ChemMedChem最新文献

The development of innovative antiviral strategies is critical to address the global health threats posed by RNA viruses, including the Zika virus (ZIKV), which can cause severe neurological complications. The lipid transporter Oxysterol Binding Protein (OSBP), essential for cholesterol and phosphatidylinositol 4-phosphate trafficking, is exploited by many positive-strand RNA viruses, making it an attractive novel antiviral target. This study investigates simplified analogues of macarangin B, a natural compound with potent OSBP-targeted antiviral activity against ZIKV, but limited stability due to its flavonol moiety. A series of analogues was synthesized, replacing the flavonol with a flavone core while retaining the essential hexahydroxanthene (HHX) motif. These compounds demonstrated improved stability (t1/2 = 16 hours), high OSBP binding affinity (4 - 69 nM), and low cytotoxicity (> 20 µM). The most active compounds exhibited antiviral activity comparable to established OSBP inhibitors and were stable in physiologic media, highlighting their potential as leads for therapeutic development. This work advances the structure-activity relationship (SAR) understanding of macarangin B analogues and provides a foundation for designing effective antivirals targeting in ZIKV infections.

Growth differentiation factor 15 (GDF15) is a TGF-β superfamily member involved in diverse physiological and pathological processes. It is expressed in various tissues and its circulating levels rise during exercise, aging, pregnancy, and conditions such as cancer, cardiovascular disease, and infections. The biological activities of GDF15, including anorexia and cachexia, are primarily mediated through the GFRAL receptor, localized in the brainstem and functioning via RET co-receptor recruitment. This signaling is crucial for energy homeostasis and nausea induction. Recent studies suggest a broader GFRAL distribution, potentially explaining GDF15's distinct roles. These findings sparked interest in leveraging GDF15-GFRAL pathways for therapeutic development. Two primary strategies include GDF15 analogues as GFRAL agonists for obesity treatment and GDF15-derived peptides as antagonists to counteract cancer-induced cachexia and related disorders. This review highlights advancements in understanding GDF15-GFRAL signaling and its implications, summarizing bioactive GDF15-derived molecules, their pharmacological applications, and offering insights into novel treatment avenues for GDF15-associated conditions.

Tumor heterogeneity remains one of the main obstacles for cancer diagnosis and treatment. The simultaneous targeting of several cancer biomarkers is an appealing approach for improved diagnostic procedures. Neurotensin receptor 1 (NTS₁) and Gastrin-Releasing Peptide Receptor (GRPR) are both G-protein coupled receptors with complementary profile of expression in several cancer types. This work proposes the design, the synthesis and the in vitro radiopharmaceutical characterization of three heterodimers, based on GRP/NT modified peptides, radiolabeled with gallium-68. Two NTS₁/GRPR targeting pharmacophores containing linear hybrids that differ in the C-terminus were synthesized (i. e., JMV 7110 and JMV 7253). The branched analogue of the silicon-containing heterodimer JMV 7110, namely JMV 7266, was also synthesized. After radiolabeling with ⁶⁸Ga, saturation binding studies performed on HT29 (NTS₁ ⁺/GRPR^-) and PC3 (NTS₁ ⁺/GRPR⁺) cells demonstrated a significant loss in NTS₁ and GRPR affinity compared to the reference monomers with the exception of the NTS₁ affinity of [⁶⁸Ga]Ga-JMV 7266 which was preserved. Considering cellular processing, NTS₁-internalization at 1 h was the highest with [⁶⁸Ga]Ga-JMV 7266 and was similar to the reference compound. Interestingly [⁶⁸Ga]Ga-JMV 7266 demonstrated lower efflux than the other linear heterodimers but also than its NT reference compound. The branched structure of [⁶⁸Ga]Ga-JMV 7266 seems beneficial for dual NTS₁/GRPR targeting.

To address the metabolic instability of cordycepin induced by adenosine deaminase (ADA) and to enhance its bioactivity, this study developed eleven novel cordycepin derivatives using molecular engineering techniques. By incorporating sterically hindered protective groups and modifying the glycosyl moiety, the research aimed to improve both stability and efficacy. Antibacterial tests revealed that five derivatives showed significantly greater activity against pathogenic strains compared to cordycepin, with better compatibility with probiotics. Compound 2 c demonstrated moderate antitumor activity against K562 and MGC-803 cells, with IC₅₀ values of 42.21 μM and 27.79 μM, respectively. Additionally, compound 4 b demonstrated notable DPPH free radical scavenging ability. These compounds also showed improved stability in ADA solutions, providing valuable insights into the structure-activity relationships of cordycepin derivatives.

