RSC medicinal chemistry最新文献

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.

Receptor-interacting serine/threonine protein-kinase 1 (RIPK1) is a critical signalling protein that regulates inflammation and cell death in response to TNF signalling. Inhibiting RIPK1 kinase activity prevents neuronal cell death in various animal models, making it a promising therapeutic target for neurodegenerative, inflammatory, and autoimmune disorders. To identify novel allosteric RIPK1 inhibitors, we used a parallel virtual screening strategy that employed structure-based pharmacophore, shape-based, and fuzzy pharmacophore similarity approaches. Structure-guided optimization enabled by X-ray crystallography led to the discovery of a potent and selective piperidinecarboxamide inhibitor with an acceptable pharmacokinetic (PK) profile and limited brain exposure. This work highlights the effectiveness of virtual screening, followed by structure-guided optimization, in identifying progressible allosteric kinase inhibitors.

Some benzodiazepines with excellent affinities to the gamma aminobutyric receptors have been reported to attenuate intracellular calcium by interacting with alpha adrenergic receptors (ARα). To identify novel benzodiazepines that selectively bind adrenergic receptors, we coupled amines to a brominated benzodiazepine starting material, and generated a library of compounds that yielded compounds with good affinity for the ARα₂ subtypes. These compounds were synthesized using a Buchwald Hartwig amination reaction employing XPhos as the most successful ligand among more than twenty ligands that were tested for this purpose and were part of the Catalexis screen platform from Millipore Sigma. The most promising compound has a K_i of 511 nM for the α_2B subtype with a 7.7-fold selectivity over the α_2A and 2.2-fold selectivity over the α_2C adrenergic receptor. Functional cell-based assays identified this compound as an ARα_2B antagonist. All synthesized compounds exhibited a good safety profile in vivo and did not influence sensorimotor coordination and behavior in mice. Overall, these findings confirm the adaptability of the benzodiazepine scaffold in medicinal chemistry enabling future work to fine-tune these compounds to develop a more potent and selective ARα_2B ligand.

Fluorescent dihydropyridine–dihydropyrimidinone (DHP–DHPM) hybrids were easily synthesized through the combination of Hantzsch and Biginelli multicomponent reactions followed by a copper-catalyzed azide–alkyne cycloaddition reaction (CuAAC, click chemistry) protocol. Nine hybrids showed promising antitumor activity for the PC3 prostate cancer cell line, notably compounds 9d and 9g. Both hybrids exhibited high selectivity for tumor cells, with significant selectivity indices (SI), particularly 9g (SI >68.8). Selectivity was qualitatively observed by the internalization of the fluorescent hybrids through high-resolution confocal laser scanning microscopy (CLSM). In silico investigations and western blotting analysis showed a selective inhibition of the isoform C of Aurora kinase by hybrid 9d. A mechanism of action including cell cycle arrest at the G₀/G₁ phase, inhibition of cell migration and invasion, and modulation of key signaling pathways such as MAPK, AKT, and mTOR are discussed.

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Taking a stand against obesity is an urgent priority, as it significantly impacts both the global economy and public health. Synthetic pancreatic lipase (PL) inhibitors represent one of the most effective therapeutics in the management of obesity. PL is a triacylglycerol acyl hydrolase from the family of serine hydrolases that play a key role in the hydrolysis of dietary fat into monoglycerides and fatty acids. Further, fatty acids get deposited in adipose tissue, which progressively results in weight gain. Over the last decade, various new drugs have been studied; however, orlistat still remains the first-line FDA-approved drug for obesity management. However, long-term use of orlistat can lead to serious health complications, including liver toxicity, osteoporosis, and gastrointestinal issues. Notably, the formation of an irreversible covalent bond of the β-lactone moiety of orlistat with the active serine site of HPL and PPL enzyme has been considered to be responsible for these complications. A deeper understanding of the crystal structure of HPL indicates that repositioning the hydrophobic lid domain, also known as the flap, opens access for designed inhibitors to interact with the active site residues: Ser152, His263, and Asp176. Additionally, predicting the mode of inhibition and the inhibition constant (K_i) value through enzyme kinetic study is helpful. This review presents a comprehensive overview of the in silico design, synthetic strategies, in vitro assays using human (HPL) and porcine (PPL) enzymes, in vivo activity, and structure–activity relationship (SAR) studies of synthetic PL inhibitors reported since 2014, aimed at the development of anti-obesity agents. Additionally, we propose the challenges to overcome and a potential path for future development in this field.

Cisplatin remains a cornerstone in the treatment of various solid tumors due to its exceptional antineoplastic efficacy. However, its clinical utility is significantly constrained by severe adverse effects, with ototoxicity emerging as particularly problematic due to its potential to cause permanent hearing impairment and substantially diminish patient quality of life. Recent investigations into mitigating cisplatin-induced ototoxicity have identified natural polyphenolic compounds as promising protective agents, attributable to their diverse biological activities and potent antioxidant properties. This review critically examines the molecular mechanisms underlying cisplatin-induced cochlear damage and systematically evaluates recent advances in employing polyphenolic compounds as otoprotective interventions. Evidence indicates these bioactive molecules attenuate cisplatin-mediated hearing loss through multiple complementary pathways, including modulation of oxidative stress, inflammatory responses, and apoptotic cascades within the cochlear architecture. However, significant challenges, such as low bioavailability and potential interference with cisplatin's antitumor efficacy, hinder their clinical translation. Based on evidence from studies published between 2010 and 2025, with a focus on advances from the last five years, this review systematically outlines protective mechanisms while critically addressing current research limitations. It further proposes future directions, highlighting advanced drug delivery systems and innovative therapeutic strategies. These insights provide a robust mechanistic framework for the rational design and development of novel otoprotective strategies that preserve cisplatin's antitumor efficacy while minimizing its ototoxic potential.

Melanin is essential for protecting human skin against harmful ultraviolet (UV) irradiation and environmental pollutants. However, excessive melanin accumulation in the epidermis can affect aesthetics, cause psychological distress, and reduce quality of life. Despite the development and utilization of several well-known tyrosinase (TYR) inhibitors as skin-whitening agents in cosmetics to address hyperpigmentation concerns, there remains a growing demand in the cosmetics market for safer, more efficient, and diverse skin-whitening agents. Guided by the binding model of thiamidol with TYR, this study synthesized and characterized 26 4-(2,4-dihydroxyphenyl)thiazole-2-carboxamide derivatives, evaluating their anti-TYR activities. Among these compounds, compound 4 exhibited the strongest anti-TYR activity (IC₅₀ = 1.51 μM) and effectively inhibited melanogenesis in the in vitro B16 cell model. Although its anti-TYR activity and anti-melanogenic effect in vitro were less than those of thiamidol (IC₅₀ = 0.72 μM), its depigmenting effect on the in vivo zebrafish embryo model was comparable to thiamidol. Additionally, compound 4 demonstrated excellent biocompatibility and exhibited lower toxicity compared to thiamidol. Overall, these results suggest that compound 4 holds potential as a promising candidate for application as a skin-whitening cosmetic ingredient.