ChemMedChem最新文献

Many studies have pointed to GABA-A receptors as a promising therapeutic target for promoting recovery after stroke, owing to their neuroprotective efficacy and the enhancement of synaptic GABAergic currents. However, identifying nanomolar-affinity ligands that evade P-glycoprotein-mediated efflux can pose a significant challenge. To overcome this barrier, we developed a structure-based machine learning workflow integrating molecular docking, which screened over 160 000 virtual analogs and identified eight synthetically accessible molecules. The synthesized compounds exhibited K_i values at the GABA-A receptor ranging from 50 to 1600 nM, with the most promising being 4d (K_i = 62 ± 11 nM) and 4h (K_i = 50 ± 3 nM), both of which confirmed PAM efficacy at GABA-A receptors. Both ligands exhibited neuroprotective activity by attenuating glutamate-induced Ca²⁺ overload, preserving mitochondrial membrane potential and enhancing cell viability following oxygen-glucose deprivation in HT-22 neurons. In MDR1-MDCKII bidirectional assays, compound 4d (azetidine derivative) exhibited symmetric permeability (efflux ratio = 0.94), while 4h (bicyclic amino alcohol) was identified as a P-gp substrate (efflux ratio = 2.04), suggesting that eliminating a single hydrogen-bond donor at the amide tail is critical for minimizing efflux. Collectively, this study identifies compound 4d as a potent, low-efflux GABA-A receptor PAM with neuroprotective properties, supporting its further investigation.

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.

Lung cancer remains a leading cause of cancer-related mortality worldwide, underscoring the need for novel therapeutic strategies. In this study, three hydroxamic acids derived from L-cysteine are synthesized to explore their biological dual effect as Glyoxalase 1 (Glo-1) inhibitors and ferroptosis inducers. Among the synthesized derivates, compound 2 exhibited the highest inhibitory potency against Glo-1 and is the most potent compound against nonsmall cell lung cancer cell lines. For this compound, an increase in intracellular reactive oxygen species (ROS), depletion of intracellular reduced glutathione (GSH) levels, and induced morphological changes is observed that correspond to ferroptosis. Furthermore, these effects are reversed by Liproxstatin-1, a potent and selective ferroptosis inhibitor. Acute and subacute toxicological assays in mice showed mild toxicity (LD₅₀ > 2000 mg kg^-1) and moderate organ damage. These in vitro and in vivo findings suggest that ferroptosis induction may serve as a side effect of Glo-1 inhibition, making compound 2 a promising lead for further development and optimization.

As a continuation of the project aimed at searching for new chemotherapeuticagents against Chagas disease or American trypanosomiasis, new selenocyanate derivatives are designed, synthesized, and biologically evaluated against the clinically more relevant dividing amastigote form of Trypanosoma cruzi, the etiologic agent of this illness. Furthermore, as all the title compounds are fluorine-containing molecules, it seemed to be reasonable to explore the role of fluorine atoms in the aromatic system and to determine the optimal position at the terminal phenoxy group, and therefore, various regioisomers are prepared. The conformationally restricted selenocyates structurally related to WC-9Se exhibited improved antiparasitic activity compared to the lead drugs, Out to be extremely potent inhibitors of T. cruzi growth. In particular, (±)-5-(3-fluorophenoxy)-2-(selenocyanatomethyl)-2,3-dihydrobenzofuran exhibited an EC₅₀ value of 0.032 µM, which resulted in the most potent selenocyanate developed in the laboratory. The presence of the fluorine atom together with the rigidity of the molecules are beneficial for the anti-T. cruzi effect. The resulting antiparasitic activity provides further insight into the role of the selenocyanate group in its effective and putative anti-T. cruzi action.

Modern drug discovery faces high rates of clinical attrition, more challenging therapeutic targets, increasing molecular complexity, and rising research and development costs. These challenges are not only due to greater scientific risk, but also the way that organizations leverage drug discovery knowledge. It is believed that effective knowledge sharing-both tools and culture-is core infrastructure that can increase the probability of success. Readily accessible knowledge hubs built on familiar software (OneNote + SharePoint → "OnePoint") and enterprise wikis (Pfizerpedia) scale well because information capture happens during daily work, not outside it. Chemistry-focused platforms, such as Roche's system based on brief "knowledge slides," turn tacit insights into reusable design precedent. At AstraZeneca, a MediaWiki-based Compound Design Database (CDD) tied to quantitative structure-activity relationship (QSAR) models and explicit tracking of the design-make-test-analyze (DMTA) cycle cut idea-to-compound time by 50% through synchronizing design and synthesis. Codifying heuristics (e.g., Drug Guru's 186 rule-encoded transformations) institutionalizes expert playbooks while training newer chemists. Furthermore, it is discussed how the durable impact of knowledge sharing depends on human systems (networks, incentives, curated "push" updates, and embedded workflows), as well as curated external knowledge streams that supply early competitive signals and context for action.

