MedChemComm最新文献

Microbial infection is one of the most pressing global challenges worldwide, and imposes significant economic burdens on healthcare systems. This work represents a rational combinatorial strategy that leverages hydrophobic harmony in multiple phenylalanine fragments, anchored to an amphiphile 16-hydroxy-palmitic acid at the N-terminus (16-HPA-D-Phe-D-Phe-OH, compound I; 16-HPA-D-Phe-D-Phe-D-Phe-OH, compound II; 16-HPA-D-Phe-D-Phe-D-Phe-D-Phe-OH, compound III), such that a viable therapeutic skeleton could be uncovered through this strategy. In pursuit of this objective, the minimum inhibitory concentrations of compounds I–III were investigated using four distinct microorganisms namely Staphylococcus aureus and B. subtilis (Gram positive), and E. coli and P. aeruginosa (Gram negative). Our systematic examination reflected that from a pool of three skeletons, compound III comprising of D-configured tetraphenylalanines displayed not only mechanoresponsive assisted hydrogelation propensities at physiological pH, but also excellent antibacterial activities in vitro, in the Gram positive micro-organisms backed by molecular modelling studies. Henceforth compound III was selected from the design and proceeded for its elaborate antibacterial activities using colony counting experiment, bacterial scanning electron microscopy and live–dead assay using flow cytometry. Furthermore, the β-sheet structured compound III, stabilized by weak non-covalent interactions, depicted optimum mechanical strength as well as proteolytic stability for 72 h when exposed to the proteolytic enzyme, proteinase K and chymotrypsin. Overall, our analysis highlights the potential of compound III as a promising candidate for future antimicrobial therapy. However, further experiments are necessary to validate these findings, and current claims are reflective of an early proof-of-concept until further preclinical data are available.

We describe the design, synthesis, and antialphaviral activity of spirodioxolane inhibitors targeting the alphavirus nsP2 helicase (nsP2hel). The spirodioxolanes are a new series of direct-acting antivirals that retain key molecular features required for inhibition of nsP2hel, including a highly substituted piperidine acetamide with its associated conformational isomerism and thermal mobility. Unlike the related oxaspiropiperidine nsP2hel inhibitors, the spirodioxolanes showed no enantioselectivity in their antiviral activity. The spirodioxolanes demonstrated antialphaviral activity against the Old World alphavirus Chikungunya virus, with some analogs also showing activity against the New World alphavirus Venezuelan equine encephalitis virus. Importantly, certain spirodioxolane analogs, such as 6b, maintained activity against viral mutants that displayed resistance to first-generation oxaspiropiperidine inhibitors, indicating their potential for optimization as a new class of broad-spectrum antialphaviral drugs.

Alzheimer's disease (AD) is a complex neurodegenerative disease with biological signatures of amyloid beta (Aβ) aggregated plaques and increased levels of bio-metals like copper (Cu), zinc (Zn), and iron (Fe). Aβ-induced lysosomal membrane permeabilization is a key event in neuronal injury in AD. Aβ aggregation also modulates mitochondria membrane potential (MMP), activates interleukin 1β and NLRP3 inflammasome eventually leading to increased reactive oxygen species (ROS) production, neuronal apoptosis and mitochondrial dysfunction. Here, we report a multi-functional compound (2f) identified through structure–activity relationship study from a series of polyfluorinated triazole compounds. Compound 2f suppressed metal induced aggregation, downregulated NLRP3 inflammasome and IL-1β expression. It has maintained the lysosomal acidic pH and restored mitochondrial membrane potential. HFIP bearing triazolo amide (2f) was found to chelate with Cu(II) and Zn(II) selectively in the presence of a range of other physiologically relevant metals. Further, a molecular dynamics (MD) simulation study revealed 2f disrupted the aggregation via interacting with chain A of pentameric Aβ. Therefore the HFIP bearing triazole amides may serve as potential scaffolds for drug development towards the treatment of AD.

Generating libraries of congeneric series of compounds and development of structure–activity relationships (SAR) is a common practice among medicinal chemists. While various computational methods are available to guide scaffold optimization, their reliability in prediction can vary. Ligand free energy perturbation (FEP+) is a rigorous computational program that computes the relative binding free energies between two congeneric ligands against a target, thereby identifying the ligand with greater binding affinity. In this study, we evaluated the FEP+ method to predict the relative binding affinity of two ligands from a congeneric series towards the target proteins. A total of 34 ligand transformations were performed, spanning across 21 soluble proteins. Relative binding free energies were calculated and compared with the experimental value to assess the accuracy of prediction. With a mean unsigned error of 0.46 kcal mol⁻¹ and coefficient of determination, R² = 0.85, the results of this work suggest that the FEP+ is a reliable tool for the medicinal chemist to predict the relative free energies of binding with good statistical significance, demonstrating its utility in SAR development in drug discovery.

