ChemMedChem最新文献

Antimicrobial resistance is a major public health threat, due to the emergence of new bacterial strains not responding to classical antibiotics. This review focuses on the use of transition metal cross-coupling strategies used to access new β-lactam derivatives, the most well-known and commonly used antibiotics. This manuscript covers the seminal studies for the synthesis of antibiotics up to the current need of accessing specific probes (by functionalizing existing drugs), crucial for the detection of resistances. These strategies also allow the linkage of a cargo to a β-lactam antibiotic for selective release for either therapeutic effect or for diagnostic purposes (in the case of probes), which will be explained in this article.

The image shows the structure of the positron emission tomography (PET) imaging agent [¹⁸F]NP3-627, which can penetrate the brain and bind to the NACHT domain of NLRP3. In the background, we see the structure of the NLRP3 inflammasome complex, whose increased expression in inflammatory conditions offers the potential for [¹⁸F]NP3-627 to quantify inflammation in e.g., Alzheimer's disease, multiple sclerosis, or associated with other causes of neurodegeneration. Such a biomarker will facilitate the development of anti-inflammatory drugs acting on the NLRP3 inflammasome, as novel treatments for these conditions. More details can be found in article 10.1002/cmdc.202400816 by Yves P. Auberson and co-workers.

2-[(4-Nitrophenyl)methyl]propanedioates and 2-[(4-aminophenyl)methyl]propanedioates were synthesized with malonates and 4-nitrobenzyl bromide as starting materials. The six compounds were spectrophotometrically characterized post-purification and evaluated for their antioxidant, anti-inflammatory, and anticancer properties with a variety of assays. The most potent compound 3c was evaluated for its efficacy in vivo in a Dalton Ascites Lymphoma murine model and evaluated computationally for its apoptosis-inducing abilities. More details can be found in article 10.1002/cmdc.202400371 by Simone Carradori, Prasanna Ramani, and co-workers.

Delivering carboxylic acid functions into cells is challenging due to their poor permeability across lipophilic membranes at physiological pH, where they are ionized. Masking carboxylic acids as esters improves cell entry, but once inside the cell, its rapid release is essential to maintain spatiotemporal control which can be beneficial for therapeutic and diagnostic applications. This study evaluates the 2-hydroxyethyl-dithio-benzyl ester functional group which undergoes selective and rapid cleavage of the disulfide bond by thioredoxin (Trx), triggering rapid self-immolation of the thio-benzyl ester releasing the carboxylic acid. Fluorescence-based assays using the pro-fluorescent BODIPY structure have demonstrated the rapid intracellular release of carboxylic acids within minutes in both eukaryotic and prokaryotic cells. The approach was tested on antibiotics, and among them, levofloxacin ester prodrug, having the 2-hydroxyethyl-dithio-benzyl ester functional group, showed significantly enhanced antimicrobial activity against resistant and intracellular bacteria compared to its methyl ester analogue.

Lipid nanoparticles (LNPs) have emerged as a transformative platform for the targeted delivery of therapeutic agents, revolutionizing treatment paradigms across a spectrum of diseases. Since the inception of liposomes in the 1960s, lipid-based nanotechnology has evolved to address limitations such as poor bioavailability, off-target effects, and instability, thereby enhancing the efficacy and safety of drug administration. This review highlights the latest advancements in LNPs technology, focusing on their application in cancer therapy, gene therapy, infectious disease management, glaucoma, and other clinical areas. Recent studies underscore the potential of LNPs to deliver messenger RNA (mRNA) and small interfering RNA (siRNA) for precise genetic intervention, exemplified by breakthroughs in RNA interference and CRISPR-Cas9 genome editing. Additionally, LNPs have been successfully employed to ameliorate conditions, demonstrating their versatility in addressing both acute and chronic disorders. However, challenges persist concerning large-scale manufacturing, long-term stability, and comprehensive safety evaluations. Future research must focus on optimizing formulations, exploring synergistic combinations with existing therapies, and expanding the scope of treatable diseases. The integration of LNPs into personalized medicine and the exploration of applications in other diseases represent promising avenues for further investigation. LNPs are poised to play an increasingly central role in the development of next-generation therapeutics.

The Hit to Lead (H2L) process is an integral part of contemporary drug discovery, encompassing the optimisation of validated Hit structures into Lead molecules. High quality leads build confidence, through activity and property profiles as well as preliminary biological data, which might include validating pharmacologic hypotheses along the way, indicating that further investment in the structure(s) and target would be worthwhile. Leads have line of sight to a development candidate and bring an understanding of what priorities Lead Optimisation should address. In this set of best practices, we detail the essential criteria that characterise a good lead, which include establishing SAR from analogues and assessing preliminary DMPK indicators, selectivity and early safety parameters. We highlight the importance of identifying liabilities of the lead series and demonstrating that each can be individually modulated whilst maintaining on target potency. We make the case for having physicochemical properties as critical optimisation parameters and how ligand efficiency metrics can enable this. Then we go over general tactics that can be used to convert hits into a lead series. These include essential steps that, when performed early, increase the chance of success such as deconstructive SAR, pharmacophore and bioactive conformation determination and scaffold optimisation. Finally, we suggest decision-making criteria to substantiate confidence in further investment or, as importantly, making a recommendation to cease further work on a series.

The drastic increase in the emergence of methicillin and vancomycin resistant S. aureus has resulted in almost negligible treatment options available to tackle these drug-resistant strains and therefore, search for newer antibiotics is essential. In this context, a new series of quaternized fused β-carbolines was synthesized and evaluated for its anti-bacterial potential. Several compounds from the series displayed potent anti-bacterial activity against Gram-positive bacteria including the drug-resistant strains with minimal cytotoxicity and promising bactericidal action.

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.