Organocatalytic Asymmetric Peroxidation of γ,δ-Unsaturated ß-Keto Esters-A Novel Route to Chiral Cycloperoxides.

A methodology for the asymmetric peroxidation of γ,δ-unsaturated ß-keto esters is presented. Using a cinchona-derived organocatalyst, the target δ-peroxy-ß-keto esters were obtained in high enantiomeric ratios of up to 95:5. Additionally, these δ-peroxy esters can be readily reduced to chiral δ-hydroxy-ß-keto esters without impacting the ß-keto ester functionality. Importantly, this chemistry opens up a concise route to chiral 1,2-dioxolanes, a common motif in many bioactive natural products, via a novel P2O5-mediated cyclisation of the corresponding δ-peroxy-ß-hydroxy esters.

An improved synthesis of adefovir and related analogues.

An improved synthesis of the antiviral drug adefovir is presented. Problems associated with current routes to adefovir include capricious yields and a reliance on problematic reagents and solvents, such as magnesium tert-butoxide and DMF, to achieve high conversions to the target. A systematic study within our laboratory led to the identification of an iodide reagent which affords higher yields than previous approaches and allows for reactions to be conducted up to 10 g in scale under milder conditions. The use of a novel tetrabutylammonium salt of adenine facilitates alkylations in solvents other than DMF. Additionally, we have investigated how regioselectivity is affected by the substitution pattern of the nucleobase. Finally, this chemistry was successfully applied to the synthesis of several new adefovir analogues, highlighting the versatility of our approach.

Synthesis and evaluation of aromatic BDSF bioisosteres on biofilm formation and colistin sensitivity in pathogenic bacteria.

The diffusible signal factor family (DSF) of molecules play an important role in regulating intercellular communication, or quorum sensing, in several disease-causing bacteria. These messenger molecules, which are comprised of cis-unsaturated fatty acids, are involved in the regulation of biofilm formation, antibiotic tolerance, virulence and the control of bacterial resistance. We have previously demonstrated how olefinic N-acyl sulfonamide bioisosteric analogues of diffusible signal factor can reduce biofilm formation or enhance antibiotic sensitivity in a number of bacterial strains. This work describes the design and synthesis of a second generation of aromatic N-acyl sulfonamide bioisosteres. The impact of these compounds on biofilm production in Acinetobacter baumannii, Escherichia coli, Burkholderia multivorans, Burkholderia cepacia, Burkholderia cenocepacia, Pseudomonas aeruginosa and Stenotrophomonas maltophilia is evaluated, in addition to their effects on antibiotic tolerance. The ability of these molecules to increase survival rates on co-administration with colistin is also investigated using the Galleria infection model.

Investigation of halogenated furanones as inhibitors of quorum sensing-regulated bioluminescence in Vibrio harveyi.

Aim: Vibrio harveyi is a Gram-negative marine bacterium that is a model system in the study of quorum sensing (QS). V. harveyi uses multichannel QS, mediated by three signaling molecules. The aim of this study was to synthesize and screen a diverse series of furanones for their potential to inhibit V. harveyi quorum sensing. Materials & methods: A library of halogenated furanones was prepared and derivatized using standard Pd-mediated coupling reactions and subsequently evaluated for their effects on V. harveyi bioluminescence. Results & conclusion: Several furanones inhibited QS-regulated bioluminescence, with gem-dichlorofuranone and tribromofuranone compounds proving especially effective. Importantly, a number of compounds were effective inhibitors of V. harveyi bioluminescence but did not have an impact on bacterial growth.

Major structure-activity relationships of resolvins, protectins, maresins and their analogues.

Resolvins, protectins and maresins are a series of polyunsaturated fatty acid-derived molecules which play important roles in the resolution of inflammation. They are termed specialized proresolving mediators and facilitate a return to homeostasis following an inflammatory response. These molecules are currently the focus of intensive investigation, primarily for their ability to suppress inflammation in chronic disease states. Researchers have employed different synthetic approaches to assess whether various structural modifications of these compounds could provide access to future therapeutics. This review summarizes the modifications made thus far and focuses on the key structure-activity relationships which have been uncovered for resolvins, protectins, maresins and their analogues.

