Analytical & Biological Chemistry Research Facility - Journal Articles
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Item Synthesis, evaluation and mechanistic insights of novel IMPDH inhibitors targeting ESKAPEE bacteria(Elsevier Ltd., 2024-10-05) Ayoub, Nour; Upadhyay, Amit; Tête, Arnaud; Pietrancosta, Nicolas; Munier-Lehmann, Hélène; O'Sullivan, Timothy P.; Irish Research Council; Science Foundation Ireland; Université Sorbonne Paris CitéAntimicrobial resistance poses a significant threat to global health, necessitating the development of novel therapeutic agents with unique mechanisms of action. Inosine 5′-monophosphate dehydrogenase (IMPDH), an essential enzyme in guanine nucleotide biosynthesis, is a promising target for the discovery of new antimicrobial agents. High-throughput screening studies have previously identified several urea-based leads as potential inhibitors, although many of these are characterised by reduced chemical stability. In this work, we describe the design and synthesis of a series of heteroaryl-susbtituted analogues and the evaluation of their inhibitory potency against IMPDHs. Our screening targets ESKAPEE pathogens, including Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli. Several analogues with submicromolar inhibitory potency are identified and show no inhibitory potency on human IMPDH nor cytotoxic effects on human cells. Kinetic studies revealed that these molecules act as noncompetitive inhibitors with respect to the substrates and ligand virtual docking simulations provided insights into the binding interactions at the interface of the NAD+ and IMP binding sites on IMPDH.Item Synthesis and reactivity of α-diazo-β-keto sulfonamides(Georg Thieme Verlag KG, 2024-06-19) Maguire, Anita R.; Judge, Evan; O'Shaughnessy, Keith A.; Lawrence, Simon E.; Collins, Stuart G.; Science Foundation Ireland; Irish Research Council; Higher Education Authority; Synthesis and Solid State Pharmaceutical Centre; European Regional Development FundCopper mediated reactions of α-diazo-β-keto sulfonamides 1 leads to a range of products including the alkyne sulfonamides 5, the enamines 6, and the α-halosulfonamides 7 and 11 with no evidence for intramolecular C–H insertion in any of the reactions, in contrast to the reactivity of the comparable α-diazo-β-keto sulfones. Use of copper(II) triflate (5 mol%) led to isolation of a series of alkyne sulfonamides 5 (up to 12%) and enamines 6 (up to 64%). Use of copper(II) chloride (5 mol%) formed, in addition, the α-halosulfonamides 7; use of stoichiometric amounts of copper(II) chloride/bromide enables facile halogenation of the β-keto sulfonamide to form the α-halosulfonamides 7 and 11 (up to 63%).Item Application of broadband acoustic resonance dissolution spectroscopy (BARDS) to the gas release behaviour during rehydration of milk protein isolate agglomerates(Elsevier Ltd, 2019) Wu, Shaozong; Fitzpatrick, John; Cronin, Kevin; Ahmed, M. Rizwan; Fitzpatrick, Dara; Miao, Song; China Scholarship Council; TeagascThe BARDS technique was applied in this study to acoustically assess the rehydration behaviour of milk protein isolate (MPI) agglomerates and to compare with regular MPI powder. The results showed that BARDS has potential to monitor the rehydration behaviour of agglomerates. The greater porosity (>70%) of agglomerated powders introduced more compressible gas into the water. The BARDS profile showed that there was faster initial gas release from the agglomerates, indicating better wetting and dispersion ability of the agglomerates with shorter t M (time of maximum gas volume in solution). At 0.10% powder addition, agglomerated MPI reached t M within 109 s, which was significantly less than the control MPI at 140 s. MPI with lactose binder (MPI-L) had a t M of 80 s at 0.10% powder addition and, larger size MPI-L had a t M of 60 s. At 0.20% and 0.30% powder addition, more time was required to wet and disperse the powders. © 2019 Elsevier LtdItem Synthesis and evaluation of aromatic BDSF bioisosteres on biofilm formation and colistin sensitivity in pathogenic bacteria(Elsevier, 2023-09-23) Gómez, Andromeda-Celeste; Horgan, Conor; Yero, Daniel; Bravo, Marc; Daura, Xavier; O'Driscoll, Michelle; Gibert, Isidre; O'Sullivan, Timothy P.; Irish Research Council; Ministerio de Ciencia e Innovación; Agència de Gestió d'Ajuts Universitaris i de RecercaThe 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.Item Organocatalytic asymmetric peroxidation of g,d-unsaturated ß-keto esters - A novel route to chiral cycloperoxides(2023-05-24) Hennessy, Mary C.; Hirenkumar, Gandhi; O'Sullivan, Timothy P.; Irish Research Council; Science Foundation IrelandA methodology for the asymmetric peroxidation of g,d-unsaturated ß-keto esters is presented. Using a cinchona-derived organocatalyst, the target d-peroxy-ß-keto esters were obtained in high enantiomeric ratios of up to 95:5. Additionally, these d-peroxy esters can be readily reduced to chiral d-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 d-peroxy-ß-hydroxy esters.