ChemMedChem最新文献

Aging naturally involves a decline in biological functions, often triggering a disequilibrium of physiological processes. A common outcome is the altered response exerted by the immune system to counteract infections, known as immunosenescence, which has been recognized as a primary cause, among others, of the so-called long-COVID syndrome. Moreover, the uncontrolled immunoreaction leads to a state of subacute, chronic inflammatory state known as inflammaging, responsible in turn for the chronicization of concomitant pathologies in a self-sustaining process. Anti-inflammatory and immunosuppressant drugs are the current choice for the therapy of inflammaging in post-COVID complications, with contrasting results. The increasing knowledge of the biochemical pathways of inflammaging led to disclose new small molecules-based therapies directed toward different biological targets involved in inflammation, immunological response, and oxidative stress. Herein, paying particular attention to recent clinical data and preclinical literature, we focus on the role of endocannabinoid system in inflammaging, and the promising therapeutic option represented by the CB2R agonists, the role of novel ligands of the formyl peptide receptor 2 and ultimately the potential of newly discovered monoamine oxidase (MAO) inhibitors with neuroprotective activity in the treatment of immunosenescence.

First-in-class drug discovery (FICDD) offers novel therapies, new biological targets and mechanisms of action (MOAs) toward targeting various diseases and provides opportunities to understand unexplored biology and to target unmet diseases. Current screening approaches followed in FICDD for discovery of hit and lead molecules can be broadly categorized and discussed under phenotypic drug discovery (PDD) and target-based drug discovery (TBDD). Each category has been further classified and described with suitable examples from the literature outlining the current trends in screening approaches applied in small molecule drug discovery (SMDD). Similarly, recent applications of functional genomics, structural biology, artificial intelligence (AI), machine learning (ML), and other such advanced approaches in FICDD have also been highlighted in the article. Further, some of the current medicinal chemistry strategies applied during discovery of hits and optimization studies such as hit-to-lead (HTL) and lead optimization (LO) have been simultaneously overviewed in this article.

Inspired by the cyclopentenone family of prostaglandins, a series of 4-aza, cross-conjugated cyclopentenones is described. Synthesised from N-protected (4R)-aza-cyclopentenone 5, the exocyclic alkene was installed using a modified Baylis-Hillman type aldol reaction, whereby carbon-carbon bond formation is accompanied by dehydration. In this manner octanal and octenal, for example, can be introduced to mimic the ω-group present in the natural prostaglandins. Similarly, a focused range of alternative substituents were introduced using different aldehydes and ketones. The presence of the tert-butyloxycarbonyl (Boc) group on the 4-amino-cyclopentenone substituent enabled subsequent derivatisation and various electrophiles were successfully incorporated. The ability of the family of 4-amino functionalised cross-conjugated cyclopentenones to block activation of nuclear factor-kappa B (NF-κB) was studied and compared with the natural prostanoid, Δ^12,14-15-deoxy-PGJ₂ (2). Thereafter, the synthesis of a series of thiol adducts from these compounds were prepared and similarly evaluated biologically. The adducts showed comparable and, on occasion, more potent inhibition of NF-κB than their cyclopentenone precursors and generally demonstrated diminished cytotoxicity. For example, cross-conjugated dieneone 12 inhibited the activation of NF-κB with an IC₅₀ value of 6.2 μM, whereas its endocyclic N-Boc (27) and N-acetyl (28) cysteine adducts blocked NF-κB activity with values of 1.0 and 8.0 μM respectively.

Alzheimer's disease (AD) is a complex neurodegenerative disorder having limited treatment options. The beta-site APP cleaving enzyme 1 (BACE-1) is a key target for therapeutic intervention in Alzheimer's disease. To discover new scaffolds for BACE-1 inhibitors, a ChemBridge DIVERSet library of 20,000 small molecules was employed to structure-based virtual screening. The top 45 compounds, based on docking scores and binding affinities, were tested for BACE-1 inhibitory activity using a FRET assay. Four compounds, 18 (5353320), 20 (5262831), 29 (5784196) and 32 (5794006) demonstrated more than 35 % inhibitory activity at 10 μM. Notably, pyrazole-5-carbohydrazide 29 (5784196) exhibited BACE-1 inhibition with an IC₅₀ value of 14.5 μM and a ki value of 0.25 μM. Additionally, it also inhibits the self-aggregation of β-amyloid, with IC₅₀ value of 14.87 μM. Molecular modeling and dynamics simulations provided insights into its interaction pattern and stability of the enzyme-inhibitor complex. These findings suggest that virtual screening is an efficient and cost-effective method for identifying potential leads for AD.

