ChemMedChem最新文献

Fluorescence detection of DNA and RNA G-quadruplexes (G4s) is a very efficient strategy to assess not only the existence and prevalence of cellular G4s but also their relevance as targets for therapeutic interventions. Among the fluorophores used to this end, turn-on probes are the most interesting since their fluorescence is triggered only upon interaction with their G4 targets, which ensures a high sensitivity and selectivity of detection. We reported on a series of twice-as-smart G4 probes, which are both smart G4 ligands (whose structure is reorganized upon interaction with G4s) and smart fluorescent probes (whose fluorescence is turned on upon interaction with G4s). The fine mechanistic details behind the excellent properties of the best prototype N-TASQ remain to be deciphered: to investigate this, we report here on the synthesis and studies of two analogues, ^TzN-TASQ and ^AlkN-TASQ, and on a careful analysis of their G4-interacting properties, investigated both in vitro and in silico. Our results show that fine-tuning their constitutive structural elements allows for increasing the efficiency of both their 'off' (i. e., a conformation with a low fluorescence) and 'on' states (i. e., a conformation with a high fluorescence), which opens interesting ways for the design of more efficient fluorogenic G4 probes.

Deuterated drugs, which are derived from the subtle exchange of a protium atom with a deuterium atom in drug molecules, exhibit significant differences in pharmaceutical characteristics compared to their parent drugs. With the advantages of improving pharmacokinetic properties, reducing toxicity, inhibiting the interconversion between chiral drugs and restricting drug interactions, deuterated drugs have attracted widespread attention from medicinal chemists. This review highlights the application of deuteration strategies in drug design, summarizing the progress of all deuterated drugs available in the market or still under investigation to provide a reference for all researchers engaged deuterated drug development.

The pro-inflammatory cytokine interleukin-17A (IL-17) plays an important role in the body's defense against bacterial and fungal infections. However, overexpression of IL-17 has been associated with several diseases, including rheumatoid arthritis, asthma, psoriasis, and even cancer. The role of IL-17 in psoriasis has been confirmed by clinical use of IL-17 antibodies, e. g. secukinumab (Cosentyx^®). Ongoing research is focused on discovering low molecular weight IL-17 inhibitors. In this publication, we present thiazole-based IL-17 inhibitors discovered through a scaffold-morphing strategy. This strategy involved ring-opening of a known scaffold and utilization of a chalcogen interaction between thiazole-sulfur and central amide-oxygen to maintain the coplanar conformation found in the parent compound. The new scaffold enabled the generation of highly potent compounds with good overall profile. The optimized compounds 11 and 15 demonstrated good exposure in rats after oral dosing. Importantly, compound 11 exhibited no adverse effects in a rat tolerability study after a four-day administration of up to 300 mg/kg/day.

Butyrylcholinesterase plays an indispensable role in organisms, and its abnormal expression poses a significant threat to human health and safety, covering various aspects including liver-related diseases, diabetes, obesity, cardiovascular and cerebrovascular diseases, and neurodegenerative diseases. In addition, toxic substances such as organophosphorus and carbamate pesticides markedly inhibit BChE activity. BChE activity serves as a critical parameter for the clinical diagnosis of acute organophosphorus pesticide poisoning and the evaluation of organophosphorus and carbamate pesticide residues. Therefore, the accurate and reliable detection of butyrylcholinesterase activity is particularly urgent and important for in-depth analysis of its biological function, diagnosis and therapy of related diseases, drug screening and sensitive detection of pesticide residues. Fluorescent probes have become a promising tool for sensing and imaging of butyrylcholinesterase, due to its advantages of high spatio-temporal resolution, high selectivity, non-invasive, high sensitivity, and tailored molecule structures. Here, this paper provides a comprehensive overview of the research progress in the sensing, imaging and therapy of butyrylcholinesterase utilizing fluorescent probes. This paper might be a useful guideline for researchers to design new high-performance fluorescence probes for BChE, and making further contributions to this intriguing field.

Tinoco A-Team Deferasirox (Def), an orally administered iron-chelating drug, has drawn significant interest in repurposing for anticancer application due to the elevated Fe demand by cancer cells. But there are also concerns about its severe off target health effects. Herein Cu(II) binding is studied as a potential off target interaction. The aqueous solution stability and speciation of the ternary complex Cu(Def)(pyridine) was studied by UV-Vis and EPR spectroscopy, ESI-mass spectrometry, and cyclic voltammetry under physiologically relevant conditions. The complex is observed to be a redox active, mononuclear Cu(II) complex in square planar geometry. UV-Vis spectroscopy demonstrates that at pH 7.4 the complex is quite stable (ϵ_337nm=10,820 M^-1 cm^-1) with a log K=16.65±0.1. Cu scavenging from the Cu transporters ceruloplasmin and albumin was also studied. Def does not inhibit ceruloplasmin activity but forms a ternary Cu(II) complex at the bovine serum albumin ATCUN site. Cu(Def)(py) displays potent but nonselective cytotoxicity against A549 cancer and MRC-5 noncancer lung cells but the potency of the ternary protein complex was more moderate. This work elucidates potential Def toxicity from Cu complexation in the body but also cytotoxic synergy between the metal and chelator that informs on new drug design directions.