Schweinfurthins (SWs) are natural products isolated from the plant genus Macaranga which display a unique cytotoxicity profile in human cancer cell lines with low nanomolar potency. Their known target is the sterol transport protein (STP) oxysterol-binding protein (OSBP), a key mediator and regulator of lipid transport between the endoplasmic reticulum (ER) and the trans-Golgi network (TGN). However, until now the underlying structure–activity relationships (SAR), as well as the cellular toxicity-target engagement relationships of SWs towards OSBP have not been well-studied. In this study, we present the first comprehensive SAR and selectivity study by characterizing 59 SW analogues utilizing our STP screening panel. Complementary detailed docking studies shine light on the SW-OSBP interactions and unravel amino acid residues critical for potent binding to OSBP. Additionally, we demonstrate cellular target engagement and correlate cancer cell cytotoxicity with Golgi fragmentation as a phenotypic consequence of OSBP inhibition by selected SW analogues. Therefore, this study will pave the way for more focused investigations and therapeutic applications of OSBP inhibitors.

In recent years, heat shock protein 90 (HSP90), a widely expressed molecular chaperone, has emerged as a promising anticancer target due to its crucial role in stabilizing and regulating the functions of numerous client proteins involved in various essential cellular processes, including protein folding, signalling pathways, and activation of tumor-associated proteins. Despite extensive developments, only one HSP90 inhibitor has gained approval, reflecting the complexity of the HSP90 chaperone machinery, associated side effects, and emergence of resistance mechanisms. To overcome these limitations, researchers have focused their attention on developing targeted protein degraders (TPDs), a revolutionary therapeutic approach that selectively eliminates specific dysregulated target proteins. TPDs exploit cellular degradation pathways, including the ubiquitin–proteasome system (UPS), lysosomal pathways, and autophagy to achieve precise protein degradation. Among these strategies, proteolysis-targeting chimeras (PROTACs) as well as HEMTAC/HIM-PROTACs have emerged as prominent UPS-based technologies. PROTACs link targets to E3 ligases for proteasomal removal, where HEMTACs exploit HSP90 to drive client ubiquitination, thereby offering significant potential for cancer therapeutics. Given HSP90's role in tumor progression and considering the potential of TPDs, researchers have designed and developed various HSP90-targeting PROTACs and HEMTAC/HIM-PROTACs, which exhibits remarkable efficacy, selectivity, antiproliferative potency, and the ability to overcome drug resistance. This review highlights the structural and biological functions of HSP90, delineates the mechanistic principles underlying its degradation, and summarizes the structure–activity relationships (SARs) inlcuding the synthetic strategies employed across different HSP90-directed TPD modalities. Furthermore, the challenges and opportunities associated with the utilization of HSP90 and their client proteins in developing TPDs-based therapeutics to tackle the unmet clinical needs in cancer have been discussed.

This perspective explores the development, preparation, and widespread application of ChemBeads, a solid reagent delivery platform designed to overcome longstanding challenges in miniaturized and automated chemical experimentation. Originating from innovation at AbbVie, ChemBeads are formed by dry-coating active reagents onto inert carrier beads, transforming poorly flowing powders into uniform, flowable materials compatible with robotic and manual dispensing. Enabled by resonant acoustic mixing (RAM) or alternative techniques like vortex mixing, ChemBeads have streamlined high-throughput experimentation (HTE) and medicinal chemistry workflows. Their applications span a wide range of transformations including photoredox catalysis, cross-electrophile coupling, C–N and C–H functionalizations and late-stage oxidations. Industrial and academic case studies highlight the critical role of ChemBeads in accelerating the development of new synthetic methodologies that would have otherwise taken significantly longer to accomplish. By solving the long standing problem of material handling at a miniaturized scale with efficiency and generality, ChemBead technology formed the foundation of the AbbVie Discovery HTE platform and positioned us as one of the industry leaders in this field. Over the years, we expanded the technology to make it greatly accessible to academic institutions by making the process economically and operationally friendly. In parallel, we extended this technology in other areas, which ultimately promoted industry–academia collaborations. The technology's expansion into biocatalysis (EnzyBeads), solubility assays, and solid form screening further demonstrates its adaptability.

