ChemMedChem最新文献

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key drug target for the treatment of different hypercholesterolemia-related diseases. A new class of small-molecule inhibitors of PCSK9 transcription, characterized by a 4-amino-2-pyridone scaffold, has been recently identified by our research group. Among them, the early lead compound 5c shows high in vitro potency and favorable in vivo tolerability. However, given the suboptimal in vitro metabolic stability of 5c, its optimization is reported herein by modification of the predicted metabolic soft spots through chemistry-driven late-stage functionalization (LSF) strategies. Microsomal stability on the newly synthesized derivatives allows drawing structure–metabolism relationships (SMRs) that, coupled with a thorough pharmacological investigation on HepG2 cells, leads to the identification of novel C3- and dual C3/NHC4-functionalized pyridones with improved stability and superior pharmacological profiles. Notably, compounds 6b, 7, and 18a emerge as the best candidates, demonstrating markedly improved metabolic stability/PCSK9 IC₅₀ ratio and comparable or lower cytotoxicity with respect to the parent compound 5c. These findings underscore the value of LSF strategies in generating optimized analogs of 5c with strong potential for further preclinical development.

Structure–activity relationships (SARs) are a cornerstone of drug discovery, aiming to elucidate the connection between chemical structures and their biological properties. While widely applied in medicinal chemistry and computer-aided molecular design, SAR traditionally assumes a direct connection (i.e., relations) between chemical structures and their activity. However, given the complexity of biological responses, these connections are often better described as associations rather than strict relationships. Beyond semantics, relations usually imply a deterministic or functional mapping, whereas, associations are treated with statistical tools that capture probabilistic patterns without assuming causality. Adopting an association-based perspective helps to avoid overstated claims and manage uncertainty more realistically. In this article, structure–property associations (SPAs) are proposed as a more accurate framework to capture the connection between chemical structures and their properties in the context of drug discovery. SPA is particularly emphasized in describing the associations between chemical structures and biological activity across different experimental levels, including both in vitro and in vivo assays.

Rare-earth (RE) salicylate phenanthroline complexes [RE(sal)₃(phen)] (RE = Y, Eu, Dy, Yb; sal = salicylate; Phen = 1,10-phenanthroline) are conveniently prepared starting from RE homoleptic carbamate precursors and salicylic aldehyde in the presence of phenanthroline. The yttrium derivative is structurally characterized by single-crystal X-ray diffraction, IR, and NMR spectroscopy, showing the mononuclear nature of the complex, while the structure of the other paramagnetic complexes are assigned on comparative IR spectra bases and elemental analyses. The antiproliferative effect of the complexes are studied in vitro on a panel of human tumor cell lines (A2780, ovarian carcinoma sensitive to cisplatin; A2780cis, ovarian carcinoma resistant to cisplatin and LN229, glioblastoma), and on nontumorigenic mesothelial cells (MeT-5A). The reactive oxygen species production is determined to investigate the intracellular mechanism of action. For the most interesting complex [Dy(sal)₃(phen)] (3), the effects on mitochondrial transmembrane potential and on cell cycle are also analyzed. Finally, epifluorescence images allow to demonstrate the uptake of the complex and to observe relevant morphological changes in cells, suggesting the occurrence of mitotic catastrophe.

Accurate predictions of compound properties are crucial for enhancing drug discovery by expediting processes and increasing success rates. This study focuses on predicting key pharmacokinetic endpoints related to Absorption, Distribution, Metabolism, and Excretion (ADME), leveraging extensive internal and newly available public hiqh-quality ADME data. Data-integration strategies are assessed for ADME prediction across six endpoints using single-source (internal or public), pooled single-task, and multitask learning models. Models trained on combined data—especially multitask models—generally outperform single-source baselines, with consistent gains on public tests and frequent gains on internal tests when public data complement and are proportionally balanced with in-house data size. Applicability domain analyses show that multitask learning reduces error for compounds with higher similarity to the training space, indicating better generalization across combined spaces. Analysis of prediction uncertainties mirrors these observations. Our study underscores that curated integration of high-quality public datasets with proprietary data can deliver more accurate and better-calibrated in silico ADME models to support computational compound design in drug discovery.

