ChemMedChem最新文献

The Farnesoid X receptor (FXR) is a bile acid-activated nuclear receptor that represents an important therapeutic target for gut-liver diseases and metabolic disorders. Recently, FXR partial agonists have gained attention for their potential to minimize side effects resulting from receptor over-activation. In this study, we report the design, synthesis, and biological evaluation of novel obeticholic acid (OCA) derivatives as selective FXR modulators. Structural modifications at the C3α position and the side chain of the bile acid scaffold led to the identification of valine derivatives 2 and 16 as metabolically stable and safe FXR modulators with reduced agonist efficacy. Further molecular dynamics simulations revealed that these compounds induce distinct conformational changes within the FXR ligand-binding domain, consistent with their partial agonist behavior and resulting in moderate modulation of FXR target genes. Unlike OCA, both compounds failed to activate other steroid-responsive receptors, including MRGPRX4 (hX4), a G-protein-coupled receptor implicated in itching in cholestatic patients, supporting their potential as safer FXR modulators with a reduced risk of pruritus-related side effects. Overall, this study elucidates key structure–activity relationships governing FXR partial agonism and hX4 binding and offers valuable chemical tools for the development of FXR-targeted therapeutics with improved safety profiles.

Urease is a metalloenzyme produced by a wide range of organisms and plays a critical role in nitrogen microbial metabolism by catalyzing the hydrolysis of urea into ammonia and carbamic acid. High urease activity can lead to excessive ammonia levels, causing nitrogen loss from the soil, and also contributes as a virulent factor in some human pathogenic infections. Given its impact, urease inhibition has garnered significant attention in agriculture, environmental sciences, and medicine. Despite efforts to develop potent and selective inhibitors, discovering new agrochemicals and drugs faces significant challenges due to chemical and metabolic stability, lack of selectivity and toxicity, typically seen in urease inhibitors. As a result, extensive chemical diversity has been reported for urease inhibition and can lay the foundation for designing new inhibitors. Previous structure–activity relationship analyses have mainly focused on small subsets of compounds, leaving a broader comprehensive understanding across all known classes yet to be described. In an effort to support new exploratory strategies, this review provides a complete overview of the chemical landscape in urease inhibitors, covering more than 8000 compounds. We discuss current challenges, the biological and practical implications of urease inhibition and highlight potential scaffolds associated with activity. By exploring the diversity of reported inhibitors, we aim to identify broad activity patterns and gain deeper insights into activity relationships that govern inhibitory efficacy, paving the way for the future directions of finding new classes of urease inhibitors.

Ketamine, a rapid-acting N-methyl-D-aspartate (NMDA) receptor antagonist, has therapeutic potential beyond anesthesia, including treatment-resistant depression. However, its low oral bioavailability due to extensive first-pass metabolism and high abuse potential limit outpatient use. This study describes the design, synthesis, and in vivo evaluation of a ketamine prodrug conjugated to tyrosine methyl ester via a hydrolytically sensitive tertiary carbamate linker to improve oral absorption, achieve sustained release, and reduce abuse risk. The prodrug displayed moderate aqueous solubility and good chemical stability at physiological pH but was rapidly metabolized in enzyme-containing media via demethylation of the tyrosine methyl ester to a demethylated prodrug, with no detectable ketamine release in vitro. In vivo pharmacokinetic studies in mice demonstrated that the prodrug underwent rapid metabolic conversion, resulting in detectable, though low, levels of released ketamine in plasma, liver, and brain. However, ketamine release was limited, and oral administration yielded very low bioavailability. These findings indicate that while tertiary carbamate-based prodrugs can undergo in vivo activation, the current design does not sufficiently promote ketamine release or systemic exposure. Further structural optimization is required to improve oral bioavailability and achieve therapeutically meaningful delivery of ketamine.

Bearing the increase in antimicrobial resistance as well as the emergence of novel viruses with pandemic potential in mind, it is obvious that development pathways need to be accelerated further. At the same time, attrition risks need to be minimized to allow that drugs reach the patient. For successful translation of novel anti-infectives, several obstacles have to be overcome. This article illustrates recent developments and advances on pharmacokinetic (PK)/pharmacodynamic (PD) methods that can be employed to optimize preclinical development. It specifically emphasizes PK/PD considerations not only for classical antibacterials and antivirals but also for novel approaches, such as proteolysis-targeting chimers, click-to-release systems, or anti-virulence concepts. Particularly, the latter, nontraditional anti-infective solutions pose novel challenges for PK/PD, as development pathways are not yet straightforward. Thus, this article also aims to provide ideas on how to tackle challenging PK/PD aspects of nontraditional anti-infectives, taking advantage and inspiration from traditional development pathways.

Two series of [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine derivatives have been synthesized and evaluated for their antitumor activities. These compounds exhibit potent antiproliferative activities against A549 and H460 cells and c-Met kinase inhibitory activities. Five compounds are highly effective against A549 and H460 cells with IC₅₀ values in 2.97–16.50 μM (the mean ± SD value of three independent determinations). Molecular docking is further performed to study the inhibitor–c-Met kinase interactions, and the results show that compound 3a is potently bound to the c-Met kinase with three hydrogen bonds, one π---π, and one CH---π interactions. Based on the preliminary results, it is deduced that compound 3a with potent c-Met kinase inhibitory activity may be a potential anticancer agent.

