RSC medicinal chemistry最新文献

The alarming rise of drug resistance has created an urgent need for novel antifungal agents. On the other hand, growing environmental concerns necessitate the development of sustainable alternatives to conventional synthetic methods for active pharmaceutical ingredients (APIs). β-Aminosulfones represent a potent yet underexplored functionality in biologically active compounds. In this work, a series of β-aminosulfone derivatives, designed as potential antifungal agents, were synthesized via a one-step, reagent-free, catalyst-free double aza-Michael addition of 2-aminobenzothiazoles, biogenic amines, or aromatic amines with different vinyl sulfones. The reactions were carried out in water under microwave irradiation (150 °C, 10 min), affording β-aminosulfones in excellent yields by simple filtration, without the need for further work-up or purification. This cost-effective process makes the production cost comparable to raw materials (e.g., compound 3d at $3.43 per g). Molecular docking, performed using the Glide module of the Schrödinger suite, revealed potential inhibitory activity against the fungal target CYP51 (PDB ID: 5V5Z), with reasonably good docking scores ranging from -5.69 to -8.25 kcal mol^-1 for benzothiazole derivatives and -5.73 to -7.05 kcal mol^-1 for biogenic amines. In silico ADMET profiling of selected compounds indicated promising drug-like attributes, satisfying Lipinski's rule. β-Aminosulfones were screened for their in vitro antifungal activity against various Candida species, and they exhibited MIC values ranging from 16 to 64 μg mL^-1. Notably, one compound (3d, 0.051 μM) showed comparable potency to fluconazole (0.052 μM) against Candida glabrata. Through ergosterol depletion assays, the mechanism of antifungal activity could be linked to the CYP51 inhibition pathway. Although these compounds exhibited moderate docking scores against 1KZN for antibacterial activity (-3.96 to -5.63 kcal mol^-1), the spot test revealed insignificant inhibition. Cytotoxicity studies with selected molecules revealed that these aza-sulfones are non-toxic to human cells, encouraging further studies with β-aminosulfone scaffolds.

Tuberculosis (TB) remains a major global health threat, exacerbated by the emergence of drug-resistant strains. The mycobacterial enzyme Pks13 has emerged as a promising drug target for novel anti-TB agents. We herein report the design, synthesis, and biological evaluation of a series of pyrimido[1,2-a]imidazole derivatives as potent Pks13-TE inhibitors. An integrated virtual and biological screening of 10.5 million commercially available compounds identified TJA-31 as a hit compound, which showed moderate Pks13-TE inhibitory activity (IC₅₀ = 1.34 μM). The systematic optimization of TJA-31 based on its physicochemical properties, docking scores, and MM/GBSA binding free energy estimates led to the synthesis of 50 analogues, among which 20 compounds exhibited submicromolar inhibition. The most promising derivative, compound 34, demonstrated significantly enhanced potency with an IC₅₀ value of 0.23 μM, representing a sixfold improvement over the hit. Molecular docking studies indicated that the high activity of compound 34 could be attributed to a halogen bond between its bromine substituent and the nitrogen atom of residue His1664, a water-mediated hydrogen bond between the Ala1564 nitrogen and the 3-methoxy oxygen, and π-π stacking interactions with residues within the Pks13-TE binding pocket. These results underscore the pyrimido[1,2-a]imidazole scaffold as a promising lead series for the development of Pks13-TE inhibitors.

The methylerythritol phosphate (MEP) pathway is essential for isoprenoid biosynthesis in many pathogenic bacteria but is absent in humans, making its enzymes attractive antibacterial targets. IspE catalyzes the ATP-dependent phosphorylation of 4-diphosphocytidyl-2-C-methylerythritol, a key step in this pathway. Using a previously identified optimized hit as a starting point, we designed and synthesized a focused library of twelve simplified analogues that retained essential pharmacophoric features while improving synthetic accessibility. Docking studies with Escherichia coli IspE guided the design and predicted binding orientations consistent with known ligand interactions. Biochemical evaluation of the library against E. coli and Klebsiella pneumoniae IspE revealed several low-micromolar inhibitors, confirming the predicted binding interactions. Structure-activity relationships indicated that the hydrophobic pocket adjacent to the cytidine-binding region is a key determinant of potency. Although the compounds showed limited whole-cell activity, these results demonstrate that simplified amide analogues can effectively engage the IspE active site and highlight the importance of the hydrophobic pocket in ligand binding. Overall, this work combines structure-based design, synthesis, and biochemical validation to provide a foundation for further optimization of simplified IspE inhibitors as potential antibacterial leads.