Colorectal cancer (CRC) is a major global health burden, driven by complex genetic and epigenetic alterations and an immunosuppressive tumor microenvironment (TME). The PD-1/PD-L1 immune checkpoint plays a central role in CRC immune evasion, making it a critical therapeutic target. Immune checkpoint inhibitors (ICIs) have achieved notable efficacy in microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) CRC, attributed to their high neoantigen burden. However, most CRC cases are microsatellite stable (MSS) and exhibit limited responsiveness to PD-1/PD-L1 blockade due to immune escape mechanisms, including β2-microglobulin and JAK/STAT mutations, HLA loss, and infiltration of regulatory T cells and myeloid-derived suppressor cells. Small-molecule inhibitors targeting PD-1/PD-L1 are emerging as promising alternatives to monoclonal antibodies, offering advantages such as oral administration, improved tissue penetration, and modulation of upstream and downstream signaling pathways. Compounds such as MPT0G612, Panaxadiol, Butyrate, Licochalcone A, and Demethylzeylasteral exhibit antitumor effects by suppressing PD-L1 expression, promoting its degradation, or enhancing T cell infiltration in the TME. Early clinical trials of CA-170, INCB086550, and ASC61 indicate encouraging activity in solid tumors, including CRC. This review summarizes the role of the PD-1/PD-L1 axis in CRC and discusses the therapeutic potential and future prospects of small-molecule inhibitors as next-generation immunotherapies for CRC.

The COVID-19 pandemic, caused by the highly transmissible SARS-CoV-2 virus, has highlighted the urgent need for effective small-molecule antivirals. To date, only a few such agents, including molnupiravir and remdesivir, have been approved by the FDA. In our previous study, a novel class of SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) inhibitors based on an N,N′-diphenylurea scaffold was identified; however, these compounds exhibited poor aqueous solubility and significant cytotoxicity. Herein, the design, synthesis, and evaluation of twenty-seven new derivatives aimed at improving solubility and reducing cytotoxicity through targeted scaffold modifications are reported. Seven analogs display enhanced aqueous solubility (kinetic solubility > 10 µM), and nine compounds show residual RdRp activity (RA—determined at 10 μM concentration of screened compounds) below 50%, with the most potent analog achieving an RA value of 34%. Despite these improvements, cytotoxicity remains a limitation across the series. These findings provide valuable structure–activity relationship insights and direct ongoing optimization efforts toward developing less toxic, soluble RdRp inhibitors with improved antiviral profiles.

Heparan sulfate (HS) is a ubiquitously expressed glycosaminoglycan (GAG) found on most mammalian cells. Its heterogeneous structure and dense negative charge allow HS to interact with a wide range of proteins, regulating their stability, localization, and engagement with cell-surface receptors. Given the role of disrupted HS-protein interactions in numerous diseases, HS mimetics represent a promising avenue for therapeutic intervention. These mimetics are designed to reproduce the functional properties of native HS while offering improved stability, scalability, and selectivity. Whereas most HS mimetics exploit naturally occurring sulfate groups to provide anionic character, this study explores phosphates as a sulfate bioisostere. Using a dendrimer-based scaffold, a focused library of phosphorylated maltose constructs was synthesized, comprising four (dimer), six (trimer), or eight (tetramer) units, with lipid-modified variants prepared for the dimer and trimer series. In vitro screening against four clinically relevant DNA viruses reveal that these phosphorylated HS mimetics display antiviral activity, albeit with reduced potency relative to their sulfated analogs.

