Synthesis, Formulation and Biological Evaluations of Chemotherapeutics Targeting Antimicrobial Resistance

The work presented in this thesis employed knowledge in medicinal chemistry to discover new compounds aiming to reduce resistance in infections caused by virulent Gram-negative bacteria, resistant to antibiotics. The general aim was to design and synthesize new inhibitors metallo-β-lactamases (MBLs), one of the most important bacterial resistance mechanism. MBLs use zinc for their catalytic activity. It has been indicated in literature that alteration of the zinc homeostasis could have effect on their efficiency. Therefore, the conception of our compounds revolved around the attempt to deprive MBLs of zinc. The new zinc-chelating agents were designed around a three-component platform, consisting of a chelator with zinc selectivity, a targeting moiety and a linker tying the first two parts together. There was a correlation between lipophilicity and toxicity towards eukaryotic cells of the compounds, while MIC efficacy in resistant clinically isolated bacteria could be maintained. The identified compounds represent a new class of antibacterial adjuvants. We also established a reliable synthetic route to natural compound iodinin from commercially available reagents. To overcome iodinin’s solubility issues, modified α-cyclodextrins which self-assemble to form nanoparticles in aqueous media were designed and synthesized. Applying these nanoparticles as a delivery system for iodinin resulted in enhanced solubility, bioavailability, and release in a controlled manner

Enhancement of iodinin solubility by encapsulation into cyclodextrin nanoparticles

Phenazine is known to regroup planar nitrogen-containing heterocyclic compounds. It was used here to enhance the bioavailability of the biologically important compound iodinin, which is near insoluble in aqueous solutions. Its water solubility has led to the development of new formulations using diverse amphiphilic a-cyclodextrins (CDs). With the per-[6-desoxy-6-(3-perfluorohexylpropanethio)-2,3-di-O-methyl]- a-CD, we succeeded to get iodinin-loaded nanoformulations with good parameters such as a size of 97.9 nm, 62% encapsulation efficiency and efficient control release. The study presents an interesting alternative to optimizing the water solubility of iodinin by chemical modifications of iodinin

Carbazole scaffolds in cancer therapy: a review from 2012 to 2018

International audienceFor over half a century, the carbazole skeleton has been the key structural motif of many biologically active compounds including natural and synthetic products. Carbazoles have taken an important part in all the existing anti-cancer drugs because of their discovery from a large variety of organisms, including bacteria, fungi, plants, and animals. In this article, we specifically explored the literature from 2012 to 2018 on the anti-tumour activities reported to carbazole derivatives and we have critically collected the most significant data. The most described carbazole anti-tumour agents were classified according to their structure, starting from the tricyclic-carbazole motif to fused tetra-, penta-, hexa-and heptacyclic carba-zoles. To date, three derivatives are available on the market and approved in cancer therapy

Enhancement of iodinin solubility by encapsulation into cyclodextrin nanoparticles

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Synthesis and biological evaluation of new dipicolylamine zinc chelators as metallo-β-lactamase inhibitors

Antibiotics are key drugs in modern healthcare, especially in hospitals, where multiresistant bacteria resides and is a potential threat to human health. In the present work, a new series of adjuvants working synergistically with the carbapenem meropenem, in which a selective zinc-chelating agent was covalently linked to the small bacterial peptide D-Ala-D-Ala, was synthesized and tested against VIM-2 and NDM-1 metallo-β-lactamases (MBLs). The nature of the linker was modified in a structure-activity relationship study. Compound 1i, having an ethyl piperidine linker, lowered the MIC of meropenem from 32 to 64 mg/L to 2 and 1–2 mg/L against VIM-2- and NDM-1-producing clinical isolates, respectively. The IC50 value of 1i against VIM-2 was 9.8 and 2.2 μM after 5 and 20 min, respectively. Compound 1i also showed intrinsic toxicity against three eukaryotic human tumoral cell lines between 50 and 120 μM

Synthesis and biological evaluation of zinc chelating compounds as metallo-β-lactamase inhibitors

International audienceThe syntheses of metallo-β-lactamase inhibitors comprising chelating moieties, with varying zinc affinities,and peptides partly inspired from bacterial peptide sequences, have been undertaken. The zinc chelatorstrength was varied using the following chelators, arranged in order of ascending binding affinity:dipicolylamine (DPA, tridentate), dipicolyl-1,2,3-triazolylmethylamine (DPTA, tetradentate) dipicolyl ethylenediamine(DPED, tetradentate) and trispicolyl ethylenediamine (TPED, pentadentate). The chosen peptideswere mainly based on the known sequence of the C-terminus of the bacterial peptidoglycan precursors.Biological evaluation on clinical bacterial isolates, harbouring either the NDM-1 or VIM-2 metallo-β-lactamase, showed a clear relationship between the zinc chelator strength and restoration of meropenemactivity. However, evaluation of toxicity on different cancer cell lines demonstrated a similar trend, and thusinclusion of the bacterial peptides did possess rather high toxicity towards eukaryotic cells

Synthesis and preclinical evaluation of TPA-based zinc chelators as metallo-β-lactamase inhibitors

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Synthesis and Preclinical Evaluation of TPA-Based Zinc Chelators as Metallo-β-lactamase Inhibitors

The rise of antimicrobial resistance (AMR) worldwide and the increasing spread of multi-drug-resistant organisms expressing metallo-β-lactamases (MBL) require the development of efficient and clinically available MBL inhibitors. At present, no such inhibitor is available, and research is urgently needed to advance this field. We report herein the development, synthesis, and biological evaluation of chemical compounds based on the selective zinc chelator tris-picolylamine (TPA) that can restore the bactericidal activity of Meropenem (MEM) against <i>Pseudomonas aeruginosa</i> and <i>Klebsiella pneumoniae</i> expressing carbapenemases Verona integron-encoded metallo-β-lactamase (VIM-2) and New Delhi metallo-β-lactamase 1 (NDM-1), respectively. These adjuvants were prepared via standard chemical methods and evaluated in biological assays for potentiation of MEM against bacteria and toxicity (IC₅₀) against HepG2 human liver carcinoma cells. One of the best compounds, <b>15</b>, lowered the minimum inhibitory concentration (MIC) of MEM by a factor of 32–256 at 50 μM within all tested MBL-expressing clinical isolates and showed no activity toward serine carbapenemase expressing isolates. Biochemical assays with purified VIM-2 and NDM-1 and <b>15</b> resulted in inhibition kinetics with <i>k</i>_inact/<i>K</i>_I of 12.5 min^–1 mM^–1 and 0.500 min^–1 mM^–1, respectively. The resistance frequency of <b>15</b> at 50 μM was in the range of 10^–7 to 10^–9. <b>15</b> showed good tolerance in HepG2 cells with an IC₅₀ well above 100 μM, and an in vivo study in mice showed no acute toxic effects even at a dose of 128 mg/kg