RSC medicinal chemistry最新文献

Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that belongs to the PI3K-related protein kinase family. It is an integral part of two functionally distinct protein complexes: mTOR complex 1 and mTOR complex 2. Its signaling pathway is linked to cell survival, growth, proliferation, and motility. Deregulation of the mTOR pathway has been reported in many types of cancer. Hence, mTOR is an attractive target for the treatment of certain cancers such as renal cell carcinoma and pancreatic tumors. In addition, hyperactivity in mTOR-mediated signaling is associated with the pathogenesis of autism spectrum disorder (ASD) and Alzheimer's disease. Recently, mTOR inhibitors have been considered as emerging pharmacotherapy for these disorders. In this research, we have used molecular modeling techniques to design three series of compounds, indoles, β-carbolines, and 4-aminoquinolines, targeting the ATP site of the mTOR kinase. Based on insights from molecular docking, we developed twenty eight derivatives of these scaffolds to explore the SAR and optimize their affinities. The prepared compounds were evaluated for their inhibitory activity against mTOR as well as other closely related kinases such as PI3K and AKt. To our delight, twenty compounds have shown sub-micromolar activities towards the mTOR kinase. Compounds HA-2l and HA-2c showed a superior IC₅₀ of 66 and 75 nM, respectively, for mTOR, while being selective against AKt and Pi3K. Upon optimization, these selective inhibitors could be useful for the management of ASD due to their relatively higher safety and, hence, suitability for long-term use. On the other hand, derivatives HA-1e, HA-2g, and HA-3d exhibited high affinities for the three enzymes, suggesting their potential utility as anticancer agents. Also, the cytotoxicity of the most active compounds was assessed using different cell-lines. Compounds HA-2g, HA-2l, and HA-3d showed sub-micromolar inhibition, in the range of 0.610–0.780 μM, against the tested cancer cell lines MDA-MB231 and HCT-116. The discovery of a clinically useful mTOR inhibitor would represent a new hope for patients of two important non-communicable diseases, cancer and ASD.

Given the growing resistance to traditional quaternary ammonium compounds (QACs) – long used as primary disinfectants – there is an urgent need for structurally distinct alternatives to effectively combat infectious threats. Quaternary phosphonium compounds (QPCs) have recently emerged as a promising alternative class, demonstrating strong activity even against highly drug-resistant strains. Herein, we present a novel series of 16 all-alkyl biscationic QPCs, designed to expand the scope of atom-economical cationic biocides and evaluate their potential as next-generation disinfectants. Strong and broad bioactivity against a panel of eight bacterial pathogens was observed, with six analogs achieving single-digit micromolar activity across all strains tested. Structure–activity analysis revealed that optimal bioactivity correlates with 10–12 carbon alkyl side chains and longer charge-separating linkers (m = 8–10), which render the structures bolaamphiphilic. Comparisons between bisQAC and bisQPC analogs suggest that substituting the ammonium center with phosphonium had minimal impact on antimicrobial potency, but synthetic versatility allowed access to novel and potent QPC structures. This work underscores the potential of bisQPCs in the development novel and potent disinfectants.

A fundamental biological mechanism, programmed cell death (PCD), is essential for tissue homeostasis, immunological control, and development. Its dysregulation is a characteristic of many diseases in multicellular organisms, including cancer, where unchecked proliferation is made possible by evading cell death. Therefore, one of the main tenets of contemporary anticancer therapies is the restoration or induction of PCD in cancer cells. One potential, least invasive method among these is photodynamic treatment (PDT). PDT uses light-activatable photosensitisers, which cause cancer cells to explode with reactive oxygen species (ROS) when exposed to light. These ROS harm important biomolecules, throw off the cellular redox equilibrium, and cause cells to die. PDT-induced cell death was previously believed to be mostly caused by autophagy, necrosis, or apoptosis. Recent research, however, has shown that it can trigger a wider range of unconventional cell death pathways. ROS can cause ferroptosis by oxidising membrane lipids, fragmenting DNA, and lowering intracellular glutathione (GSH) levels. Similarly, necroptosis or pyroptosis can result from severe oxidative stress activating death receptor signalling. Sometimes, in response, cells use survival strategies like autophagy, which can also lead to cell death. This review explores these new, unconventional methods of cell death and how PDT can be used to take advantage of them. Next-generation photosensitisers based on iridium (Ir), ruthenium (Ru), and rhenium (Re) complexes are given special attention because they provide deep tissue penetration, improved photostability, and adjustable ROS production. Their incorporation into PDT has revolutionary potential for improving cancer treatment precision and conquering therapeutic resistance.

Correction for ‘Emerging opportunities in the rewiring of biology through proximity inducing small molecules’ by Michael M. Hann, RSC Med. Chem., 2025, https://doi.org/10.1039/d5md00608b.

In light of the growing challenge posed by drug resistance, the focus of our research has been on the development of novel antibacterial substances. The approach involves the attachment of antibacterial functional groups to oligosaccharide, known as cyclodextrin, utilising antimicrobial peptides possessing hydrophobic groups and cationic groups as a model system. The cyclodextrin derivative, which contains seven pairs of indole rings and guanidino groups, was synthesised and exhibited potent antibacterial properties that were selective for Enterococcus faecalis. Conversely, a compound comprising a single set of functional groups was selectively antibacterial against Staphylococcus aureus. These were unique phenomena in that they were completely different from the peptides containing indole and guanidino groups and the previously reported antibacterial cyclodextrins modified with alkylamino groups that showed a broad antibacterial spectrum. The results will lead to the discovery of new chemical compounds (or functional groups) those will demonstrate specific antibacterial properties for pathogens and may be useful in the fields of cyclodextrin chemistry and development of antibacterial drugs and materials, particularly in the fight against multidrug-resistant pathogens.