Recent Developments in the Practical Application of Novel Carboxylic Acid Bioisosteres.

BACKGROUND: The carboxylic acid moiety is an important functional group which features in the pharmacophore of some 450 drugs. Unfortunately, some carboxylic acid-containing drugs have been withdrawn from market due to unforeseen toxicity issues. Other issues associated with the carboxylate moiety include reduced metabolic stability or limited passive diffusion across biological membranes. Medicinal chemists often turn to bioisosteres to circumvent such obstacles. OBJECTIVE: The aim of this review is to provide a summary of the various applications of novel carboxylic acid bioisosteres which have appeared in the literature since 2013. RESULTS: We have summarised the most recent developments in carboxylic acid bioisosterism. In particular, we focus on the changes in bioactivity, selectivity or physicochemical properties brought about by these substitutions, as well as the advantages and disadvantages of each isostere. CONCLUSION: The topics discussed herein highlight the continued interest in carboxylate bioisosteres. The development of novel carboxylic acid substitutes which display improved pharmacological profiles is a testament to the innovation and creativity required to overcome the challenges faced in modern drug design.

Synthesis and evaluation of novel furanones as biofilm inhibitors in opportunistic human pathogens.

Diseases caused by biofilm-forming pathogens are becoming increasingly prevalent and represent a major threat to human health. This trend has prompted a search for novel inhibitors of microbial biofilms which could, for example, be used to potentiate existing antibiotics. Naturally-occurring, halogenated furanones isolated from marine algae have proven to be effective biofilm inhibitors in several bacterial species. In this work, we report the synthesis of a library of novel furanones and their subsequent evaluation as biofilm inhibitors in several opportunistic human pathogens including S. enterica, S. aureus, E. coli, S. maltophilia, P. aeruginosa and C. albicans. A number of the most potent compounds were subjected to further analysis by confocal laser-scanning microscopy for their effects on P. aeruginosa and C. albicans biofilms individually, in addition to mixed polymicrobial biofilms. Lastly, we investigated the impact of a promising candidate on survival rates in vivo using a Galleria mellonella model.

Structure-activity relationships of furanones, dihydropyrrolones and thiophenones as potential quorum sensing inhibitors.

Since their initial isolation from the marine alga Delisea pulchra, bromofuranones have been investigated as potential inhibitors of quorum sensing (QS) in various bacterial strains. QS is an important mechanism by which bacteria co-ordinate their molecular response to the environment. QS is intrinsically linked to bacterial antibiotic resistance. Inspired by nature, chemists have developed a wide variety of synthetic analogs in an effort to elucidate the structure-activity relationships of these compounds, and to ultimately develop novel antimicrobial agents. In this work, we describe advances in this field while paying particular attention to apparent structure-activity relationships. This review is organized according to the main ring systems under investigation, namely furanones, dihydropyrrolones and thiophenones.

Sulfonamide-based diffusible signal factor analogs interfere with quorum sensing in Stenotrophomonas maltophilia and Burkholderia cepacia.

Aim:Stenotrophomonas maltophilia (Sm) and Burkholderia cepacia complex (BCC) are Gram-negative bacterial pathogens, which are typically multidrug resistant and excellent biofilm producers. These phenotypes are controlled by quorum sensing (QS) systems from the diffusible signal factor (DSF) family. We aim to interfere with this QS system as an alternative approach in combatting such difficult-to-treat infections. Materials & methods: A library of sulfonamide-based DSF bioisosteres was synthesized and tested against the major phenotypes regulated by QS. Results & conclusion: Several analogs display significant antibiofilm activity while the majority increase the action of the last-resort antibiotic colistin against Sm and BCC. Most compounds inhibit DSF synthesis in the Sm K279a strain. Our results support the strategy of interfering with QS communications to combat multidrug resistance.

Modulation of antibiotic sensitivity and biofilm formation in Pseudomonas aeruginosa by interspecies signal analogues.

