ChemMedChem最新文献

A series of four titanium(IV) complexes based on asymmetric diaminobis(phenolato)-bis(alkoxo) ligands with different substitutions and acetyl functional groups was synthesized and characterized. All complexes were analyzed by ¹H NMR,¹³C NMR, and HRMS. Three complexes were analyzed by X-ray crystallography; interestingly, whereas two complexes were similar to previously published structures showing C₁ asymmetrical mononuclear octahedral coordination sphere, one structure of a bulky iodinated complex indicated formation of a unique pseudo-C₂ symmetrical hepta-coordinated dimer, where computational studies indicated mostly subtle solvent and temperature effects. High hydrolytic stability was recorded for all derivatives, with t_½ of more than 3 days for hydrolysis in 10% D₂O organic solutions, with enhanced solubility in PBS/DMSO (up to 0.25 mg/mL in <0.5% DMSO aqueous solution). All complexes were highly cytotoxic toward human ovarian A2780 and colon HT-29 cancer cell lines (IC₅₀ values in the range of 0.5–10 µM). Cellular uptake studies showed that the studied complexes possess marked membrane permeability, pointing to high potential as anticancer therapeutics.

Covalent organic frameworks (COFs) are an emerging class of porous organic polymers with a broad spectrum of possible applications because of their large void spaces and modular pores. Despite excellent cytocompatibility, porosity, and biodegradability of COFs, their practical implementations in nanomedicine have been limited due to low water dispersibility and poor processability into nanodimensions. There are limited reports on nanoscale covalent organic frameworks, which can exhibit excellent drug loading capacity and pH-responsive drug release. Herein, a water-dispersible 2D COF-based nanocarrier is reported for pH-responsive targeted delivery of therapeutics (doxorubicin) to cancer cells. Particularly, a hydrolytically susceptible boronate ester-based covalent organic framework (COF-5) is supramolecularly stabilized with an amphiphilic polymer, Pluronic F127 (PLU), to obtain COF-PLU nanoparticles with a size of ~185 nm and a thickness of ~25 nm. A high doxorubicin loading in the COF-based nanocarrier (>90% drug loading efficiency and ~35% drug loading capacity) and pH-responsive drug release are observed. Furthermore, the surface modification of Dox-loaded polymer-stabilized COF-5 with hyaluronic acid demonstrates selective delivery of doxorubicin to cancer cells. Our study demonstrates a facile strategy for developing a pH-responsive COF-based nanocarrier with excellent drug-loading capacity for targeted delivery of therapeutics to cancer cells.

Chagas disease and leishmaniasis are neglected tropical diseases with limited treatment options. This study reports a hit-to-lead optimization of morpholinephenylbenzamides, starting from hit 1, which showed potent activity against Trypanosoma cruzi (IC₅₀ 0.29–0.76 μM) and Leishmania infantum (IC₅₀ 10.7 μM), despite a suboptimal ADME profile. A structure–activity relationship study of twenty-four novel derivatives provided key pharmacophoric insights. While Trypanosoma cruzi was less susceptible to chemical modifications, compound 20 exhibited potency comparable to benznidazole (IC₅₀ 3.58 μM) with significantly improved selectivity, lipophilicity, and solubility relative to compound 1. Against Leishmania infantum, six derivatives maintained activity, with compound 24 showing a 1.5-fold potency increase IC₅₀ 7.6 μM). Additionally, compound 16 stood out for its superior ADME profile, including enhanced permeability and metabolic stability. These findings validate the morpholinephenylbenzamide scaffold as a robust class with dual antiparasitic activity.

The liver X receptor is a promising target for diseases with dysregulated cholesterol levels. In addition to enhanced reverse cholesterol transport, however, LXR activation induces hepatic lipogenesis. Since the subtype LXRα is dominant in the liver, one strategy to overcome this is the development of LXRβ-selective agonists. We optimized the reported compound 2 with efficacy-based preference for LXRβ by scaffold hopping to enhance potency and selectivity. Among the four different scaffolds, which were obtained from computer-assisted design and subsequent synthesis, compound 7 emerged as the most promising scaffold. The spiro[indan-1,4′-piperidine] scaffold of 7 demonstrated superior pharmacokinetic and pharmacodynamic properties, warranting its further investigation towards a pharmacological tool compound.

The continuous rise and spread of antimicrobial resistance poses a severe threat to global health and creates an urgent need for the development of new classes of antibiotics. One promising target is FabV, an enoyl-acyl carrier protein reductase that is crucial for the survival of certain pathogenic Gram-negative species such as the opportunistic nosocomial bacterium P. aeruginosa. Previously, our group investigated the structure–activity relationship of diaryl ether-based inhibitors of FabV and uncovered p-N,N-dimethylsulfamoyl phenyl substitution as a privileged motif, exemplified by compounds 1a (IC₅₀ = 0.25 μM) and 1e (IC₅₀ = 0.19 μM). In the present study, we explored skeletal modifications of the diaryl ether scaffold with the aim of improving aqueous solubility of the compounds while maintaining potent activity. Our efforts uncovered compound 6k (IC₅₀ = 0.53 μM), in which the alkyl chain is replaced by a 3-cyanocyclobutyl group and which shows a fivefold increase in kinetic solubility compared to the parent compound 1a. Similarly, benzene-to-pyridine replacement in the A-ring led to significant solubility gains with minimal loss of potency. These results showcase an effective strategy for optimizing solubility in inhibitors targeting enzymes with highly lipophilic natural substrates.

