Pyrroles are important building blocks in natural products and medicinal chemistry; they can be linked together in various ways to make a multitude of functional oligomers and macrocycles. One simple way in which pyrroles have not previously been linked together is through the (3-positions of two pyrroles to make a chalcone. To address this knowledge gap, we report herein an efficient method for synthesizing (beta,(beta '-linked bispyrrolyl chalcones, proceeding via a Knoevenagel-type reaction of a pyrrolyl aldehyde, followed by a late-stage Friedel-Crafts reaction to attach the second pyrrole. We envisage that the obtained structures may be elaborated in the future within medicinal chemistry programs.

Imipramine is a tricyclic antidepressant (TCA) that inhibits the serotonin reuptake transporter (SERT). However, the clinical use of TCAs such as imipramine is limited by side-effects arising from antagonism of several off-target receptors. In this work, stereospecific fluorination is investigated as a strategy for enhancing the potency and selectivity of imipramine through conformational bias. In contrast to prediction, fluorination of imipramine is found to confer reduced potency and selectivity towards SERT, and this may be attributable to clashes between fluorine and hydroxyl-bearing amino acid residues within the SERT binding site.

WEHI-601 is a statine-containing peptidomimetic that inhibits the malarial aspartyl protease, plasmepsin V. In this work, stereoselective fluorination is investigated as a strategy for enhancing the potency of WEHI-601 through conformational bias. Consistent with prediction, a fluorostatine-containing analogue of WEHI-601 is found to deliver stronger antimalarial activity than the lead compound, attributable to conformational preorganisation of the FCCO segment within the peptidomimetic backbone. However, the magnitude of the improvement is small, and this is discussed with reference to the hydrogen bonding capability of the vicinal fluoro-alcohol motif.

The introduction of a fluorine into aliphatic substituents of lead candidates can impart unique structural characteristics that allow fine tuning of drug interactions; therefore, mild, specific, or late‐stage fluorination procedures are of growing interest in medicinal chemistry, with the potential to be applied in F‐18 radiochemistry. In this work, we demonstrate the feasibility of “reagent‐less” electrochemical fluorination leading to mono‐ and gem‐difluorinated proline cores featured in important fibroblast‐activating protein inhibitors. Our study highlights the importance of using the appropriate activator substituents for allowing the process, the impact of different reaction parameters, and characterizes the various byproducts that are generated in the reaction. We have tested the reaction using a commercially available batch system and flow apparatus, achieving maximum yields of >90% (batch) for mono‐ and of 6% (batch) and 9% (flow) for the gem‐difluorinated proline model. These proof‐of‐concept results indicate that the flow approach is more efficient, but that different activating substituents will be needed to achieve higher yields.

A concise total synthesis of the C2-symmetric marine alkaloid, phenazine-1,6-diyldimethanol, is reported. X-ray crystal structures for three phenazine derivatives are presented, and a simple and general NMR-based method for distinguishing 1,6-from 1,9-disubstituted phenazines is described.

The pentafluorosulfanyl group (-SF5) is one of the most promising fluorinated functional groups, recently developed as an alternative to the trifluoromethyl group (-CF3) in drug design. Fluorine-18 allows researchers to investigate in vivo activity and biodistribution of novel fluorinated drugs; however, currently no methods are reported to radiolabel -SF5 moieties. In this work we report the first successful radiolabelling of such a group by isotopic exchange, and we show peculiar reaction trends. We studied this reaction using model compounds and functionalized amino acids, also adopting an unbiased approach to reaction optimization to minimize cognition bias. The results have been analyzed by standard statistical methods and Artificial Intelligence (AI) tools. Finally, we serendipitously discovered the production of two radioactive products from one precursor, that we hypothesize being positional radioisotopologues that interact differently with the chromatographic stationary phase; if further proven, this finding hints, for the first time, at a case of chemical differences between molecules containing 19F and 18F.

When present within an organic molecule, the C–F bond tends to align in predictable ways with neighbouring functional groups, due to stereoelectronic effects such as hyperconjugation and electrostatic attraction/repulsion. These fluorine-derived conformational effects have been exploited to control the shapes, and thereby enhance the properties, of a wide variety of functional molecules including pharmaceutical agents, liquid crystals, fragrance chemicals, organocatalysts, and peptides. This comprehensive review summarises developments in this field during the period 2010–2024.

Covalent drugs can offer significant advantages over noncovalent drugs, in terms of pharmacodynamics (i.e. target-binding properties). However, the development of covalent drugs is sometimes hampered by pharmacokinetic limitations (e.g. low bioavailability, rapid metabolism, and toxicity due to off-target binding). Polymeric nanoparticles offer a potential solution to these limitations. Delivering covalent drugs via polymeric nanoparticles provides myriad benefits in terms of drug solubility; permeability; lifetime; selectivity; controlled release; and the opportunity for synergistic administration alongside other drugs. In this short review, we examine each of these benefits in turn, illustrated through multiple case-studies.

Peptides that are composed of an alternating pattern of α- and γ-amino acids are potentially valuable as metabolism-resistant bioactive agents. For optimal function, some kind of conformational restriction is usually required to either stabilize the dominant 12-helix, or else to divert the peptide away from this conformation in a controlled way. Herein, we explore stereoselective fluorination as a method for controlling the conformations of α/γ-hybrid peptides. We show through a combination of X-ray, NMR and CD analyses that fluorination can either stabilize or disrupt the 12-helix, depending on the fluorine stereochemistry. These findings could inform the ongoing development of diverse functional hybrid peptides.

