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.

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.

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.

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.

Treatment of neovascular eye diseases like age-related macular degeneration require a compound that is not toxic to ocular cells, that can reduce inflammation and inhibit angiogenesis. Homoisoflavonoids, naturally occurring compounds isolated primarily from the Hyacinthaceae sub-family of plants, have shown promise as anti-inflammatories and inhibitors of angiogenesis. A series of sulphur analogues, (3-benzylidene thiochroman-4-ones), were synthesised via a three-step procedure. These compounds were evaluated for selectivity towards endothelial cells over non-endothelial cells and their ability to inhibit COX-II over COX-I.Their potential anti-angiogenic activity was assessed using the Matrigel tube formation assay. (3Z)-3-[(3-bromophenyl)methylidene]-6-methoxy-2,3-dihydro-4H-1-benzothiopyran-4-one (10) was most active with respect to anti-proliferation against human retinal endothelial cells (HREC cells) (GI₅₀ 3.07 μM). All demonstrated selectivity with all GI₅₀ values against retinal pigment epithelial cell line ARPE-19 >100 µM, with the exception of (3Z)-6-bromo-3-[(4-nitrophenyl)methylidene]-2,3-dihydro-4H-1-benzothiopyran-4-one (12), which was not toxic to either. (3Z)-3-[(3-bromophenyl)methylidene]-6-methoxy-2,3-dihydro-4H-1-benzothiopyran-4-one (10) showed significant reduction in angiogenesis properties in a Matrigel-based tube formation assay (38.79%, 5 µM, 56.41%, 10 µM). (3Z)-6-bromo-3-[(3-bromophenyl)methylidene]-2,3-dihydro-4H-1-benzothiopyran-4-one (7) was found to be the most active against COX-II with inhibition of 22.7 % (4.35 nM). The 3-benzylidene thiochroman-4-ones show promise as antiangiogenic agents, but limited selectivity to COX-II over COX-I.

Drug repurposing and repositioning are concepts that involve identifying alternative therapeutic uses for existing drug candidates or molecular series. During the COVID-19 pandemic, hundreds of antivirals were developed, many of which remain unexplored for other diseases. Concurrently, machine learning (ML) has become a valuable tool in early drug discovery for screening the most promising compounds for a target. In this work, an ExtraTrees ML model is developed to predict inhibitory activity against cruzain, the main cysteine protease of Trypanosoma cruzi, the causative agent of Chagas disease. The model is used to screen a proprietary library of peptidomimetic compounds originally designed to target SARS-CoV-2 M^pro and human cathepsin L. High-affinity cruzain inhibitors are identified, some containing P1 moieties not previously reported in cruzain inhibitors, expanding the known chemical space for this target. Selected hits are validated using isothermal titration calorimetry and some compounds display more favorable enthalpic and entropic contributions to binding than similar peptidomimetic nitrile-based inhibitors. Notably, this is achieved without highly lipophilic R-groups, preserving drug-like properties. This work also highlights how compound libraries derived from global health efforts can be effectively repurposed for neglected tropical diseases with ML models.

Factor VIIa (FVIIa) catalyzes the first step of the blood coagulation cascade. The expected wide therapeutic window between antithrombotic efficacy and bleeding risk makes FVIIa an attractive drug target. However, no FVIIa inhibitors have reached the market so far, mostly due to poor oral bioavailability. To date, in all ligand-bound X-ray crystal structures of FVIIa, the binding pocket of FVIIa is in an active, open form. Here, we present an X-ray crystal structure of the FVIIa–tissue factor complex with a bound oxazole-based inhibitor at 1.9 Å resolution, with an extensively remodeled active site and a collapsed S1 pocket. Using collectively 0.17 ms of atomistic molecular dynamics simulations, we observed conformational transitions between the collapsed and open forms of the S1 pockets of FVIIa and 12 other serine peptidases out of 16 studied, indicating an equilibrium of open and collapsed states of the S1 pocket in FVIIa and the majority of the serine proteases studied. Therefore, our results point to a general S1 pocket plasticity, which provides the basis for a completely new way of inhibiting FVIIa and other serine proteases.