An expedited synthesis of 2-sulfonamido-substituted 4H-chromene derivatives via reaction between para-quinone methides and ynamides in the presence of triflic acid at room temperature is described. Most of the synthesized compounds displayed potent antiplasmodial activity against both the chloroquine-sensitive and -resistant strains of Plasmodium falciparum with a good selectivity index.

Castration-resistant prostate cancer relies on intratumoral androgen synthesis mediated by cytochrome P450 17A1 (CYP17A1). Treatment with the only clinically used CYP17A1 inhibitor, abiraterone, is limited by resistance and side effects, underscoring the urgent need for new CYP17A1 inhibitors with greater selectivity and improved safety profiles. In response to this challenge, we designed, synthesized, and biologically evaluated 30 novel piperidine derivatives. All compounds were initially screened in the H295R cell line to assess their inhibitory activity toward both CYP17A1 and off-target CYP21A2. Compounds were further evaluated in cell viability assays using prostate cancer cells and a normal prostate cell line. The most potent and selective compounds were subjected to further biological studies: IC₅₀ determination, steroid profiling, cell migration assay, aldo–keto reductase family 1 member C3 inhibition assays, absorption, distribution, metabolism, and excretion prediction, and solubility testing. Several compounds emerged as the most active and selective leads, highlighting their potential for pharmaceutical development.

Small molecules that simultaneously suppress nitric oxide (NO) and interleukin‑6 (IL‑6) offer a strategy to alleviate pathological inflammation. Building on our previous work with aryl‑substituted azaheterocycles, we synthesized 33 new pyrimidine and azolopyrimidine derivatives bearing amino, amide, hydroxyl, or halide groups to enhance hydrogen‑bonding capacity and improve inhibitory activity against both mediators. Screening in C57BL/6J mouse peritoneal macrophages identified nine compounds that markedly inhibited NO production at 50 µM. Two leads—triazolo[1,5‑a]pyrimidine 12bc and dihydropyrimidine carboxamide 7a—emerged as potent dual inhibitors. Compound 7a showed IC₅₀ values of 0.47 µM (NO) and 0.1 µM (IL‑6); 12bc gave 8.66 µM (NO) and 0.85 µM (IL‑6), both with acceptable cytotoxicity. In human PBMC‑derived monocytes, both compounds dose‑dependently suppressed LPS‑induced IL‑6 secretion; 12bc was slightly more potent, reducing IL‑6 to near‑baseline at 100 µM, comparable to dexamethasone. In an LPS/ATP pyroptosis model, they protected monocytes from inflammatory death, with 12bc nearly restoring normal cell morphology. Docking studies into mouse iNOS and IL‑6 suggested plausible binding modes and structure–activity relationships. These (azolo)pyrimidine scaffolds represent promising leads for safe, dual‑acting anti‑inflammatory agents.

Zhi et al. reported compound 36 as a potent reversible inhibitor of human recombinant monoacylglycerol lipase (hrMAGL; IC₅₀ = 15 nM) with excellent selectivity over other targets. To develop potential PET tracers for imaging MAGL, we synthesized compound 36 as a reference compound. Surprisingly, we observed a significant discrepancy between the reported potency and our findings in two well-established in vitro assays. Compound 36 exhibited no inhibition of endocannabinoid hydrolysis in HEK293 lysates overexpressing human MAGL in a glycerol-based assay at 1 μM. In the competitive ABPP assay, it appeared completely inactive inhibiting MAGL in mouse whole-brain proteome even at 100 μM. In addition, eight structural analogs (2–9) of compound 36 also failed to show any significant MAGL inhibition. Interestingly, when the synthetic substrate 4-nitrophenyl acetate, also used by Zhi et al., was employed, compound 36 inhibited MAGL more effectively than in glycerol-based assay, with an IC₅₀ value of 143 nM, being almost 10-fold less potent than reported. In our reversibility assay, compound 36 exhibited measurable MAGL inhibition only at a concentration of 100 μM. In summary, this study contradicts the earlier report and therefore, compound 36 should be used with caution as a research tool in studies exploring MAGL inhibition.

Hu antigen R (HuR), an RNA-binding protein implicated in cancer, inflammation, and neurodegenerative disorders, represents a challenging target for drug discovery due to its large solvent-exposed RNA-binding interface and pronounced conformational flexibility. HuR contains tandem RNA recognition motifs (RRM1 and RRM2) that undergo substantial rearrangements between an apo open state and an RNA-bound closed conformation. Here, we investigated both states using molecular dynamics (MD) simulations. While the RNA-bound complex maintained a stable closed architecture, the apo form displayed extensive interdomain motions, highlighting the intrinsic flexibility of HuR. Because conventional MD simulations failed to capture the open-to-closed transition, we developed a novel application of Supervised MD (SuMD), previously employed for intermolecular recognition processes, to characterize HuR intramolecular domain closure. Using a multistep supervision protocol based on selected interdomain residue pairs, SuMD reproduced a closed conformation resembling the experimental RNA-bound structure and identified a plausible reclosure pathway. Per–residue interaction analyses revealed key contributions from the RRM1–RRM2 linker region, particularly Arg97, together with Arg136 and Arg147 of RRM2, consistent with mutagenesis data. These findings extend the applicability of SuMD to intramolecular conformational transitions, provide mechanistic insight into HuR domain closure, and offer a structural framework for identifying druggable conformational states for future HuR-targeted drug discovery.