MedChemComm最新文献

Salicylic acid (SA) is a natural lipophilic active ingredient commonly used in cosmetics and skin disease treatments, offering benefits such as exfoliation, anti-inflammation effects, antibacterial properties, oil control, and acne alleviation. However, its poor water solubility, low bioavailability, and potential side effects, such as allergies, irritation, and dryness, hinder its widespread application. In this study, we prepared a betaine–salicylic acid (BeSA) cocrystal and systematically characterized its crystal structure, biological activity, and clinical efficacy. The results showed that BeSA has significantly lower irritancy and cytotoxicity than SA, but exhibits excellent anti-inflammatory and antioxidant properties as well as high moisturizing and anti-acne efficacy, making it a potential alternative to SA. Further, quantum chemical calculations and molecular docking simulations were conducted to investigate the intrinsic mechanisms underlying the excellent bioactivity of BeSA cocrystals. This study introduces an innovative solution for safer and more effective skincare formulations based on SA and offers theoretical guidance regarding material engineering and further material optimization, which has crucial implications for both industry and academia.

The discovery of selective and potent inhibitors through de novo pathways is essential to combat drug resistance in chronic hepatitis B (CHB) infections. Recent studies have highlighted that neplanocin A (NepA) derivatives are biologically selective inhibitors of the hepatitis B virus (HBV). In this study, we designed, synthesized, and evaluated various pyrazolo[3,4-d]pyrimidine-based NepA analogues (4a–h) for their anti-HBV activity. Notably, analogue 4g demonstrated significant activity against HBV replication, with EC₅₀ (HBV DNA) = 0.96 μM, CC₅₀ > 100 μM and EC₅₀ (HBsAg) = 0.82 μM, showing selective inhibition of HBsAg secretion. The SAR analysis concluded that replacing the polar 4-NH₂ group with –CH₃ also acted as a weak H-bonding donor, and the presence of 3-iodo was found to be desirable for the activity/toxicity profile. The nucleoside analogues exhibited a distinct mechanism of action compared to existing nucleoside analogues for the selective inhibition of HBsAg secretion. Based on these findings, compound 4g represents a promising lead molecule for the development of new anti-HBV agents with unique mechanisms of action.

Fv-antibodies targeting the transmembrane protease serine 2 (TMPRSS2) were screened from an Fv-antibody library for inhibiting SARS-CoV-2 infection. Fv-antibodies were derived from the variable region of heavy-chain immunoglobulin G (IgG), which consisted of three complementarity-determining regions (CDRs) and frame regions (FRs). The Fv-antibody library was prepared through site-directed mutagenesis of CDR3 region. The proteolytic cleavage site (S2′ site) of TMPRSS2 on the spike protein (SP) of SARS-CoV-2 was used as a screening probe for the library. Two Fv-antibodies were screened and subsequently expressed as soluble recombinant proteins. The binding affinities of the expressed Fv-antibodies were estimated using a surface plasmon resonance (SPR) biosensor. The two expressed Fv-antibodies specifically bound to the active site of TMPRSS2 which interacts with S2′ site in the proprotein convertase (PPC) region. The neutralizing activities of the two expressed Fv-antibodies were demonstrated using a cell-based infection assay with pseudo-viruses that expressed the SP of four types of SARS-CoV-2 variants: Wu-1 (D614), Delta (B.1.617.2), Omicron (BA.2), and Omicron (BA.4/5). Additionally, a docking simulation was performed to analyze the interaction between the screened Fv-antibodies and the active sites of TMPRSS2.

PROteolysis TArgeting Chimeras (PROTACs), also known as ligand-directed degraders (LDDs), are an innovative class of small molecules that leverage the ubiquitin–proteasome system to induce the degradation of target proteins. Structure based design methods are not readily applicable for designing LDDs due to the dynamic nature of the ternary complexes. This study investigates the dynamic properties of five LDD-mediated BRD4–cereblon complexes, focusing on the challenges of evaluating linker efficiency due to the difficulty in identifying suitable computational metrics that correlate well with the cooperativity or degradation propensity of LDDs. We uncovered that protein frustration, a concept originally developed to understand protein folding, calculated for the residues in the protein–protein interface of the LDD-mediated ternary complexes recapitulate the strength of degradation of the LDDs. Our findings indicated that hydrophobic residues in the interface are among the highly frustrated residues pairs, and they are crucial in distinguishing strong degraders from weak ones. By analyzing frustration patterns, we identified key residues and interactions critical to the effectiveness of the ternary complex. These insights provide practical guidelines for designing and prioritizing more efficient degraders, paving the way for the development of next-generation LDDs with improved therapeutic potential.

NF-κB inducing kinase (NIK) is the central regulatory component of noncanonical NF-κB signalling and has been implicated in a variety of cancers and immune disorders. While NIK has been pursued as a target for such diseases through the design of orthosteric inhibitors, these inhibitors have not resulted in an approved drug. To develop new modalities for NIK-targeting by small molecules, we recently reported a class of chromanol fragments that bind to an unknown allosteric site on the catalytic domain of NIK. Here we report the design of a covalent probe to identify the location of this allosteric binding site. Acrylamide probe 2 (K_d: 24.5 μM) was determined to specifically adduct C573 out of 11 total cysteines on the catalytic domain of NIK, thereby identifying the allosteric binding site of our developed ligands.

