oroidin and 2-aminoimidazole

Porphyromonas gingivalis is one of the main etiological organisms in periodontal disease. On oral surfaces P. gingivalis is a component of multispecies biofilm communities and can modify the pathogenic potential of the community as a whole. Accumulation of P. gingivalis in communities is facilitated by interspecies binding and communication with the antecedent colonizer Streptococcus gordonii. In this study we screened a library of small molecules to identify structures that could serve as lead compounds for the development of inhibitors of P. gingivalis community development. Three small molecules were identified that effectively inhibited accumulation of P. gingivalis on a substratum of S. gordonii. The structures of the small molecules are derived from the marine alkaloids oroidin and bromoageliferin and contain a 2-aminoimidazole or 2-aminobenzimidazole moiety. The most active compounds reduced expression of mfa1 and fimA in P. gingivalis, genes encoding the minor and major fimbrial subunits, respectively. These fimbrial adhesins are necessary for P. gingivalis co-adhesion with S. gordonii. These results demonstrate the potential for a small molecular inhibitor-based approach to the prevention of diseases associated with P. gingivalis.

Topics: Bacterial Adhesion; Bacterial Proteins; Benzimidazoles; Biofilms; Carbon-Sulfur Lyases; Fimbriae Proteins; Humans; Image Processing, Computer-Assisted; Imaging, Three-Dimensional; Imidazoles; Microbial Interactions; Microscopy, Confocal; Pili, Sex; Porphyromonas gingivalis; Pyrroles; Small Molecule Libraries; Streptococcus gordonii

A series of ageladine A analogs that include 2-aminoimidazo[4,5-c]azepines (seven-membered rings) and 2-amino-3H-imidazo[4,5-c]pyridine (six-membered rings) derivatives were synthesized and evaluated for their anticancer effects against several human cancer cell lines and MMP-2 inhibition in vitro. Only compounds possessing the aromatic azepine (seven-membered ring) core showed anticancer activity with IC(50) values in the low micromolar range.

Topics: Antineoplastic Agents; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Imidazoles; Matrix Metalloproteinase 2; Matrix Metalloproteinase Inhibitors; Oxidation-Reduction; Pyrroles; Structure-Activity Relationship

Bacteria of the genus Acinetobacter spp. are rapidly emerging as problematic pathogens in healthcare settings. This is exacerbated by the bacteria's ability to form robust biofilms. Marine natural products incorporating a 2-aminoimidazole (2-AI) motif, namely from the oroidin class of marine alkaloids, have served as a unique scaffold for developing molecules that have the ability to inhibit and disperse bacterial biofilms. Herein we present the anti-biofilm activity of a small library of second generation oroidin analogues against the bacterium Acinetobacter baumannii.

Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Biofilms; Humans; Imidazoles; Microbial Sensitivity Tests; Molecular Structure; Pyrroles; Small Molecule Libraries; Stereoisomerism; Structure-Activity Relationship

A second-generation library of 2-aminoimidazole-based derivatives incorporating a "reversed amide" (RA) motif in comparison to the marine natural product oroidin were synthesized and subsequently assayed for antibiofilm activity against the medically relevant Gram-negative proteobacteria P. aeruginosa and A. baumannii. Most notably, an in-depth activity profile is reported for the most active subclass of derivatives that bear linear aliphatic chains off the amide bond. Additionally, further structural modifications of the core template, such as removal of the amide bond or substitution with a triazole isostere, resulted in the discovery of analogues with antibiofilm activities that varied with respect to their inhibition and dispersal properties of P. aeruginosa and A. baumannii biofilms.

Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Biofilms; Drug Design; Imidazoles; Microbial Sensitivity Tests; Molecular Structure; Pseudomonas aeruginosa; Pyrroles; Small Molecule Libraries; Stereoisomerism; Structure-Activity Relationship

The marine alkaloid oroidin along with a small library of reverse amide (RA) 2-aminoimidazoles were synthesized and assayed for anti-biofilm activity against PAO1 and PA14, two strains of the medically relevant gamma-proteobacterium Pseudomonas aeruginosa. Analogues that contained a long, linear alkyl chain were more potent inhibitors than the natural product at preventing the formation of PAO1 and PA14 biofilms. The most active compound in the series was also shown to disperse established PAO1 and PA14 biofilms at low micromolar concentrations.

Topics: Anti-Bacterial Agents; Biofilms; Humans; Imidazoles; Microbial Sensitivity Tests; Molecular Structure; Pseudomonas aeruginosa; Pyrroles; Small Molecule Libraries; Stereoisomerism; Structure-Activity Relationship