ACS Medicinal Chemistry Letters最新文献

The global rise of multidrug-resistant bacteria has prompted an urgent need for new antibiotics, yet resistance continues to outpace discovery due to Gram-negative barriers, drug permeability issues, and limited industry investment. In this study, we synthesized a series of 1-hydroxypyridin-2(1H)-one derivatives targeting Pseudomonas aeruginosa for analyses of antibacterial efficacy. Among these, LP07 displayed potent antibacterial activity across multiple strains, enhanced by subinhibitory colistin. Scanning electron microscopy suggested membrane-associated morphological changes, including surface collapse, shrinkage, and irregular cell shape, consistent with bactericidal effects. Safety profiling showed low CYP inhibition, minimal hERG liability, and no mammalian cytotoxicity. Taken together, LP07’s whole-cell activity and observed membrane effects support its promise as a lead for further optimization.

The dysregulation of the mesenchymal-epithelial transition factor (c-MET) signaling pathway is linked to the development and drug resistance of non-small cell lung cancer (NSCLC), highlighting the need for small-molecule inhibitors targeting c-MET. In this study, we identified six potential c-MET inhibitors from a compound library using structure-based and AI-based virtual screening. Four compounds demonstrated c-MET inhibitory activity, with compound 2 exhibiting potent inhibition at an IC₅₀ of 40.1 nM. Further studies showed that compound 2 effectively inhibited NSCLC cell proliferation, comparable to that of positive controls. ADMET predictions indicate favorable drug-like properties, suggesting its potential as a novel c-MET inhibitor. Molecular dynamics simulations revealed that compound 2 stabilizes its conformation through interactions with Ala1221, Pro1158, and Lys1110, providing valuable insights for further drug development.

Tubulin inhibitors, such as taxanes and vinca alkaloids, target the microtubule and are limited by multidrug resistance, toxicity, and myelosuppression. Phenylahistin derivatives, a natural marine product, exert an anticancer effect by depolymerizing microtubules and disrupting vasculature and treat chemotherapy-induced neutropenia by activating GEF-H1, which binds to the colchicine site. To discover new phenylahistin derivatives, 24 novel furan-type phenylahistin derivatives were designed and synthesized by replacing the 1,3-imidazol-4-yl group with furan-type substitutions. Antitumor proliferation screening showed that 10u (16 nM) and 10v (21 nM) were more effective than plinabulin (26 nM). Compounds 10u and 10v induced cell death through the mitochondrial pathway. Compounds 10u and 10v also induced cancer cell apoptosis by inhibiting Bcl-2, upregulating P53, reducing mitochondrial membrane potential, and elevating ROS levels, disrupting microtubule networks, inducing G2/M arrest, and promoting apoptosis via caspase-3 activation. And molecular docking revealed that the furan-based derivatives formed important bonds with β-tubulin.

The 5-HT2A and 5-HT2C receptors are key therapeutic targets for CNS disorders. We investigated whether a nonhallucinogenic dual 5-HT2A/5-HT2C agonist could offer novel treatment potential. Large screening of in-house structurally diverse compounds revealed centhaquin, an FDA-approved hypovolemic shock drug, as a selective 5-HT2C agonist (EC50: 35 nM). We then synthesized 22 aza-aryl analogs with modified piperazine groups, and identified two dual agonists, 3ci and 3dh (EC50 < 1 μM), with no 5-HT2B activity up to 10 μM. Molecular docking highlighted critical interactions with Ser159 (5-HT2A) and Ser138 (5-HT2C) on the upper side of the orthosteric binding pocket. Pharmacokinetic studies in mice demonstrated that 3ci was rapidly absorbed in the plasma and brain (T_max = 0.08 h; C_max = 936.4 ng/mL plasma, 2446.8 ng/g brain). Both compounds (3ci and 3dh, 20 mg/kg, i.p.) triggered a head-twitch response but were less potent than the hallucinogenic control 2,5-dimethoxy-4-iodoamphetamine, suggesting a reduced hallucinogenic liability. These results highlight 3ci as a promising lead for developing 5-HT2A/2C dual agonists to treat CNS disorders.

Hypertension is implicated in the highest number of deaths worldwide. Despite awareness of its complications and the availability of several antihypertensive treatments, hypertension remains poorly controlled, often due to adverse effects that can hinder adherence. Angiotensin-converting enzyme (ACE), a key enzyme of the renin-angiotensin system (RAS), is an important therapeutic target. Bioactive peptides have been extensively researched for their biological activities, including their antihypertensive potential. Here, we describe two novel peptides, MSFLEHFLELK (PepDB_AHP1) and VWTNCYHLYPAH (PepDB_AHP4). Both peptides interact with residues at ACE’s active site, such as His353, Ala354, and Val380. IC₅₀ values were 331.2 and 88.63 μM, respectively. These peptides may serve as models for further optimization aimed at the development of novel ACE-inhibitory drugs.

CDK-based PROTAC therapeutics are a promising new approach in oncology. In this microperspective, we summarize the landscape of anticancer PROTAC development targeting the CDK family as of 2024. We discuss the applications and outcomes of computational screening, alternative degradation strategies, different linkers, SAR, and the use of new E3 ligases. Finally, we explore the potential to enhance pharmacokinetic properties through the incorporation of different linkers in heterobifunctional molecules.

Provided herein are novel substituted 1,1′-biphenyl compounds as glucagon receptor agonists, pharmaceutical compositions, use of such compounds in treating type 2 diabetes mellitus and obesity, and processes for preparing such compounds.

This study reports the synthesis, cytotoxic evaluation, and mechanistic insights of an amphiphilic triamino glycosylated antitumor ether lipid (GAEL). A series of aryl-substituted tricationic d-galacto-GAELs were synthesized to mimic cationic amphiphilic drug (CAD)-like structural characteristics. Among the series, the quinoline-bearing triamino GAEL (compound 17) exhibited the highest cytotoxicity in 2D cultures against drug-sensitive and drug-resistant ovarian, breast, pancreatic, liver, prostate, and brain cancer cells, completely eliminating all cells, whereas cisplatin and doxorubicin were less effective. GAEL 17 also demonstrated superior efficacy in an SK-OV-3 3D tumor spheroid model, fully disintegrating spheroids and inducing cell death at concentrations ≥25 μM. In contrast, doxorubicin reduced viability but did not eradicate spheroids at 50 μM, likely due to slower drug action or limited penetration over 48 h exposure. GAEL 17 retained caspase-independent, non-apoptotic cell death. LysoTracker assay indicated lysosomal disruption, while LipidTOX staining showed dose-dependent fluorescence, consistent with CAD-like lipid accumulation.