Biorefining Twin Transition: Digitalisation for Bio-based Chemicals/Materials - Discovery, Design and Optimisation.

The article discusses the production of platform chemicals from various biological sources, including glycerol, lignin, cellulose, bio-oils, and sea products. It presents the results of catalytic and downstream processes involved in the conversion of these biomass-derived feedstocks. The experimental approaches are complemented by numerical descriptions, ranging from density functional theory (DFT) calculations to kinetic modellingof the experimental data. This multi-scale modelling approach helps to understand the underlying mechanisms and optimize the production of platform chemicals from renewable resources.

Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold-Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa.

We have developed compounds with a promising activity against Acinetobacter baumannii and Pseudomonas aeruginosa, which are both on the WHO priority list of antibiotic-resistant bacteria. Starting from DNA gyrase inhibitor 1, we identified compound 27, featuring a 10-fold improved aqueous solubility, a 10-fold improved inhibition of topoisomerase IV from A. baumannii and P. aeruginosa, a 10-fold decreased inhibition of human topoisomerase IIα, and no cross-resistance to novobiocin. Cocrystal structures of 1 in complex with Escherichia coli GyrB24 and (S)-27 in complex with A. baumannii GyrB23 and P. aeruginosa GyrB24 revealed their binding to the ATP-binding pocket of the GyrB subunit. In further optimization steps, solubility, plasma free fraction, and other ADME properties of 27 were improved by fine-tuning of lipophilicity. In particular, analogs of 27 with retained anti-Gram-negative activity and improved plasma free fraction were identified. The series was found to be nongenotoxic, nonmutagenic, devoid of mitochondrial toxicity, and possessed no ion channel liabilities.

Top Selling (2026) Small Molecule Orphan Drugs: A Journey into Their Chemistry.

This review describes, from a chemical point of view, the top "blockbuster" small molecule orphan drugs according to their forecasted sales in 2026. Orphan drugs are intended for the treatment, prevention, or diagnosis of a rare disease or condition. These molecules are mostly addressed to the treatment of rare forms of cancer. The respiratory and central nervous systems represent other common therapeutic subcategories. This work will show how the orphan drugs market has significantly grown and will account for a consistent part of prescriptions by 2026.

FDA-Approved Small Molecules in 2022: Clinical Uses and Their Synthesis.

This review describes the recently FDA-approved drugs (in the year 2022). Many of these products contain active moieties that FDA had not previously approved, either as a single ingredient or as part of a combination. These products frequently provide important new therapies for patients with multiple unmet diseases. The diverse small molecules are described according to the date of approval and their syntheses is discussed. This review comprises classical chemical scaffolds together with innovative drugs such as a deuterium-containing drug.

New Halogen-Containing Drugs Approved by FDA in 2021: An Overview on Their Syntheses and Pharmaceutical Use.

This review describes the recent Food and Drug Administration (FDA)-approved drugs (in the year 2021) containing at least one halogen atom (covalently bound). The structures proposed throughout this work are grouped according to their therapeutical use. Their synthesis is presented as well. The number of halogenated molecules that are reaching the market is regularly preserved, and 14 of the 50 molecules approved by the FDA in the last year contain halogens. This underlines the emergent role of halogens and, in particular, of fluorine and chlorine in the preparation of drugs for the treatment of several diseases such as viral infections, several types of cancer, cardiovascular disease, multiple sclerosis, migraine and inflammatory diseases such as vasculitis.

Practical Synthesis and Application of Halogen-Doped Pyrrole Building Blocks.

A practical access to four new halogen-substituted pyrrole building blocks was realized in two to five synthetic steps from commercially available starting materials. The target compounds were prepared on a 50 mg to 1 g scale, and their conversion to nanomolar inhibitors of bacterial DNA gyrase B was demonstrated for three of the prepared building blocks to showcase the usefulness of such chemical motifs in medicinal chemistry.

New N-phenylpyrrolamide DNA gyrase B inhibitors: Optimization of efficacy and antibacterial activity.

The ATP binding site located on the subunit B of DNA gyrase is an attractive target for the development of new antibacterial agents. In recent decades, several small-molecule inhibitor classes have been discovered but none has so far reached the market. We present here the discovery of a promising new series of N-phenylpyrrolamides with low nanomolar IC50 values against DNA gyrase, and submicromolar IC50 values against topoisomerase IV from Escherichia coli and Staphylococcus aureus. The most potent compound in the series has an IC50 value of 13 nM against E. coli gyrase. Minimum inhibitory concentrations (MICs) against Gram-positive bacteria are in the low micromolar range. The oxadiazolone derivative 11a, with an IC50 value of 85 nM against E. coli DNA gyrase displays the most potent antibacterial activity, with MIC values of 1.56 µM against Enterococcus faecalis, and 3.13 µM against wild type S. aureus, methicillin-resistant S. aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). The activity against wild type E. coli in the presence of efflux pump inhibitor phenylalanine-arginine ß-naphthylamide (PAßN) is 4.6 µM.

Overcoming problems of poor drug penetration into bacteria: challenges and strategies for medicinal chemists.

INTRODUCTION: Bacterial cell walls and membranes provide essential protection for bacteria against environmental influences. Different bacteria possess different cell envelopes and understanding each of these structures is crucial for the design of effective antibacterial drugs whose targets are intracellular. Optimal properties of drugs that are required for their entry into bacteria are still hard to predict. The guidelines that are suitable and well established for the penetration of a drug into eukaryotic cells are poorly adaptable to the complex world of pathogens. Areas covered: The factors that govern the penetration of anti-infection drugs into bacteria are examined and the available strategies to overcome this therapeutically very important barrier are reviewed. The areas covered include optimization of the physicochemical properties of compounds, utilization of iron-chelating compounds, i.e. siderophores, the use of efflux pump inhibitors, and of carriers such as liposomes. Expert opinion: Although several rules governing permeation have recently been proposed for effective antibacterial drugs, none of them has been so far established as the 'golden' rule. Thus, new research is needed to find a more general approach on how to increase the concentration of antibacterial compounds in bacterial cells.