Late-stage modification of bioactive compounds: Improving druggability through efficient molecular editing.

Synthetic chemistry plays an indispensable role in drug discovery, contributing to hit compounds identification, lead compounds optimization, candidate drugs preparation, and so on. As Nobel Prize laureate James Black emphasized, "the most fruitful basis for the discovery of a new drug is to start with an old drug"1. Late-stage modification or functionalization of drugs, natural products and bioactive compounds have garnered significant interest due to its ability to introduce diverse elements into bioactive compounds promptly. Such modifications alter the chemical space and physiochemical properties of these compounds, ultimately influencing their potency and druggability. To enrich a toolbox of chemical modification methods for drug discovery, this review focuses on the incorporation of halogen, oxygen, and nitrogen-the ubiquitous elements in pharmacophore components of the marketed drugs-through late-stage modification in recent two decades, and discusses the state and challenges faced in these fields. We also emphasize that increasing cooperation between chemists and pharmacists may be conducive to the rapid discovery of new activities of the functionalized molecules. Ultimately, we hope this review would serve as a valuable resource, facilitating the application of late-stage modification in the construction of novel molecules and inspiring innovative concepts for designing and building new drugs.

Discovery of novel and selective farnesoid X receptor antagonists through structure-based virtual screening, preliminary structure-activity relationship study, and biological evaluation.

Farnesoid X receptor (FXR) is a bile acids receptor and plays a crucial role in regulating bile acids, lipids, and glucose metabolism. Previous research suggests that inhibiting FXR activation can be beneficial in reducing cholesterol and low-density lipoprotein cholesterol (LDL-C) levels, offering potential treatment options for metabolic syndrome with lipid disorders. Herein, we report p-acetylaminobenzene sulfonate derivatives as a novel scaffold of FXR antagonists by multistage screening. Among these derivatives, compound F44-A13 exhibited a half-maximal inhibitory concentration of 1.1 µM. Furthermore, compound F44-A13 demonstrated effective inhibition of FXR activation in cellular assays and exhibited high selectivity over eleven other nuclear receptors. Besides, compound F44-A13 significantly suppressed the regulation of FXR target genes Shp, Besp, and Cyp7a1, while reducing cholesterol levels in human hepatoma HepG2 cells. Pharmacological studies conducted on C57BL/6 mice further confirmed that compound F44-A13 had beneficial effects in reducing cholesterol, triglycerides, and LDL-C levels. These findings highlight that F44-A13 is a highly selective FXR antagonist that might serve as a useful molecule for further FXR studies as well as the development of FXR antagonists for the potential treatment of metabolic diseases with lipid disorders.

Discovery of 3-oxo-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin derivatives as SARS-CoV-2 main protease inhibitors through virtual screening and biological evaluation.

The COVID-19 caused by SARS-CoV-2 has led to a global pandemic that continues to impact societies and economies worldwide. The main protease (Mpro) plays a crucial role in SARS-CoV-2 replication and is an attractive target for anti-SARS-CoV-2 drug discovery. Herein, we report a series of 3-oxo-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin derivatives as non-peptidomimetic inhibitors targeting SARS-CoV-2 Mpro through structure-based virtual screening and biological evaluation. Further similarity search and structure-activity relationship study led to the identification of compound M56-S2 with the enzymatic IC50 value of 4.0 µM. Moreover, the molecular simulation and predicted ADMET properties, indicated that non-peptidomimetic inhibitor M56-S2 might serve as a useful starting point for the further discovery of highly potent inhibitors targeting SARS-CoV-2 Mpro.

Functional screening and rational design of compounds targeting GPR132 to treat diabetes.

Chronic inflammation due to islet-residing macrophages plays key roles in the development of type 2 diabetes mellitus. By systematically profiling intra-islet lipid-transmembrane receptor signalling in islet-resident macrophages, we identified endogenous 9(S)-hydroxy-10,12-octadecadienoic acid-G-protein-coupled receptor 132 (GPR132)-Gi signalling as a significant contributor to islet macrophage reprogramming and found that GPR132 deficiency in macrophages reversed metabolic disorders in mice fed a high-fat diet. The cryo-electron microscopy structures of GPR132 bound with two endogenous agonists, N-palmitoylglycine and 9(S)-hydroxy-10,12-octadecadienoic acid, enabled us to rationally design both GPR132 agonists and antagonists with high potency and selectivity through stepwise translational approaches. We ultimately identified a selective GPR132 antagonist, NOX-6-18, that modulates macrophage reprogramming within pancreatic islets, decreases weight gain and enhances glucose metabolism in mice fed a high-fat diet. Our study not only illustrates that intra-islet lipid signalling contributes to islet macrophage reprogramming but also provides a broadly applicable strategy for the identification of important G-protein-coupled receptor targets in pathophysiological processes, followed by the rational design of therapeutic leads for refractory diseases such as diabetes.

Discovery of 2-(furan-2-ylmethylene)hydrazine-1-carbothioamide derivatives as novel inhibitors of SARS-CoV-2 main protease.

The COVID-19 posed a serious threat to human life and health, and SARS-CoV-2 Mpro has been considered as an attractive drug target for the treatment of COVID-19. Herein, we report 2-(furan-2-ylmethylene)hydrazine-1-carbothioamide derivatives as novel inhibitors of SARS-CoV-2 Mpro developed by in-house library screening and biological evaluation. Similarity search led to the identification of compound F8-S43 with the enzymatic IC50 value of 10.76 µM. Further structure-based drug design and synthetic optimization uncovered compounds F8-B6 and F8-B22 as novel non-peptidomimetic inhibitors of Mpro with IC50 values of 1.57 µM and 1.55 µM, respectively. Moreover, enzymatic kinetic assay and mass spectrometry demonstrated that F8-B6 was a reversible covalent inhibitor of Mpro. Besides, F8-B6 showed low cytotoxicity with CC50 values of more than 100 µM in Vero and MDCK cells. Overall, these novel SARS-CoV-2 Mpro non-peptidomimetic inhibitors provide a useful starting point for further structural optimization.

Rh-Catalyzed Reaction of Vinyl Azides with Isonitriles and Alkynes/Benzynes.

In contrast to well-known transformations of vinyl azides via azirine intermediates or initiating at the alkene moiety, herein we report a Rh(I)-catalyzed coupling reaction of vinyl azides with isonitriles at the azide moiety to form active vinyl carbodiimide intermediates and following tandem cyclization with unsaturated compounds, such as alkynes and benzynes, to give different classes of azaheterocycles. Mechanistically, controlled experiments and DFT calculations disclose that Rh-nitrene is the vital species in the first coupling step, and the Rh(I) catalyst can also play an important role in the cyclization step of alkynes.