Cancer caused 9.9 million deaths in 2020, and natural products and/or their structural analogs represent the greatest number of approved small-molecules antitumor agents. Benzopyran and quinoline heterocycles have demonstrated cytotoxic activity against different cancer cell lines. Due to its high therapeutic potential, we report the synthesis of 2-propanamide- and 2-propanamine-dihydrobenzopyrans bearing different amine moieties in the side chain, as well as the 7-carbon prenylated derivatives (analogous to natural polyalthidin). Next, we synthesized the 2-substituted and 2,3-disubstituted quinolines as benzopyran analogs. We evaluated the cytotoxic activity of all nitrogenated derivatives against human cancer cell lines, including A549 (lung cancer), A2058 (melanoma), HepG2 (hepatocellular carcinoma), MCF-7 (breast cancer), and Mia PaCa-2 (pancreas cancer) by the MTT assay. Structure–activity relationship analysis revealed: (i) the benzopyran core was twofold more cytotoxic than quinoline analogs and reached ED₅₀ values in the low micromolar range (ED₅₀ < 10 μM) against A2058, HepG2, and MCF-7; (ii) benzopyran amides showed higher cytotoxicity than benzopyran amines against MCF-7, and afforded better results for studied lines except for Mia PaCa-2; and (iii) the amine moiety introduced at 2-position played a key role for activity; (iv) benzyl and p-fluorobenzyl substituents protecting phenol group at 6-position afforded a similar cytotoxicity.

Polymer-drug conjugates (PDCs) are a promising strategy to enhance the delivery of poorly soluble drugs, particularly in cancer therapy. By improving solubility and enabling site-specific accumulation, PDCs minimize systemic toxicity while maximizing therapeutic efficacy. PDCs often employ stimuli-responsive linkers, such as Schiff's bases, to achieve controlled drug release in tumor microenvironments or acidic intracellular compartments. In this study, we designed a novel PDC by conjugating the anticancer agent farnesal (Far) to ∈-Poly-L-Lysine (PL) via an imine bond, without using additional linkers. PL is a natural, biodegradable, water-soluble polymer with inherent anticancer properties, while Far is a hydrophobic isoprenoid with potent antitumor activity. The conjugate (Far-PL) displayed pH-responsive behavior, remaining stable at physiological pH but releasing drugs under acidic tumor (pH 6.5) and endosomal (pH 5.5) conditions. Far-PL exhibited enhanced cytotoxicity against A549 lung cancer cells compared to its components alone, while showing reduced toxicity towards noncancerous cells (Arlo cells). The amphiphilicity allows the conjugate to self-assemble into stable nanoparticles with a positive surface charge, narrow size distribution, and 100% drug content—clearly exceeding conventional nanoparticles (5–10 wt%). This effective PDC design demonstrates strong potential to maximize tumor-selective activity while minimizing off-target effects, offering a promising platform for future cancer therapeutics.

Described herein are the design, synthesis, and preliminary antimicrobial evaluations of fluorinated pyrrolidine analogs of the potent antiparasitic agents: febrifugine and halofuginone. Molecular modeling is used to confirm that this “isosteric” replacement of a 3-hydroxy with a 3-fluoro group might be well tolerated at the most widely reported molecular target of this compound class, prolyl-tRNA synthetase. The synthesis of the fluorinated analogs is then detailed including the separate preparation of both the trans−2,3- and cis−2,3-diastereomeric forms. These synthetic compounds are subsequently assessed for their ability to inhibit the growth of pathogenic fungi (C. albicans and F. graminearum) and representative Gram-positive and Gram-negative bacteria (Bacillus sp. CS93 and E. coli). Notably, the 3-fluoro halofuginone analog has anti-C. albicans activity at levels comparable to the natural product iturin A.

Eukaryotic mRNAs made by in vitro transcription have emerged as medical modalities for vaccination and protein replacement therapy. The 5′ cap is an essential feature of eukaryotic mRNAs providing stability, reducing immunogenicity, and serving as starting point for translation initiation. The “cap epitranscriptome” comprises several natural 5′ cap modifications that can impact mRNA interactions and fate. Manipulating this privileged structure provides a powerful handle to optimize mRNA properties and to build a toolbox for investigating and controlling mRNA-related processes. In this article, the impact of natural 5′ cap modifications on mRNA translation, immunogenicity, and stability is highlighted. Then, it is shown how non-natural 5′ cap modifications have been used to manipulate and optimize various mRNA properties. Finally, non-natural modifications can equip mRNA with reactive handles, which provide a toolbox for studying interactions and controlling the function of mRNAs.

An efficient and feasible method has been developed for the synthesis of spirooxindole-tetrahydrocarbazole (SOTC) derivatives via AlCl₃-catalyzed cascade approach. This one-pot protocol enables rapid access to structurally diverse spiro-fused carbazole scaffolds, which are of significant interest in medicinal chemistry. The reaction proceeds under mild conditions, offering a broad substrate scope with excellent yields. A library of 28 novel compounds is synthesized and evaluated for anticancer activity using in vitro cytotoxicity and in silico molecular docking studies. Among them, nine compounds exhibit >50% growth inhibition in A549 lung cancer cells, and compound 8 shows the highest cytotoxic activity with an IC₅₀ value of 69.5 µM (A549). Additionally, three compounds demonstrate cytotoxic activity in SKOV3 ovarian cancer cells. These results highlight the potential of SOTC scaffolds as promising leads for further anticancer drug development. Taken altogether, the combination of synthetic efficiency, in silico evaluation, and anticancer activities will pave the way for these compounds to act as promising candidates for anticancer drug development.