Tertiary amides such as peptoids are a novel class of peptidomimetics that offer enhanced structure, activity, and stability compared to many naturally occurring antimicrobial peptides. Guanidino compounds have gained interest in medicinal chemistry as cell-penetrating molecules. This work investigates the changes in the antibacterial activity of modified guanidino groups on the structure of active guanidino tertiary amides by incorporating lipophilic, hydrophobic, and extra cationic groups, thereby combining the properties of the tertiary amide in the peptoid backbone with the important role of addition of extra cationic and lipophilic residues, such as those in AMPs, but supported by guanidine backbones. A library of active antibacterial bromo-phenyl and dichloro-phenyl-based guanidinium tertiary amides, including three series, was designed. These compounds exhibited MICs of 1–2 μg mL⁻¹, 4–8 μg mL⁻¹, and 16.5–35.6 μg mL⁻¹ against S. aureus, E. coli, and P. aeruginosa, respectively. Tertiary amides with their guanidine bearing an alkylated cationic group of 3C (19a and 20a) and 6C (19b and 20b) length resulted in the most active molecules against all tested strains. Additionally, at 8× MIC, compound 19b was the most effective S. aureus biofilm disruptor, disrupting 75% of the biofilm, while compound 19g was the most active molecule against E. coli biofilm, with 50% disruption. The membrane permeability and QCM-D studies suggested that the designed cationic tertiary amides could depolarize and disrupt the bacterial cell membrane. The most potent peptoids were non-toxic, with HC₅₀ of more than 50 μg mL⁻¹.

Peptide-based hydrogels stimulate stem cell differentiation into neurons, improve neuroprotection, and aid in spinal cord/brain injury repair by moderating inflammatory responses and activating endogenous healing pathways. Peptoid-based hydrogels, with superior enzymatic stability and tunable properties, offer a promising alternative but remain unexplored in neurodegenerative therapies. Thus, future study should focus on optimizing peptoid-based hydrogel formulations, which could considerably progress neuroregenerative therapies in neuroscience research.

This study evaluates the antimycobacterial potential of tanshinone I (TI), tanshinone IIA (TIIA), and cryptotanshinone (CPT), natural compounds isolated from Salvia miltiorrhiza, against Mycobacterium tuberculosis, the primary etiological agent of tuberculosis. Given the global challenge posed by antimicrobial resistance and the complexity of current treatment regimens, we aimed to identify effective and safe alternative therapies. The compounds' in vitro activity was initially assessed via minimum inhibitory concentration (MIC₉₀) and cytotoxicity index (CI₅₀) determinations, yielding MIC₉₀ values of 1.03, 0.38, and 1.21 μg mL⁻¹ for TI, TIIA, and CPT, respectively, with low toxicity and high selectivity indices. A narrow antimicrobial spectrum was observed upon testing against representative bacteria, fungi, and non-tuberculous mycobacteria (NTM). Combination assays with rifampicin revealed synergism for TI and indifference for TIIA and CPT, as determined by the fractional inhibitory concentration index (FICI). Scanning electron microscopy (SEM) revealed morphological alterations in the bacilli's cell wall, suggesting it as a possible target of the compounds' mechanism of action. Whole genome sequencing (WGS) of resistant strains identified mutations predominantly in PE_PGRS family genes, supporting the hypothesis that tanshinones modulate cell wall structure. Finally, efficacy was confirmed against multidrug-resistant clinical isolates, with MIC₉₀ values near 1 μg mL⁻¹. These findings position TI, TIIA, and CPT as promising candidates for developing new therapies against drug-resistant tuberculosis.

So far, several interesting reports dealing with N-heterocyclic carbene (NHC) complexes bearing silver and gold have been published, highlighting their versatility in several research fields and their various applications as well. However, most of the reported NHC complexes have been synthetically obtained and studied as racemates, whereas less is still known about the properties of enantiopure complexes. Aiming at contributing to fill this gap, herein a new series of enantiopure NHC complexes of silver(I) and gold(I) bearing an imidazole derivative, opportunely substituted, with one or two asymmetric carbons has been synthesized. These complexes have been characterized by ¹H and ¹³C NMR, mass spectrometry, and elemental analysis and studied for their anticancer, anti-inflammatory and antioxidant properties. The most active complex was also further investigated for its ability in modulating two main enzymes involved in cancer and inflammatory diseases, viz. human topoisomerase I (hTopoI) and murine inducible nitric oxide synthase (iNOS). The outcomes highlight the role of the configuration and substituents in the regulation of the above-mentioned targets, strengthening the need to widen the studies on enantiopure NHC complexes, which may represent useful compounds to be further developed for the obtaining of tailored therapeutic regimens.

Structured RNAs are increasingly explored as novel pharmacological targets for a range of diseases. Therefore, evaluating methods for RNA-focused hit discovery is crucial. Biolayer Interferometry (BLI), a label-free technique that detects biomolecular interactions by measuring changes in white light interference near the sensor surface, offers high throughput and multiplexing capabilities. While BLI has been widely adopted for protein-targeted screening, its application in RNA-targeted drug discovery remains largely unexplored. In this study, we demonstrate the effective use of BLI to investigate RNA–small molecule interactions using three different riboswitches, which are potential targets for novel antibiotics. Furthermore, we describe the successful use of BLI to identify fragment binders of these RNA targets. We combined the BLI experiments with ligand-based NMR as an orthogonal validation method and were able to identify seven competitive fragment binders of the flavin mononucleotide (FMN) riboswitch, each featuring scaffolds distinct from the previously known ligands.