salmonella Typhimurium and Pseudomonas aeruginosa. The substitution pattern of the 4(5)-phenyl group and the nature of the N1-substituent were found to have a major effect on the biofilm inhibitory activity. The most active compounds of this series were shown to inhibit the biofilm formation at low micromolar concentrations. Furthermore, the influence of 6 imidazo[1,2-a]pyrimidines and 18 imidazo[1,2-a]pyrimidinium salts on the biofilm formation was tested. These compounds are the chemical precursors of the 2-aminoimidazoles in our synthesis pathway. A good correlation was found between the activity of the imidazo[1,2-a]pyrimidinium salts and their corresponding 2-aminoimidazoles, supporting the hypothesis that the imidazo[1,2-a]pyrimidinium salts are possibly cleaved by cellular nucleophiles to form the active 2-aminoimidazoles. However, the imidazo[1,2-a]pyrimidines did not show any biofilm inhibitory activity, indicating that these molecules are not susceptible to in situ degradation to 2-aminoimidazoles. Finally, we demonstrated the lack of biofilm inhibitory activity of an array of 37 2N-substituted 2-aminopyrimidines, which are the chemical precursors of the imidazo[1,2-a]pyrimidinium salts in our synthesis pathway.

Diversity-oriented synthesis of dibenzoazocines and dibenzoazepines via a microwave-assisted intramolecular A(3)-coupling reaction.

An unprecedented, diversity-oriented strategy for the generation of 6,7-dihydro-5H-dibenzo[c,e]azepines and 5,6,7,8-tetrahydrodibenzo[c,e]azocines by a microwave-assisted copper-catalyzed intramolecular A(3)-coupling reaction is presented.

A divergent synthesis of substituted 2-aminoimidazoles from 2-aminopyrimidines.

A new divergent and efficient synthesis of substituted 2-aminoimidazoles 5 and 6 has been developed starting from the readily available 2-aminopyrimidines 1 and alpha-bromocarbonyl compounds 2, using conventional heating or microwave irradiation. Thus, the cleavage of 1,2,3-substituted imidazo[1,2-a]pyrimidin-1-ium salts 4 with hydrazine or secondary amines led to 1,4,5-trisubstituted 2-aminoimidazoles 5, when the hydrazinolysis of 2-hydroxy-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-4-ium salts 3, followed by a novel Dimroth-type rearrangement, resulted in formation of 2-amino-1H-imidazoles 6. The relevant pathway of transformations was identified by characterization of the intermediates.

A new colorimetric test for solid-phase amines and thiols.

A new, efficient, sensitive, and reliable color test for the visual detection of resin-bound primary and secondary amines is described. The reaction between amines and 1-methyl-2-(4'-nitrophenyl)-imidazo[1,2- a]pyrimidinium perchlorate (DESC) provides the "on-bead generated" colored stable intermediate azadiene. The developed protocols allow detection of resin-bound primary amines in the presence of secondary amines. The test can also be used for the detection of resin bound thiols.

Transition metal-catalyzed orthogonal solid-phase decoration of the 2(1H)-pyrazinone scaffold using a sulfur linker.

A new transition metal-catalyzed orthogonal solid-phase protocol for the synthesis of highly substituted 2(1H)-pyrazinones was developed, on the basis of Chan-Lam arylation and Liebeskind-Srogl cross-coupling reactions. This strategy opens the way for the generation of small libraries of 2(1H)-pyrazinone analogues for biological screening.

Efficient one-pot, two-step, microwave-assisted procedure for the synthesis of polysubstituted 2-aminoimidazoles.

A microwave-assisted, one-pot, two-step protocol was developed for the construction of polysubstituted 2-aminoimidazoles. This process involves the sequential formation of imidazo[1,2-a]pyrimidinium salts from readily available 2-aminopyrimidines and alpha-bromocarbonyl compounds, followed by opening of the pyrimidine ring with hydrazine. [reaction: see text]