Lung cancer, particularly NSCLC, is the leading cause of cancer-related deaths worldwide, accounting for over 80% of cases. Mutations in the epidermal growth factor receptor (EGFR) are key drivers of NSCLC. Although three generations of EGFR tyrosine kinase inhibitors (TKIs) have been developed, resistance limits their efficacy. The dibenzodiazepinone scaffold exhibits diverse biological activities, however, reports on its derivatives for treating NSCLC with EGFR mutations, particularly triple mutations, are rare. Guided by the binding model of DDC4002 with EGFR^T790M/V948R, this study synthesized and characterized 36 dibenzodiazepinone analogues, evaluating their antiproliferative activity against NSCLC cell lines. Structure–activity relationship analysis highlighted the importance of substituents at the C2 and N10 positions. Compound 33 exhibited the strongest inhibitory effects, especially for H1975™ cells (EGFR^{L858R/T790M/C797S}) with a 2.4-fold lower IC₅₀ (2.7 μM) than osimertinib (6.5 μM). It effectively inhibited colony formation, migration of H1975™ cells, induced G0/G1 arrest, and promoted apoptosis through suppressing EGFR and AKT phosphorylation. These findings demonstrate the potential of optimizing the dibenzodiazepinone framework for developing novel potent molecules against osimertinib resistant NSCLC cells, providing valuable insights for future research.

A novel series of procaine derivatives incorporating 1,2,3-triazole and isoxazoline scaffolds were developed and evaluated for their anticancer potential, particularly against esophageal cancer. Initially, the synthesized compounds were screened for their kinase inhibitory activity against PI3K, mTOR, CDK1, CDK4, EGFR, and VEGFR2, where they exhibited excellent inhibitory potency against PI3K and mTOR. Among the synthesized compounds, 8e, 8f, and 8g emerged as the top-performing kinase inhibitors. These three candidates were subsequently tested against a panel of human cancer cell lines, including breast, cervical, lung, liver, and esophageal cancer cells. Notably, they demonstrated superior cytotoxic activity against esophageal cancer cells. Of these, compound 8e was identified as the most potent and was further evaluated against six esophageal cancer cell lines (Eca109, TE1, TE13, KYSE30, KYSE70, and KYSE150) with diverse genotypic backgrounds. Compound 8e exhibited the highest activity against Eca109 cells. Further investigations revealed that compound 8e significantly inhibited Eca109 cell viability, as confirmed by the MTT assay, and induced apoptosis, as evidenced by annexin V/PI dual staining and DAPI nuclear staining. It also caused G0/G1 cell cycle arrest, decreased mitochondrial membrane potential, and demonstrated marked telomerase inhibitory activity. In addition, wound healing and transwell assays confirmed its ability to suppress the migration and invasion of Eca109 cells. Western blot analysis revealed that compound 8e modulated the expression of key apoptotic regulators (Bcl-2, Bax, and p53) and downregulated the PI3K/Akt/mTOR signaling pathway. In an orthotopic xenograft mouse model, compound 8e significantly reduced tumor volume and increased body weight in a dose-dependent manner, indicating potent in vivo efficacy with favorable tolerability. Biochemical analyses showed that compound 8e mitigated oxidative stress by regulating MDA, SOD, and GSH levels and suppressed pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6. Immunohistochemical staining further confirmed reduced expression of PI3K and p-Akt (Ser473) in tumor tissues. Pharmacokinetic evaluation via both intravenous and oral administration demonstrated that compound 8e possesses excellent bioavailability, highlighting its potential as a promising therapeutic candidate for the treatment of esophageal cancer.

Tissue fibrosis is a common consequence of many different acute and chronic injuries, which severely impairs the function of affected organs. A significant challenge is the lack of effective strategies to treat fibrotic disorders. The metabolic dysregulation underlying fibrosis may be reversed by the small molecule caffeic acid phenethyl ester (CAPE), but there are limitations which prevent its clinical use. Following the identification of caffeic acid derivative 1 from an in-house library screen, we performed structure–activity relationship studies which led to the discovery of novel small molecule inhibitors of extracellular matrix (ECM) collagen secretion. The small molecules increased PPARG and CD36 expression (markers of fatty acid metabolism), suggesting a mechanism of action involving a metabolic shift from fibrotic-to-normal state. The compounds identified in this study provide a foundation for further development towards a novel, first-in-class therapeutic agent for fibrosis.