ChemMedChem最新文献

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.

Bufotenin (also spelt as bufotenine) and its methylated derivative, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), are potent psychedelics that are found in many plants but also excreted by some species of toads. The compounds are regulated differently around the world, and although used in traditional medicine, 20^th-century prohibition culture has slowed research into their utility for ameliorating psychological disorders and inflammatory and neurodegenerative diseases. However, the global trend toward legalization and a renewed interest in the therapeutic potential of psychedelics has increased the number of clinical and preclinical studies of these and related materials. This necessitates access to large amounts of these compounds, but they are not commercially available on scale, leaving researchers with a need to either contract out, or make their own. The first bufotenin synthesis was reported in 1935 by Hoshino and coworkers, and novel syntheses are still being disclosed in the 2020s. This is the first effort to collate and compare all extant academic and patent syntheses (as of fall 2024) into a single review so that researchers can identify the most appropriate route for their own purposes. We conclude by highlighting outstanding challenges that are ripe for solutions to reduce the cost of any future commercial-scale production.

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.

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.

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.

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.

Polydopamine (PDA)-based nanoparticles demonstrate significant potential for breast cancer photodynamic therapy and photothermal therapy, owing to their nanoscale dimensions and superior biocompatibility. However, their efficacy is limited by the tumor microenvironment and shallow near-infrared (NIR) laser penetration. In this study, we developed a novel nanoparticle system, MnO/Ce6@PDA, with a PDA core loaded with photosensitizer chlorin e6 (Ce6) and coated with manganese oxide (MnO) for synergistic PTT/PDT. Utilizing the photoresponsive properties of PDA and Ce6, along with the oxidative capacity of MnO, the nanoparticles demonstrated strong photothermal conversion and catalytic activity. Coating with tumor cell membrane (MnO/Ce6@PDA@CCM) preserved adhesion proteins such as integrins and cadherins, enabling homotypic targeting and tumor-specific accumulation. Under NIR laser irradiation at different wavelengths, the nanoparticles generate significant amounts of reactive oxygen species and singlet oxygen, resulting in the death of tumor cells via mitochondrial and cell membrane damage. The release of Mn²⁺ ions during tumor microenvironment-responsive degradation not only enhanced T1-weighted magnetic resonance contrast, but also potentiated chemodynamic therapy via Fenton-like reactions, enabling real-time imaging-guided combinatorial antitumor efficacy.

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.