Targeting oxidative phosphorylation (OXPHOS) in cancer metabolism offers a promising alternative to glycolytic inhibition. Herein, the synthesis and in vitro biological evaluation of 30 6-indolyl ester derivatives as potential OXPHOS inhibitors are reported. Screening against a panel of 5 mammalian cancerous cell lines and 1 noncancerous cell line using galactose- and glucose-containing media identified 11 hits with strong activity under OXPHOS-dependent conditions. Selectivity index (SI) and OXPHOS inhibition index (OI) analyses using IC₅₀ values obtained across a panel of 8 cancerous and noncancerous cell lines confirm compound 28 as a standout inhibitor, with an OI value of  >91 and a SI value of 9.88 against pancreatic cancer cell line MiaPaCa-2. Additional hits (e.g., compounds 13, 20, 37) also demonstrate strong OXPHOS-specific activity and moderate to good selectivity with breast cancer and pancreatic cancer cell lines. In silico assessment using OSIRIS and SwissADME tools validate their physicochemical properties and drug-likeness. These findings support further investigation of 6-indolyl esters, specifically compound 28, as a structurally simple and synthetically accessible scaffold for the development of novel OXPHOS-targeting anticancer agents.

This work explores the toxicity profile and anticancer mechanisms of reported anti-HIV carboxyphenyl porphyrin–fullerene dyads, PB₃C₆₀ and PB₃C₇₀, together with their precursor porphyrin PB₃OH, within noncationic porphyrin-based donor–π–acceptor (D–π–A) assemblies. This study evaluates the patented compounds meso-tris-p-carboxyphenyl porphyrin-fullerene (P-F) dyads, PB₃C₆₀ and PB₃C₇₀, and precursor PB₃OH within noncationic donor–π–acceptor (D–π–A) assemblies as amphiphilic photosensitizers (PSs) for glioblastoma photodynamic therapy (PDT). Emphasis is placed on light-induced apoptosis, mitochondrial disruption in glioma-derived cells, along with the already reported anti-HIV properties, indicating potential for dual-action therapy in immunocompromised individuals. Given the critical need for therapies effective in immunocompromised patients, further investigation into noncationic P-F dyads could yield dual-action agents. P-F dyads were administered to tumour-derived as well as nontransformed cells and subjected to PDT. PB₃C₆₀ exhibited the highest selective phototoxicity in gliomblastoma cells under PDT, inducing apoptosis with moderate ROS and mitochondrial fragmentation. PB₃OH caused nonspecific cytotoxicity via excessive ROS, while PB₃C₇₀ triggered apoptosis even without light. PB₃C₆₀ showed strong potential as a targeted photosensitizer for glioblastoma, with light-dependent selectivity for cancer cells. Unlike PB₃OH and PB₃C₇₀, its apoptotic effect was both specific and light activated, highlighting PB₃C₆₀'s promise as a nanohybrid therapeutic for glioblastoma.

Screening identified 2-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid (1) as a 55 µM dynaminGTPase inhibitor. Synthesis of three 1-based libraries shows no potency enhancement. However, S-isostere-based 3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (16) gives rise to Libraries 4–6. Library 4 retains the C6-ester of 1; only H-bond capable analogs (–OH, –CO₂H) improves dynamin inhibition (IC₅₀ < 20 µM), with C3′-CO₂H 17j returning an IC₅₀ = 1.3 ± 0.5 µM. N-methylation gives Library 5 and essentially removes activity. Most (>80%) of Library 6 analogs are dynamin active. Highest potency is noted with H-bond-accepting aromatic moieties: C3′-OAc 19p, C2′,C3′,C4′-tri-OAc 19r, and C3′,C4′-di-OMe 19y (IC₅₀ values of 5.1, 5.2 and 7.2 µM, respectively). A N,N-dimethylaminopropyl chain enhances activity with C4′-OH 19u to 21, but has no effect with C4′-OH 17u to 20. This may be due to compound remodeling within the active site to best align two of the three H-bond-donating groups (of 19u vs. 17u). There appears to be a minimum requirement of two H-bond donors. Combined this work has identified seven new analogs: C3′–CO₂H 17j, C2′–OH 17s, C3′,C4′-di-OMe 18y, C3′-OAc 19p, C2′,C3′,C4′-tri-OAC 19r, C3′,C4′-di-OMe 19y, and C4′-O(CH₂)₃NMe₂ 21 with dynamin IC₅₀ values of 1.3–10.0 µM. 118 compounds aresynthesized and screened.