Seven different enzymes comprise the galactosyltransferases family, of which β-1,4-galactosyltransferase I (β-1,4-GALT1) is the major contributor to galactosylation activity in cells. Since abnormalities in galactosylation are associated with many pathophysiological conditions, β-1,4-GALT1 is an interesting new target for drug discovery and molecular probe design. There are several known β-1,4-GALT1 inhibitors, but most of them suffer from low cell permeability and thus low in vivo activity. In the present work, we describe an in silico screening performed using commercially available virtual compound libraries that led us to the discovery of novel β-1,4-GALT1 inhibitors. A virtual screening campaign was performed by docking compound libraries to the binding site of β-1,4-GALT1, followed by biological evaluation of selected hits for their β-1,4-GALT1 inhibitory activity. The IC₅₀ values were determined for the best performing inhibitors to obtain new chemotypes of β-1,4-GALT1 inhibitors.

The activation of the STING-mediated signaling pathway leads to the secretion of type I interferon (IFN) and the activation of tumor-specific T cells. STING, a pattern recognition receptor located on the endoplasmic reticulum membrane of immune cells, binds with endogenous cyclic dinucleotides. STING undergoes phosphorylation, triggering the STING-TBK1-IRF3 pathway and NF-κB pathway, resulting in the release of IFN-β and other pro-inflammatory cytokines, ultimately enhancing the activation of tumor-specific T cells. This mechanism serves to complement the limitations of immune checkpoint inhibitors and enhances the efficiency of the immune response. This study selected benzimidazole compounds GSK and SR-717, which exhibit promising potential as patented medicines, as our lead compounds. Aiming to address the challenges associated with the short half-life of benzimidazole compounds and the limited molecular activity of SR-717, we designed and synthesized a series of STING agonists (compounds 6~29). The compound 17 showed excellent agonistic activity on hSTING protein in vitro. The cytotoxicity tests of all the synthesized compounds were performed in vitro. Performed in vivo pharmacokinetic studies on the most promising compounds and conducted molecular docking analyses.

Our research group previously discovered CTN1122, an imidazo[1,2-a]pyrazine compound with promising antileishmanial activity against intramacrophage amastigotes of Leishmania major and L. donovani strains. CTN1122 effectively targets Leishmania casein kinase 1 (L-CK1.2) and exhibits a favorable safety profile. To further explore its chemical space, we developed a convergent strategy to modify the C2 position of the imidazo[1,2-a]pyrazine core using Suzuki-Miyaura coupling of the corresponding triflate intermediate. Among 15 newly synthesized analogs, seven derivatives featuring variously substituted phenyl rings at C2 demonstrated L-CK1.2 inhibition within micromolar to submicromolar ranges and antileishmanial activity in vitro with low cytotoxicity in macrophages. Compounds 7 d and 7 l were particularly potent, with IC₅₀ values of 1.25 μM and 0.92 μM against L. major, and 1.44 μM and 2.34 μM against L. donovani, respectively. They showed IC₅₀ L-CK1.2=0.30 μM and 0.57 μM with enhanced selectivity indices (SI=3.8 and 1.6) over the human CK1ϵ ortholog. Additionally, four C2 analogs and two C5 isomers exhibited notable antiparasitic effects without strongly inhibiting L-CK1.2, indicating a possible alternative mechanism of action. Compound 7 k displayed the highest general activity, with IC₅₀ values of 0.31 μM on L. major and 0.27 μM on L. donovani, coupled with favorable selectivity indexes.

An efficient and concise synthesis of highly functionalized bridged coumarins has been developed through a diastereoselective double Michael addition reaction of p-quinols with various 4-hydroxy coumarins under catalyst-free conditions in H₂O-DMSO (8 : 2). The method has been applied to oxindoles for the synthesis of a variety of bridged-oxindoles and bridged-spiroxindoles in presence of a DABCO base using H₂O-EtOH (8 : 2) as solvent medium. The strategy is simple, highly atom economical as there is no by-product and environmentally benign (E-factor=0.1-0.9). The synthesized compounds were screened against triple-negative breast cancers and found that bridged coumarin (3 a) and oxindole (5 d) compounds exhibit potent anti-cancer activity at 6.6 and 8.8 μM (IC₅₀) concentrations respectively. Further analysis revealed that 3 a and 5 d caused elevated early and total apoptosis by arresting the MDA-MB-468 cells in G2/M phase of the cell cycle. Overall, our results demonstrate that bridged coumarin (3 a) and oxindole (5 d) compounds-based approach attenuates the cancer progression and may pave a path for the translational outcome.

This study explores the synthesis and evaluation of novel 1,2,3-triazole-methyl-1,4-naphthoquinone hybrids, focusing on their electrochemical properties and antiparasitic efficacies against two human blood-dwelling parasites Plasmodium falciparum and Schistosoma mansoni. Using copper-catalyzed azide-alkyne cycloaddition (CuAAC), a well-established tool in click chemistry, two synthetic routes were assessed to develop α- and β-[triazole-methyl]-menadione derivatives. By optimizing the CuAAC reaction conditions, yields were significantly improved, reaching up to 94 % for key intermediates and resulting in the formation of a library of approximately 30 compounds. Biological evaluation of the compounds in antiparasitic drug assays demonstrated notable antischistosomal potencies, while no significant activity was observed for the same series against P. falciparum parasites. Electrochemical and 'benzylic' oxidation studies confirmed that the active 'benzoyl' metabolite responsible for the antiplasmodial activity of plasmodione cannot be generated. These findings highlight the potential of triazole-linked menadione hybrids as promising early candidates for antischistosomal drug development, and provides insights into structure-activity relationships crucial for future therapeutic strategies.