Medicinal chemistry has driven the evolution of oncology drug discovery, transitioning from early cytotoxic agents to modern precision-guided therapies. This opinion article traces the historical trajectory of medicinal chemistry practices, beginning with the era of conventional chemotherapy and moving through the development of targeted therapies utilizing various precision oncology strategies. It then explores the recent wave of innovations-such as proximity inducers and drug conjugates-that have significantly redefined the druggable proteome. While these emerging modalities promise transformative benefits for patients, they also introduce unique challenges related to delivery, selectivity, and acquired resistance. We conclude with a perspective on the future of oncology that the integration of these novel strategies with computational design, advanced proteomics, and biomarker-driven approaches will be essential to accelerate the development of next-generation personalized cancer therapies.

TEAD proteins are attractive cancer targets due to their role in cell proliferation and metastasis. We report the development of MSC-4070, a CNS-penetrant TEAD1,2,4 inhibitor derived from phenotypic screening hit optimization. Starting with azaindole and lactam scaffolds, we systematically designed compounds to enhance brain penetration while maintaining target potency. Analysis of molecular properties revealed that N-methylation significantly reduced efflux ratios in Caco-2 and MDCK-MDR1 assays without compromising activity. MSC-4070 exhibited favorable pharmacokinetics with brain-to-plasma ratios of 2.5-4 and K _{pu, u} values of 0.5-1, confirming its CNS penetration. This compound demonstrated potent activity in the TEAD reporter assay (IC₅₀ 14 nM) and cell viability assays (IC₅₀ 30-149 nM), with selectivity for TEAD1,2,4 over TEAD3. Our findings indicate that while molecular weight and TPSA influence CNS penetration, efflux transporter interactions are more predictive of brain exposure. MSC-4070 represents a promising candidate for targeting TEAD-driven tumors in the central nervous system.

SARS-CoV-2 non-structural protein 14 (nsp14) is essential for viral mRNA cap guanine-N7 methylation and represents a promising but underexplored antiviral target. Herein we describe a structure-guided campaign based on a hit from a focussed SAM mimetic library. Systematic SAR exploration guided by six X-ray co-crystal structures in complex with SARS-CoV-2 led to compound 26, a bi-substrate inhibitor that bridges the SAM and RNA cap binding sites. Compound 26 achieved nanomolar potency against nsp14 from SARS-CoV-2 (IC₅₀ = 53 nM), SARS-CoV-1, and two alphacoronaviruses, with excellent selectivity over human RNMT and flaviviral MTase. In general, the compounds demonstrated favourable metabolic stability, passive permeability, and no HepG2 cytotoxicity. However, cellular antiviral activity was limited, revealing disconnects between enzyme inhibition and phenotypic response. These findings provide a structural framework for optimizing bi-substrate methyltransferase inhibitors against coronaviruses with a view for pan-coronaviral activity.

Histone deacetylase 8 (HDAC8) is a class I enzyme associated with various diseases, including cancer and neurological disorders. Although small-molecule HDAC inhibitors have been developed, their lack of selectivity often leads to off-target effects and toxicities. Alternatively, targeting specific HDAC isoforms for their degradation represents a more precise therapeutic strategy. This review focuses on the design and development of proteolysis-targeting chimeras (PROTACs) that selectively degrade HDAC8. We explore how existing selective HDAC8 inhibitors can be leveraged as warheads in PROTACs to effectively eliminate the enzyme. Recent studies have successfully designed HDAC8-selective PROTACs by linking HDAC8 inhibitors to E3 ubiquitin ligase recruiters such as VHL and CRBN. These PROTACs have demonstrated high potency in degrading HDAC8 in various cancer cell lines with single-digit nanomolar DC₅₀ values, showing superior anti-proliferative effects compared to their parent inhibitors. Therefore, apart from these handful of reports, more research related to HDAC8-PROTAC should provide a better therapeutic development technology for HDAC8-associated disorders while avoiding any therapy-related adversities and complications.

