Synthesis, antimicrobial activity and acid dissociation constants of methyl 5,5-diphenyl-1-(thiazol-2-yl)pyrrolidine-2-carboxylate derivatives.

In this study, a series of polysubstituted methyl 5,5-diphenyl-1-(thiazol-2-yl)pyrrolidine-2-carboxylate derivatives were designed and synthesized by the cyclization reaction of methyl 1-(benzoylcarbamothioyl)-5,5-diphenylpyrrolidine-2-carboxylates and 2-bromo-1-(4-substituted phenyl)ethanones in 70-96% yield. The starting pyrrolidine derivatives were synthesized via a 1,3-dipolar cycloaddition reaction in 83-88% yield. The stereochemistry of one of these methyl 5,5-diphenyl-1-(thiazol-2-yl)pyrrolidine-2-carboxylate derivatives was characterized by a single crystal X-ray diffraction study and the acid dissociation constants of these compounds were determined. An antimicrobial screening was performed against different bacterial and fungal strains and against the M. tuberculosis H37Rv strain. Interesting antibacterial activity was observed for two compounds against the A. baumannii strain with MIC values of 31.25 µg/mL (Ampicillin: 125 µg/mL) and against the M. tuberculosis H37Rv strain with MIC values of 0.98-1.96 µg/mL (Isoniazid: 0.98 µg/mL, Ethambutol: 1.96 µg/mL). Therefore, these structures can be considered as good starting points for the development of new powerful antimycobacterial agents.

Synthetic Entries to and Biological Activity of Pyrrolopyrimidines.

This review summarizes recent literature (2000-2015) on the synthesis and pharmaceutical properties of pyrrolopyrimidines. These modified pyrimidine bases, fused to a pyrrole ring, and their corresponding nucleosides display a broad applicability in medicinal chemistry. This overview is divided into three main sections, according to the respective isomers: pyrrolo[2,3-d]pyrimidines, pyrrolo[3,2-d]pyrimidines, and pyrrolo[3,4-d]pyrimidines. Each section contains a description of common retro-synthetic strategies, with particular attention for newly reported synthetic entries to the scaffold. Next, the synthetic strategies and the ways in which the scaffolds can be further modified are exemplified according to the biological properties of the obtained products.

Microbial inhibition of oral epithelial wound recovery: potential role for quorum sensing molecules?

Awareness of the impact of microbiota in both health and disease is growing. Using a new in vitro oral mucosa co-culture model, we recently showed a clear inhibition of epithelial wound healing in the presence of an oral microbial community. In this paper, we have used the same model in combination with specific oral microbial species to obtain a better insight into the role of the oral microbiota in wound healing. Monocultures of Klebsiella oxytoca and Lactobacillus salivarius significantly inhibited wound healing with ~20%, whereas Streptococcus mitis and S. oralis enhanced the healing process with ~15% in 24 h. Yet, neither S. oralis or S. mitis were able to counteract the inhibitory effects from K. oxytoca on wound healing. Other tested microbial species had no effect on wound healing. Apart from this species-dependency, the inhibitory effect on wound healing depended on a microbial threshold concentration. Further mechanistic experiments with K. oxytoca excluded different microbial factors and hypothesized that quorum sensing molecules might play a role in the inter-kingdom signalling during wound healing. These results are important for the development of new strategies for the management of (infected) wounds and ulcerations.

Straightforward entry to pyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones and their ADME properties.

A straightforward synthesis of pyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones was developed starting from 2-chloropyridine-3-carboxylic acid by esterification, nucleophilic aromatic substitution and amide formation in one step, and ring closure allowing their synthesis with two identical or two different group attached to nitrogen. The structural diversity of these [2,3-d]pyrimidine-2,4(1H,3H)-diones resulted in significant variation in the biopharmaceutical properties. This was reflected by the broad range in fasted state simulated intestinal fluid solubility values (12.6 µM to 13.8 mM), Caco-2 permeability coefficients (1.2 × 10(-6)cm/s to 90.7 × 10(-6)cm/s) and in vitro-predicted human in vivo intrinsic clearance values (0 to 159 ml/min/kg).

Design, synthesis and structure-activity relationships of some novel, highly potent anti-invasive (E)- and (Z)-stilbenes.

In our ongoing exploration of the structure-activity landscape of anti-invasive chalcones, we have prepared and evaluated a number of structurally related (E)- and (Z)-stilbenes. These molecules exhibited an extraordinary high in vitro potency in the chick heart invasion assay, being active up to 10nmolL(-1), a concentration level a 100-fold lower than the lowest effective doses that have been reported for natural analogues. Furthermore, they possess an interesting pharmacological profile in silico.