Incorporating fluorine atoms into the backbone of an α/γ-hybrid peptide is shown to either stabilize or break the 12-helix, depending on the fluorine stereochemistry. Fluorine can also set the handedness of the helix.

Side chain-fluorinated amino acids are useful tools in medicinal chemistry and protein science. In this review, we outline some general strategies for incorporating fluorine atom(s) into amino acid side chains and for elaborating such building blocks into more complex fluorinated peptides and proteins. We then describe the diverse benefits that fluorine can offer when located within amino acid side chains, including enabling 19F NMR and 18F PET imaging applications, enhancing pharmacokinetic properties, controlling molecular conformation, and optimizing target-binding.

Phenazine is a tricyclic heteroarene that forms the core of diverse functional molecules including DNA intercalators.However, 2,8-disubstituted phenazines are rare, and this potentially limits the medicinal development of this class of heterocycles.Here we describe the synthesis of two new members of this compound class (i.e.dimethyl phenazine-2,8-dicarboxylate and the corresponding diacid), following a synthetic route that involved inter-and intramolecular Buchwald-Hartwig N-arylations.We also detail a simple NMR-based method for proving the 2,8-disubstitution pattern, in order to counterbalance suspected structural misassignments elsewhere in the peer-reviewed and patent literature.

Peptides that are composed of backbone-extended amino acids can adopt conformations resembling natural α-peptidic motifs, making them promising scaffolds for biological and medicinal chemistry. In order to unlock the full potential of this class of molecules, the ability to control their secondary structures is essential. Here we show that stereoselective fluorination can be harnessed as a tool for influencing the helical character of a γ-hexapeptide. Fluorination is shown to either stabilize or disrupt the 9-helical conformation depending on the C−F stereochemistry, and fluorination also sets the handedness of the helix. These results provide fundamental knowledge that could expedite the future development of backbone-extended peptides for medicinal applications.

The SF5 group has great potential in influencing the drug-like features of organic molecules due to its chemical stability, hydrophobic surface, electron-withdrawing capability and unique octahedral geometry. However, the difficulty in synthesising SF5-containing compounds, particularly in aromatic systems, has impeded the widespread incorporation of this group into desired scaffolds in medicinal chemistry. The most troublesome step operationally involves the synthesis of the intermediate species ArSF4Cl from aryl-disulfides. Here, we report an analytical-scale synthesis of ArSF4Cl using flow microfluidic technology, allowing for safer handling of reagents and avoiding the need for gloveboxes or Cl2 cylinders. The system is fairly straightforward to prepare, clean to assemble and can be adapted easily to further developments. As well as making progress towards continuous de novo syntheses of ArSF5 compounds, this result broadly highlights the potential of flow chemistry in providing new avenues to perform challenging batch reactions. Graphical abstrac

Prolyl hydroxylase (PHD) enzymes play a critical role in the cellular responses to hypoxia through their regulation of the hypoxia inducible factor α (HIF-α) transcription factors. PHD inhibitors show promise for the treatment of diseases including anaemia, cardiovascular disease and stroke. In this work, a pharmacophore-based virtual high throughput screen was used to identify novel potential inhibitors of human PHD2. Two moderately potent new inhibitors were discovered, with IC50 values of 4 μM and 23 μM respectively. Cell-based studies demonstrate that these compounds exhibit protective activity in neuroblastoma cells, suggesting that they have the potential to be developed into clinically useful neuroprotective agents.

Histone deacetylase enzymes (HDACs) are potential targets for the treatment of cancer and other diseases, but it is challenging to design isoform-selective agents. In this work, we created new analogs of two established but non-selective HDAC inhibitors. We decorated the central linker chains of the molecules with specifically positioned fluorine atoms in order to control the molecular conformations. The fluorinated analogs were screened against a panel of 11 HDAC isoforms, and minor differences in isoform selectivity patterns were observed.

Piperine, a natural product derived from peppercorns, has a variety of biological activities that make it an attractive lead compound for medicinal chemistry. However, piperine has some problematic physicochemical properties including poor aqueous solubility and a susceptibility to UV-induced degradation. In this work, we designed an analog of piperine in which the central conjugated hydrocarbon chain is replaced with a vicinal difluoroalkane moiety. We show that this fluorinated analog of piperine has superior physicochemical properties, and it also has higher potency and selectivity towards one particular drug target, acetylcholinesterase. This work highlights the potential usefulness of the threo-difluoroalkane motif as a surrogate for E-alkenes in medicinal chemistry.

Inflammatory bowel disease (IBD) is a chronic and life-long disease characterized by gastrointestinal tract inflammation. It is caused by the interplay of the host's genetic predisposition and immune responses, and various environmental factors. Despite many treatment options, there is no cure for IBD. The increasing incidence and prevalence of IBD and lack of effective long-term treatment options have resulted in a substantial economic burden to the healthcare system worldwide. Biologics targeting inflammatory cytokines initiated a shift from symptomatic control towards objective treatment goals such as mucosal healing. There are seven monoclonal antibody therapies excluding their biosimilars approved by the US Food and Drug Administration for induction and maintenance of clinical remission in IBD. Adverse side effects associated with almost all currently available drugs, especially biologics, is the main challenge in IBD management. Natural products have significant potential as therapeutic agents with an increasing role in health care. Given that natural products display great structural diversity and are relatively easy to modify chemically, they represent ideal scaffolds upon which to generate novel therapeutics. This review focuses on the pathology, currently available treatment options for IBD and associated challenges, and the roles played by natural products in health care. It discusses these natural products within the current biodiscovery research agenda, including the applications of drug discovery techniques and the search for next-generation drugs to treat a plethora of inflammatory diseases, with a major focus on IBD.