The rise of antimicrobial resistance has spurred the search for innovative antibiotics, with monocyclic 3-amino-β-lactams - aztreonam standing out as key example - showing significant potential. In particular, C4-functionalized 3-amino-β-lactams have emerged as a promising subclass that can potentially improve the activity, stability and cellular permeability of the compounds. This review outlines various synthetic methodologies available for the construction of 3-amino-β-lactams bearing a heteroatom-containing substituent at C4, with the heteroatom connected to the ring system either directly or via a methylene bridge. Special attention is devoted to 3-amino-4-hydroxymethyl-β-lactams and 3-amino-4-acetoxy-β-lactams as versatile synthetic intermediates. Moreover, the effect of these C4 substituents on the biological activity of the corresponding 3-amino-β-lactams is discussed in detail. A better understanding of synthetic protocols and antibacterial properties related to this underexplored class of monocyclic 3-amino-β-lactams might contribute to address the current antibiotics problems we are facing more efficiently.

The image shows a scene where the mushroom motif is linked to the chemical formulas of purpurogallin derivatives – colchicine, fomenanthriol, and aurantricholone – natural pigments in mushroom caps. These compounds appear as orange, red, or brown dyes, echoing the mushrooms’ colors. It also represents the mushroom season, popular in Europe during autumn. A blue “shield” symbolizes the protective effect of our developed purpurogallines, which block influenza endonuclease, depicted as scissors ready to cleave RNA. More details can be found in article 10.1002/cmdc.202400577 by Milan Kožíšek, Aleš Machara, and co-workers.

The cover feature represents the beauty of interconnectedness amid diversity. The variation of each part shows that it may look random at first, but the connectivity of every fragment reveals a pattern of the union of its pieces showing that no matter different things are, there is an exceptional force binding us together. This concept holds true in diversifying the benzofuropyridine moiety using different functionality resulting into a more comprehensive understanding of its substitution patterns. More details can be found in article 10.1002/cmdc.202400514 by Tanatorn Khotavivattana and co-workers.

Atropisomersm is an emerging feature in recent drug candidates due to the increasing complexity of the targeted protein surfaces. The developability of the drug candidates requires that their atropisomer interconversion is either fast or very slow at ambient temperature therefore the understanding and predictability of the isomerization rate is of great importance. Through a series of selective MCL-1 inhibitors we studied how structural features influence the interconversion of atropisomers. Besides basic observations such as stability in solution, we also carried out NMR kinetics at varying temperatures and a quantum chemical assessment of the isomerization process. The results of our theoretical studies and experimental investigations matched nicely when it came to predicting the presence or absence of isomerization at ambient temperature. For certain compounds we also measured the rotational barrier that fitted nicely the predicted values. The better understanding of how structural elements impact atropisomer stability enables the more efficient optimization of this important feature.

A novel and concise approach to rare 2,3,5-triamino-imidazole scaffolds via Ni-catalyzed coupling of alkylisocyanides and N,N'-diarylguanidines has been developed. This reaction features include mild conditions (thermal or visible light activation), a wide substrate scope, and high efficiency. The coupling proceeds through a Ni^II/Ni^IV catalytic cycle, involving two-electron aerobic oxidation and the sequential insertion of two isocyanide units into Ni-N bonds.Testing these compounds against pathogens of the ESKAPE panel showed their high activity with a minimum inhibitory concentration down to 0.38 μg/mL.

Idiopathic pulmonary fibrosis (IPF) is a progressive and chronic interstitial lung disease characterized by irreversible loss of lung function and a poor prognosis. Type I collagen, a major component of the extracellular matrix, plays a central role in the pathogenesis of fibrosis and is considered a key molecular target for therapeutic intervention. While current anti-fibrotic therapies demonstrate limited efficacy in slowing disease progression, their clinical impact remains suboptimal due to poor pharmacokinetic properties and non-curative therapy. Moreover, the development of effective anti-fibrotic agents targeting collagen synthesis is hindered by the absence of robust, cost-effective, high-throughput drug screening platforms. In this study, we established a novel screening system designed to identify small molecules that inhibit the expression of the COL1A2 gene, which encodes type I collagen. Utilizing this system, we screened a library of natural and synthetic compounds developed at Nagasaki University and identified lamellarin D as a potent inhibitor of COL1A2 expression and subsequent type I collagen production. These findings suggest that lamellarin D, through its unique molecular mechanism, may serve as the foundation for the development of a new class of IPF treatments aimed at targeting the underlying fibrotic processes.