Pseudomonas aeruginosa, a significant opportunistic pathogen, can participate in inter-species communication through signaling by cis-2-unsaturated fatty acids of the diffusible signal factor (DSF) family. Sensing these signals leads to altered biofilm formation and increased tolerance to various antibiotics, and requires the histidine kinase PA1396. Here, we show that the membrane-associated sensory input domain of PA1396 has five transmembrane helices, two of which are required for DSF sensing. DSF binding is associated with enhanced auto-phosphorylation of PA1396 incorporated into liposomes. Further, we examined the ability of synthetic DSF analogues to modulate or inhibit PA1396 activity. Several of these analogues block the ability of DSF to trigger auto-phosphorylation and gene expression, whereas others act as inverse agonists reducing biofilm formation and antibiotic tolerance, both in vitro and in murine infection models. These analogues may thus represent lead compounds to develop novel adjuvants improving the efficacy of existing antibiotics.

Synthesis of novel quinine analogs and evaluation of their effects on Trypanosoma cruzi.

AIM: Chagas disease is a tropical disease caused by the hemoflagellate protozoan Trypanosoma cruzi. There is no vaccine for Chagas disease and available drugs (e.g., benznidazole) are effective only during the acute phase, displaying a variable curative activity in the established chronic form of the disease. New leads with high efficacy and better toxicity profiles are urgently required. Materials & methods: A library of novel quinine derivatives was synthesized using Heck chemistry and evaluated against the various developmental forms of T. cruzi. RESULTS AND CONCLUSION: Several novel quinine analogs with trypanocidal activity have been identified with the para-nitro-substituted derivative displaying a submicromolar IC50, which is 83-times lower than quinine and three-times lower than benznidazole. Transmission electron microscopy analysis demonstrated that these compounds induced a marked vacuolization of the kinetoplast of intracellular amastigotes and cell-derived trypomastigotes.

Aromatic lipoxin A4 and lipoxin B4 analogues display potent biological activities.

Lipoxins are a group of biologically active eicosanoids typically formed by transcellular lipoxygenase activity. Lipoxin A4 (LXA4) and Lipoxin B4 (LXB4) biosynthesis has been detected in a variety of inflammatory conditions. The native lipoxins LXA4 and LXB4 demonstrate potent antiinflammatory and proresolution bioactions. However, their therapeutic potential is compromised by rapid metabolic inactivation by PG dehydrogenase-mediated oxidation and reduction. Here we report on the stereoselective synthesis of aromatic LXA4 and LXB4 analogues by employing Sharpless epoxidation, Pd-mediated Heck coupling, and diastereoselective reduction as the key transformations. Subsequent biological testing has shown that these analogues display potent biological activities. Phagocytic clearance of apoptotic leukocytes plays a critical role in the resolution of inflammation. Both LXA4 analogues (1R)-3a and (1S)-3a were found to stimulate a significant increase in phagocytosis of apoptotic polymorphonuclear leukocytes (PMN) by macrophages, with comparable efficacy to the effect of native LXA4, albeit greater potency, while the LXB4 analogue also stimulated phagocytosis with a maximum effect observed at 10-11 M. LX-stimulated phagocytosis was associated with rearrangement of the actin cytoskeleton consistent with that reported for native lipoxins. Using zymosan-induced peritonitis as a murine model of acute inflammation (1R)-3a significantly reduced PMN accumulation.

Synthesis of non-symmetric bis(oxazoline)-containing ligands and their application in the catalytic enantioselective Nozaki-Hiyama-Kishi allylation of benzaldehyde.

We report the good to high-yielding three-step synthesis of non-symmetrical bis(oxazoline)-containing ligands possessing an N-thienylaniline unit. The convergent synthesis employed a palladium-catalysed aryl amination of 2-(2'-bromothiophene)nitrile as the key step, with sixteen ligands prepared in total. These ligands were subsequently applied in the chromium-catalysed enantioselective Nozaki-Hiyama-Kishi allylation of benzaldehyde with an optimal enantioselectivity of 73%.

Model studies toward the synthesis of the bioactive diterpenoid, harringtonolide.

In model studies towards the synthesis of harringtonolide, the construction of the tropone moiety via arene cyclopropanation was investigated. The installation of the lactone ring was accomplished by way of a Diels-Alder cycloaddition of various indenones and a-pyones. The incorporation of the key bridge methyl group and subsequent control of its stereochemistry is also outlined.