Correction for ‘Chiral hydroxymethyl-1H,3H-pyrrolo[1,2-c]thiazoles: the search for selective p53-activating agents for colorectal cancer therapy’ by Mees M. Hendrikx et al., RSC Med. Chem., 2024, 15, 1652–1663, https://doi.org/10.1039/D4MD00076E.

Current therapeutic options for leishmaniasis are severely limited, highlighting an urgent need to develop more effective and less toxic drugs to combat a major global public health challenge. Clemastine fumarate displays good levels of antileishmanial efficacy, but further optimisation is challenged by its difficult synthesis. Here, we demonstrate that simple N-linked analogues are easier to access, can exhibit higher selectivity and show comparable efficacy in a mouse model of Leishmania amazonensis infection.

Antimicrobial resistance (AMR) poses a significant global health threat, rendering many infections untreatable. To combat AMR, repurposing approved drugs has emerged as a cost-effective strategy. Bismuth drugs, when combined with antibiotics, have been proven to be effective against Helicobacter pylori, including antibiotic-resistant strains. However, bismuth drugs alone exhibit limited antimicrobial activity against a narrow spectrum of pathogens. Therefore, a novel approach to enhance the efficacy and broaden the antimicrobial spectrum of bismuth drugs is highly desirable. Herein, we show that a naturally occurring monoterpenoid, hinokitiol, could potentiate the antimicrobial activity of bismuth drugs. We demonstrate a strong synergy between hinokitiol and colloidal bismuth subcitrate (CBS) against various Gram-positive and Gram-negative bacterial strains, including methicillin-resistant Staphylococcus aureus (MRSA). Moreover, the combination of hinokitiol and CBS exhibits anti-biofilm activity by preventing biofilm formation and eliminating S. aureus persister cells. Importantly, the combination therapy demonstrates promising antimicrobial efficacy in murine infection models including skin wound, gastrointestinal and blood infections. Mechanistic studies reveal that hinokitiol enhances bismuth ion (Bi(III)) accumulation and reduces intracellular iron levels. By using thermal proteome profiling combined with dynamic quantitative proteomics analysis, we demonstrate that the bismuth–hinokitiol combination propagated the bismuth binding and interfered with ribosome synthesis, the glycolysis process, impaired bacterial cell wall synthesis and pathogenesis in MRSA. Our finding highlights the potential of combinatorial hinokitiol and bismuth drugs in the fight against AMR.

Antiplatelet agents are the cornerstone for the treatment and prevention of cardiovascular diseases. However, they can induce severe side effects such as gastrointestinal bleeding. The main aim of this study is to determine the effect that novel guanidine-based derivatives exert on platelet aggregation. From a screening, in collaboration with the Psychoactive Drug Screening Project service of several compounds from our in-house library of α2-adrenoceptors' ligands, four compounds showed high to medium affinity towards α2C-adrenoceptors and H2 histamine receptors. Based on the structure of these compounds, another two in-house α2-adrenoceptors' ligands were also selected. The effect of the six compounds on platelet aggregation was investigated by light transmission aggregometry and optical microscopy. Flow cytometry was used to analyse their effect on platelet activation by measuring the expression of GPIIb/IIIa and P-selectin platelet receptors. Finally, the potential effect of those compounds on tumour cell-induced platelet aggregation was studied on three cancer cell lines from different origins using optical microscopy. We found that three of these compounds, with very good affinity towards H2 histamine receptors, significantly inhibited platelet aggregation, induced by both ADP and collagen, at the highest concentrations tested, and that tumour cell-induced platelet aggregation was also modulated by these derivatives. Our findings suggest that these aryl guanidine-like systems have an antiplatelet effect that could be also beneficial to reduce tumour cell–platelet interactions.

Escherichia coli translocase MraY is the target for bacteriolytic protein E from bacteriophage ϕX174, interacting at a site close to Phe-288 on helix 9, on the extracellular face of the protein. A peptide motif Arg-Trp-x-x-Trp from protein E was used to design a set of triazinedione peptidomimetics, which inhibit particulate MraY (6d IC₅₀ 48 μM), and show antimicrobial activity against Gram-negative and Gram-positive antibiotic-resistant clinical strains (7j MIC Acinetobacter baumannii 16 μg mL⁻¹, Staphyloccoccus aureus MRSA 2–4 μg mL⁻¹). Docking against a predicted structure for E. coli MraY revealed two possible binding sites close to helix 9, the binding site for protein E. Antimicrobial activity of analogue 6j was found to be synergistic with bacitracin in Micrococcus flavus, consistent with a link between this inhibition site and undecaprenyl phosphate uptake. Alkaloid michellamine B, also predicted to bind in the cleft adjacent to helix 9, was also found to be synergistic with bacitracin. These data provide experimental evidence that the unusual hydrophobic cleft adjacent to helix 9 in MraY is involved in uptake of undecaprenyl phosphate, in addition to recently identified transporters UptA and PopT, and that this process can be targeted by small molecules as a novel antibacterial mechanism.