The 33-mer gliadin peptide and its deamidated derivative, known as 33-mer DGP, are proteolytically resistant peptides central to the pathomechanism of celiac disease (CeD), the autoimmune presentation of gluten-related disorders (GRD). Both peptides can form spontaneous oligomers in the nanomolar concentration, leading to the formation of nanostructures. In other protein-related diseases, oligomers and aggregates are central in their pathomechanism; therefore, it was hypothesized that the oligomerization of proteolytical-resistant 33-mer gliadin peptides could be an underrecognized disease trigger. This review focuses on the current understanding of 33-mer peptides and their oligomers in vitro and cellular experiments. We intend to give the necessary details that incentivize the chemistry community to get involved in the effort to understand the self-assembly of gliadin peptides and the role of their supramolecular structures in CeD and the other GRD. More research is needed to design effective and safe chemical and/or nutritional interventions beyond the gluten-free diet.

This cover image highlights the structure and anticancer properties of Zn(II)-curcumin complexes. Curcumin whose structure is given in yellow reacts with Zn(II) ion to form the fluorescent green colored Zn(II)-curcumin complex. The two DNA double helix structures represent the DNA binding potential of Zn(II)-curcumin complexes. The cell membrane in cyan and cell organelle in blue indicate the cellular uptake and internalization of Zn(II)-curcumin complex. The white bulb highlights the light irradiation of curcumin derivatives. More details can be found in the article 10.1002/cmdc.202400558 by Sankarasekaran Shanmugaraju and co-workers.

This cover illustrates the encapsulation of amyloid beta (Aβ) peptides within reverse micelles, symbolizing the controlled aggregation of Aβ oligomers within these nano-sized environments. The reverse micelles facilitate a rapid coalesce-and-separate process, where the Aβ peptides inside are brought together to form oligomers. The size of these oligomers is constrained by the physical dimensions of the reverse micelle, offering a unique way to study their aggregation process in a controlled setting. This artwork captures the dynamic interaction and precise regulation of oligomer size within the micelles. More details can be found in article 10.1002/cmdc.202400310 by Jerry Chun Chung Chan and co-workers.

Dr. Philipp Stockmann, Dr. Lydia Kuhnert,* Wencke Leinung, Dr. Tamara Krajnović, Prof. Sanja Mijatović, Prof. Danijela Maksimović-Ivanić, Prof. Walther Honscha, Prof. Evamarie Hey-Hawkins*

Wencke Leinung was mistakenly omitted from the list of authors for this work. This co-author's name now appears correctly, as listed above.

The corrected Acknowledgements now read: “We thank Cathleen Lakoma and Birte K. Scholz for skillful technical assistance. This research was funded by the Ministry of Science, Technological Development and Innovation of the Republic of Serbia (grant number No. 451–03-47/2023-01/200007). Financial support from the Graduate School Leipzig School of Natural Sciences – Building with Molecules and Nano-objects (BuildMoNa) is gratefully acknowledged. Open Access funding enabled and organized by Projekt DEAL.”

Ritonavir, a protease inhibitor sold under the brand name Norvir®, is an antiviral medication that effectively targets the human immunodeficiency virus (HIV). Being probably the most important and best-known example of the crystal polymorphism in the field of pharmaceutics, ritonavir has been extensively studied in the last 30 years, which eventually led to the discovery of its new polymorph, Form III, in 2023. So far, two crystal structures of both Forms I and II of ritonavir were deposited in CCDC database. The aim of this study was to revisit those crystal structures, using NMR crystallography by recording the ¹³C CP/MAS NMR spectra and performing GIPAW NMR calculations with CASTEP. The obtained results revealed the major discrepancies between the calculated and experimental NMR chemical shift values. Those differences were explained at the molecular level, as resulting from the differences in the experimentally determined and DFT-optimized positions of some atoms, mostly those forming phenyl and thiazole rings. This work is an example of how NMR crystallography can be used to verify and improve the already published crystal structures.