Following up on the discovery of multiple series of GPR39 antagonists via high-throughput screening (HTS), appropriate hit expansion and medicinal chemistry efforts lead to the identification of potent and selective GPR39 antagonists. Among these, compound 61 emerges as the front runner of this series, demonstrating high potency, appropriate physicochemical properties governing systemic exposure, in both rat and dog, and the absence of undesired off-target pharmacology such as cardiac ion channels (i.e., hERG, hNav1.5, and Cav1.2). In vivo evaluations show compound 61 to be a selective coronary vasodilator that reduced no-reflow and infarct size in a rodent model of ischemia-reperfusion. This first-in-class drug demonstrates the benefit of GPR39 inhibition in myocardial ischemia.

Focal adhesion kinase (FAK) has emerged as a promising therapeutic target for cancer owing to its key roles in the development and aggressiveness of tumor malignancy. However, exploring the clinical translation of FAK inhibitors has been recently hindered by their lack of selectivity and specificity for cancer cells. In this study, the synthesis and biological evaluation of a trimeric β-glucuronidase-responsive albumin-binding prodrug programmed for the selective delivery of a potent FAK inhibitor within solid tumors are reported. When activated by β-glucuronidase, a glycosidase overexpressed in the microenvironment of numerous tumors, this prodrug induces a remarkable inhibition of breast cancer cell (MDA-MB-231) growth with an IC₅₀ value of 0.63 ± 0.02 μM. Furthermore, mechanistic studies show that upon enzymatic activation, the prodrug delays cell cycle progression by arresting cells in the G2/M phase. These results indicate that our delivery strategy may be applied as a promising new FAK-targeted therapy for cancer.

Complexes are emerging as promising alternatives for the treatment of neglected parasitic and viral infections, which urgently require new therapeutic strategies due to limited effective drugs. In this study, a series of [Pt(II)(phpy)(PR₃)Cl] complexes, where phpy is 2-phenylpyridine, and PR₃ represents triphenylphosphine (PPh₃), 1,3,5-triaza-7-phosphaadamantane (PTA), para-benzoic acid-diphenylphosphine (PPh₂(Php-COOH), or tris(2-carboxyethyl)phosphine (TCEP), are synthesized and systematically evaluated for their chemical properties and in vitro biological activities. Chemical reactivity, including ligand exchange with L-histidine and N-acetylcysteine, hydrophilic/lipophilic balance, and interactions with bovine serum albumin (BSA) and DNA, was correlated with biological outcomes. The novel TCEP complex exhibited exceptional chloride stability and intrinsic fluorescence but lacked antiviral and antileishmanial activity. The PTA derivative showed selective antileishmanial activity, achieving a selectivity index (SI) of 10.8 and reducing the infectivity index by 40% at 12 µM. Also, PTA showed selective antitumor activity in ovarian cancer (SI 9.1). In contrast, the PPh₂(Php-COOH) derivative demonstrated significant antiviral activity, inhibiting Mayaro virus and Zika virus replication by 94% and 78%, respectively, at 50 µM. These findings underscore the potential of coordination chemistry to fine-tune biological activity and support the rational design of metal-based therapeutics for neglected diseases.

Human elastase 1 has been shown to possess an important role in maintaining skin stability and elasticity through the proteolytic cleavage of elastin (ELN), a hydrophobic protein that serves as a key component of extracellular matrix in the skin. The development of antielastase agents represents a promising therapeutic approach for treating skin pathologies characterized by elastin degradation, with applications in both dermatology and cosmetology. Reversible inhibitors represent a therapeutic strategy, offering selective inhibition of elastase proteolytic activity while preserving the function of other physiologically essential serine proteases. Using porcine pancreatic elastase (PPE) as a well-established surrogate of human skin elastase, a focused series of noncovalent inhibitors designed to bind the catalytic area of PPE is assayed. Several compounds display an antielastase activity, including N-(2-bromophenyl)-2-(6-chloro-1-(3,5-dimethylbenzyl)-1H-benzo[d]imidazol-2-ylthio)acetamide (7) that exhibits the most potent inhibitory effects (IC₅₀ = 41.1 µM), similar to standard compound oleanolic acid (IC₅₀ value of 25.7 µM). The observed structure-activity relationship is further validated through molecular docking and dynamic studies, which provide mechanistic understanding of the binding interactions and establish suggestions for further rational drug design.

The cover art depicts a novel chemotype of azolopyrimidine-6-carbonitriles as antiproliferative compounds. A fence represents a non-selective compounds that protect sheep (normal HEK-293 cells) against wolves (cancer cells), whereas a shepherd is selective against A-172 cell line and shepherd dog is selective against T-24 cells with CDK2 as plausible target. Two «wolves in sheep’s clothing» represent compounds with cytotoxicity against HEK-293 cells only. The sheep side is purple and wolf side is yellow according to MTT assay colors. More details can be found in the Research Article by Konstantin V. Savateev and co-workers (DOI: 10.1002/cmdc.202500535).