N-substituted 2-aminoimidazole inhibitors of MRSA biofilm formation accessed through direct 1,3-bis(tert-butoxycarbonyl)guanidine cyclization.

Antibiotic resistance is a significant problem and is compounded by the ability of many pathogenic bacteria to form biofilms. A library of N-substituted derivatives of a previously reported 2-aminoimidazole/triazole (2-AIT) biofilm modulator was constructed via α-bromoketone cyclization with 1,3-bis(tert-butoxycarbonyl)guanidine, followed by selective substitution. Several compounds exhibited the ability to inhibit biofilm formation by three strong biofilm forming strains of methicillin resistant Staphylococcus aureus (MRSA). Additionally, a number of members of this library exhibited synergistic activity with oxacillin against planktonic MRSA. Compounds with this type of dual activity have the potential to be used as adjuvants with conventional antibiotics.

Mechanism of the Pd-catalyzed decarboxylative allylation of α-imino esters: decarboxylation via free carboxylate ion.

The Pd-catalyzed decarboxylative allylation of α-(diphenylmethylene)imino esters (1) or allyl diphenylglycinate imines (2) is an efficient method to construct new C(sp(3))-C(sp(3)) bonds. The detailed mechanism of this reaction was studied by theoretical calculations [ONIOM(B3LYP/LANL2DZ+p:PM6)] combined with experimental observations. The overall catalytic cycle was found to consist of three steps: oxidative addition, decarboxylation, and reductive allylation. The oxidative addition of 1 to [(dba)Pd(PPh(3))(2)] (dba = dibenzylideneacetone) produces an allylpalladium cation and a carboxylate anion with a low activation barrier of +9.1 kcal mol(-1). The following rate-determining decarboxylation proceeds via a solvent-exposed α-imino carboxylate anion rather than an O-ligated allylpalladium carboxylate with an activation barrier of +22.7 kcal mol(-1). The 2-azaallyl anion generated by this decarboxylation attacks the face of the allyl ligand opposite to the Pd center in an outer-sphere process to produce major product 3, with a lower activation barrier than that of the minor product 4. A positive linear Hammett correlation [ρ = 1.10 for the PPh(3) ligand] with the observed regioselectivity (3 versus 4) supports an outer-sphere pathway for the allylation step. When Pd combined with the bis(diphenylphosphino)butane (dppb) ligand is employed as a catalyst, the decarboxylation still proceeds via the free carboxylate anion without direct assistance of the cationic Pd center. Consistent with experimental observations, electron-withdrawing substituents on 2 were calculated to have lower activation barriers for decarboxylation and, thus, accelerate the overall reaction rates.

Disconnecting the Estrogen Receptor Binding Properties and Antimicrobial Properties of Parabens through 3,5-Substitution.

Commercially utilized parabens are employed for their antimicrobial properties, but a weak binding to the estrogen receptor alpha (ERα) may lead to breast cancer in some applications. Modification of the paraben scaffold should allow for a disconnection of these observed properties. Toward this goal, various 3,5-substituted parabens were synthesized and assessed for antimicrobial properties against S. aureus as well as competitive binding to the ERα. The minimum inhibitory concentration assay confirmed retention of antimicrobial activity in many of these derivatives, while all compounds exhibited decreased xenoestrogen activity as determined by a combination of competitive enzyme linked immunosorbent assay (ELISA), proliferation, and estrogen receptor binding assay. Thus, these changes to the paraben scaffold have led to a multitude of paraben derivatives with antimicrobial properties up to 16 times more active than the parent paraben and that are devoid or significantly diminished of potential breast cancer causing properties.

C-C bond-forming reactions via Pd-mediated decarboxylative alpha-imino anion generation.

Alpha-imino anions are generated under neutral reaction conditions via a Pd-mediated decarboxylation of allyl diphenylglycinate imines with concomitant formation of a pi-allylpalladium species. The resulting delocalized anion can attack the pi-allyl-Pd(II) species or be intercepted by aldehydes to afford homoallylic amines or protected 1,2-amino alcohols, respectively.

Decarboxylative Generation of 2-Azaallyl Anions: 2-Iminoalcohols via a Decarboxylative Erlenmeyer Reaction.

Condensation between the tetrabutylammonium salt of 2,2-diphenylglycine and aldehydes results in a decarboxylative Erlenmeyer reaction, affording 1,2-diaryl-2-iminoalcohols as a mixture of diastereomers in good yields. The diastereomeric ratio shifts over time, with the anti diastereomer and the syn oxazolidine tautomer serving as the kinetic and thermodynamic products, respectively. Addition of Lewis acids can catalyze the rates of reaction and product equilibration. The results highlight the stereochemical promiscuity of 1,2-diaryl-2-iminoalcohols in the presence of Lewis acids and Brønsted bases.

Palladium-catalyzed decarboxylative generation and asymmetric allylation of α-imino anions.

A palladium-catalyzed asymmetric decarboxylative allylic alkylation of allyl 2,2-diphenylglycinate imines using (S,S)-f-binaphane as a chiral supporting ligand has been developed. This transformation allows for decarboxylative generation and enantioselective allylation of nonenolate α-imino (2-azaallyl anions) to afford α-aryl homoallylic imines.

A flexible approach to 1,4-di-substituted 2-aminoimidazoles that inhibit and disperse biofilms and potentiate the effects of ß-lactams against multi-drug resistant bacteria.

The pyrrole-imidazole alkaloids are a 2-aminoimidazoles containing family of natural products that possess anti-biofilm activity. A library of 1,4-di-substituted 2-aminoimidazole/triazoles (2-AITs) was synthesized, and its anti-biofilm activity as well as oxacillin resensitization efficacy toward methicillin resistant Staphylococcus aureus (MRSA) was investigated. These 2-AITs were found to inhibit biofilm formation by MRSA with low micromolar IC50 values. Additionally, the most active compound acted synergistically with oxacillin against MRSA lowering the minimum inhibitory concentration (MIC) 4-fold.

Structural studies on 4,5-disubstituted 2-aminoimidazole-based biofilm modulators that suppress bacterial resistance to ß-lactams.

A library of 4,5-disubstituted 2-aminoimidazole triazole amide (2-AITA) conjugates has been successfully assembled. Upon biological screening, this class of small molecules was discovered as enhanced biofilm regulators through non-microbicidal mechanisms against methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Acinetobacter baumannii (MDRAB), with active concentrations in the low micromolar range. The library was also subjected to synergism and resensitization studies with ß-lactam antibiotics against MRSA. Lead compounds were identified that suppress the antibiotic resistance of MRSA by working synergistically with oxacillin, a ß-lactam antibiotic resistant to penicillinase. A further structure-activity relationship (SAR) study on the parent 2-AITA compound delivered a 2-aminoimidazole diamide (2-AIDA) conjugate with significantly increased synergistic activity with oxacillin against MRSA, decreasing the MIC value of the ß-lactam antibiotic by 64-fold. Increased anti-biofilm activity did not necessarily lead to increased suppression of antibiotic resistance, which indicates that biofilm inhibition and resensitization are most likely occurring via distinct mechanisms.

Tandem C-C bond-forming processes: interception of the pd-catalyzed decarboxylative allylation of allyl diphenylglycinate imines with activated olefins.

Interception of the Pd-catalyzed decarboxylative allylation of allyl diphenylglycinate imines with appropriately functionalized Michael acceptors, followed by Heck cyclization, allows for the efficient construction of relatively complex organoamine frameworks in one reaction vessel. The initial intercepted decarboxylative allylation is remarkably insensitive toward solvent and catalyst, typically proceeding under ambient conditions.