The identification of novel anti-tubercular agents capable of eliciting lethal responses against drug-resistant tuberculosis is critically needed to address the escalating mortality from tuberculosis. Mycobacterium tuberculosis, the etiological agent of this disease, employs a highly efficient energy-producing machinery, the oxidative phosphorylation pathway. Mycobacterium can withstand extreme environmental conditions due to the robust functionality of this multicomponent pathway, which satisfies its energy requirements, during both the persistent phase under stress and the active growth phase. Considering the significance of this biological pathway, in this review we described the dynamics of oxidative phosphorylation and the rationale for targeting its essential components. Furthermore, we provide a comprehensive overview of literature-reported inhibitors, targeting key elements of this pathway, namely, type II NADH dehydrogenase, cytochrome-bd oxidase, and ATP synthase.

Colorectal cancer (CRC) progression involves a coordinated interaction between COX-2-mediated inflammation and EGFR-driven proliferation. Current monotherapies often fail due to incomplete pathway suppression and resistance development, highlighting the need for multi-targeted strategies. This study aimed to design and synthesize novel pyrazole-ar-turmerone hybrids capable of simultaneously inhibiting COX-2 and EGFR, thereby achieving enhanced anti-proliferative efficacy in inflammation-associated colorectal cancer. Two hybrid molecules (compounds 1 and 2) were synthesized and characterized. Their dual-target potential was evaluated in silico using network pharmacology and molecular docking against COX-2 and EGFR crystal structures. In vitro assays in IL-1β-stimulated HT-29 colorectal cancer cells were used to assess anti-proliferative effects by MTT, clonogenic, and CFSE flow cytometry analyses. Mechanistic studies were performed through Western blotting and PGE₂ ELISA/rescue experiments to examine inhibition of COX-2 activity and EGFR-ERK1/2 signaling. Both compounds showed high COX-2 selectivity (SI = 14.38 and 23.57) and potent COX-2 inhibition (IC₅₀ = 0.63 and 1.04 μM), together with EGFR kinase inhibition (IC₅₀ = 37.56 and 57.56 μM). Both hybrids exhibited low cytotoxicity yet significantly suppressed IL-1β-induced HT-29 cell proliferation, with GI₅₀ values of 5.85 μM (compound 1) and 9.57 μM (compound 2). Mechanistic analysis confirmed reduced PGE₂ production, inhibition of EGFR-ERK1/2 activation, and downregulation of cyclin D1 and PCNA expression. The pyrazole-ar-turmerone hybrids function as potent dual COX-2/EGFR inhibitors exhibiting selective anti-proliferative activity in inflammation-driven CRC. These compounds represent promising leads for the development of next-generation dual-target therapeutics against colorectal cancer therapy.

Pharmaceuticals are increasingly detected in the environment, raising concerns about their ecological impact. Global monitoring efforts have revealed widespread contamination, with many sites exceeding safety thresholds for aquatic health. Traditional post-hoc monitoring approaches are reactive, identifying contamination only after environmental exposure has occurred. This highlights the need for predictive tools that assess environmental fate earlier in the drug development process. This review examines current and emerging strategies for early screening of pharmaceutical persistence, toxicity, and bioaccumulation, emphasising in silico approaches such as quantitative structure-activity relationship (QSAR) modelling, machine learning, and molecular docking, alongside complementary analytical techniques, including high-performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR), liquid chromatography/gas chromatography-mass spectrometry (LC/GC-MS), and ion mobility spectrometry (IMS) for validating predictions and characterising complex environmental samples. Together, these tools offer a proactive framework for integrating environmental risk considerations into the pharmaceutical design and development pipeline.