This Perspective article highlights recent studies in which continuous flow approaches exploiting photochemical, electrochemical, and thermal reactions led to the discovery and subsequent exploitation of new reactions and reactivity patterns.

Formation of amide bonds is of immanent importance in organic and synthetic medicinal chemistry. Its presence in “traditional” small‐molecule active pharmaceutical ingredients, in linear or cyclic oligo‐ and polypeptidic actives, including pseudopeptides, has led to the development of dedicated synthetic approaches for the formation of amide bonds starting from, if necessary, suitably protected amino acids. While the use of solid supported reagents is common in traditional peptide synthesis, similar approaches targeting amide bond formation in continuous‐flow mode took off more significantly, after a first publication in 2006, only a couple of years ago. Most efforts rely upon the transition of traditional approaches in flow mode, or the combination of solid‐phase peptide synthesis principles with flow chemistry, and advantages are mainly seen in improving space‐time yields. This Review summarizes and compares the various approaches in terms of basic amide formation, peptide synthesis, and pseudopeptide generation, describing the technological approaches and the advantages that were generated by the specific flow approaches. A final discussion highlights potential future needs and perspectives in terms of greener and more sustainable syntheses.

The spread of antimicrobial resistance (AMR) represents a major global health challenge, weakening the efficacy of antibiotics such as β-lactams, which are, nowadays, the most widely used drugs for treating bacterial infections. Among the different resistance mechanisms, the production of β-lactamases, particularly metallo-β-lactamases (MBLs), significantly compromises the activity of these antibiotics. Despite progress in developing serine-β-lactamase inhibitors (SBLi), no MBL inhibitors (MBLi) are currently available in clinical practice. This Perspective provides an outlook on AMR mechanisms, with a focus on the expression of MBL enzymes, and showcases the main classes of MBLi proposed to date, which mainly act through coordination of the zinc ion(s) populating the active site of the MBL class of enzymes. Furthermore, the Perspective describes current strategies aimed at overcoming the limited cellular permeability of MBLi, one of the major hurdles preventing their translation into clinical studies.

Herein we disclose a telescoped flow strategy to access electronically differentiated bisaryl ketones as potentially new and tunable photosensitizers containing both electron-rich benzene systems and electron-deficient pyridyl moieties. Our approach merges a light-driven (365 nm) and catalyst-free reductive arylation between aromatic aldehydes and cyanopyridines with a subsequent oxidation process. The addition of electron-donating and withdrawing substituents on the scaffold allowed effective modification of the absorbance of these compounds in the UV-vis region, while the continuous flow process affords high yields, short residence time, and high throughput.

The generation of peptidomimetic substructures for medicinal chemistry purposes requires effective and divergent synthetic methods. We present in this work an efficient flow process that allows quick modulation of reagents for Joullié‐Ugi multicomponent reaction, using spiroindolenines as core motifs. This sterically hindered imine equivalent could successfully be diversified using various isocyanides and amino acids in generally good space‐time yields. A telescoped flow process combining interrupted Fischer reaction for spiroindolenine synthesis and subsequent Joullié‐Ugi‐type modification resulted in product formation in very good overall yield in less than 2 hours compared to 48 hours required in batch mode. The developed protocol can be seen as a general tool for rapid and facile generation of peptidomimetic compounds. We also showcase preliminary biological assessments for the prepared compounds.