ChemMedChem最新文献

In this study, we analyzed publicly accessible data related to the Staphylococcus aureus NorA protein, a well-known efflux pump involved in antimicrobial resistance. Our analysis revealed several inconsistencies in data annotation, and significant issues concerning the homogeneity across datasets, which compromise the reliability of data-driven approaches aimed at identifying novel Staphylococcus aureus NorA efflux pump inhibitors (EPIs). To address these challenges, we propose a standardized pipeline for experimental procedures and data annotation, designed to enhance the consistency and quality of EPI datasets submitted to repositories, thereby increasing the utility of publicly available datasets for the discovery of potential EPIs. By implementing this framework, the findings reported herein aim to foster more reliable and reproducible research outcomes in drug discovery projects targeting NorA or other efflux pumps.

The serine/threonine protein kinase CK2, a tetramer composed of a regulatory dimer (CK2β₂) bound to two catalytic subunits CK2α, is a well-established therapeutic target for various pathologies, including cancer and viral infections. Several types of CK2 inhibitors have been developed, including inhibitors that bind to the catalytic ATP-site, bivalent inhibitors that occupy both the CK2α ATP-site and the αD pocket, and inhibitors that target the CK2α/CK2β interface. Interestingly, the bivalent inhibitor AB668 shares a similar chemical structure with the interface inhibitor CCH507. In this study, we designed analogs of CCH507 using structure-based and fragment-based approaches. The ability of these analogs to bind the CK2α/CK2β interface was evaluated using biolayer interferometry and fluorescence anisotropy-based assays. Their potency to inhibit CK2 kinase activity was determined using the bioluminescent ADP-Glo assay. These experiments allowed us to investigate which chemical modifications prevent the binding of the compounds at the CK2α/CK2β interface. Seven out of sixteen compounds conserved the ability to bind at the protein-protein interface, among which three compounds exhibited better interface inhibition compared to CCH507.

Multicomponent reactions have long been recognized as some of the most versatile tools in organic chemistry, with extensive applications in biomedical science and the pharmaceutical industry. In this study, we explored the potential of the Passerini reaction by designing and synthesizing new low molecular mass gelators that can serve as novel formulations for prolonged anesthesia. These gelators address critical issues like poor solubility, low bioavailability, and short plasma half-life, all of which hinder therapeutic efficacy. To further understand the gelation mechanism, we performed density functional theory (DFT) calculation for confirming the presence of non-covalent interactions during gel formation. Additionally, we evaluated the antimicrobial properties of the synthesized compounds, aiming to counter the rise of infectious diseases. These innovative antimicrobial agents could offer solutions to the growing problem of antibiotic resistance, which renders many existing therapies ineffective. Overall, this study aims to develop advanced formulations and antimicrobial agents through the Passerini reaction, providing new strategies for treating infections, minimizing side effects, and combating antibiotic resistance.

The breast cancer resistance protein (BCRP/ABCG2) plays a major role in the multidrug resistance of cancers toward chemotherapeutic treatments. It was demonstrated that cholesterol regulates the ABCG2 activity, suggesting that lower levels of membrane cholesterol decrease the ABCG2 activity in mammalian cells. However, the precise mechanism remains unclear. To better understand the role of cholesterol in the ABCG2 activity, we studied the ABCG2-mediated efflux of different substrates in the presence of different concentrations of cholesterol. Moreover, we synthetized derivatives of cholesterol linked either to known ABCG2 inhibitors or fluorescents probes. A chalcone-cholesterol was synthetized to investigate the influence of cholesterol on ABCG2 inhibition, and a BODIPY-cholesterol was developed to track cholesterol trafficking on mammalian cells and investigate the behavior of cholesterol as an ABCG2 substrate. The obtained results with three different substrates of ABCG2 showed that cholesterol did not affect the intracellular amount of substrates nor the transport activity.

The development of novel therapeutic strategies enabling the selective destruction of tumors while sparing healthy tissues is of great interest to improve the efficacy of cancer chemotherapy. In this context, we designed a β-glucuronidase-responsive albumin-binding prodrug programmed to release a potent Isocombretastatin A-4 analog within the tumor microenvironment. When injected at a non-toxic dose in mice bearing orthotopic triple-negative mammary tumors, this prodrug produced a significant anticancer activity, therefore offering a valuable alternative to the systemic administration of the parent drug.

A diversity-oriented collection of furan-2-carboxamides with antibiofilm activity against P. aeruginosa is reported. The design involved the bioisosteric replacement of the labile furanone ring by a furan-2-carboxamide moiety to explore its influence on biological activity. After evaluation, carbohydrazides and triazoles showed significant antibiofilm activity, and 4b resulted in the most remarkable compound (58 % inhibition). Furthermore, treating P. aeruginosa with three active carboxamides reduced some virulence factors (pyocyanin and proteases), confirming the anti-quorum sensing properties of the derivatives and suggesting LasR as a plausible target. Molecular docking proposed that carbohydrazides share a similar binding mode to related furanones inside LasR with an excellent docking score, while higher derivatives diminished in silico affinity.

After more than 15 years of decline, the Malaria epidemy has increased again since 2017, reinforcing the need to identify drug candidates active on new targets involved in at least two biological stages of the Plasmodium life cycle. The SUB1 protease, which is essential for parasite egress in both hepatic and blood stages, would meet these criteria. We previously reported the structure-activity relationship analysis of α-ketoamide-containing inhibitors encompassing positions P4-P2'. Despite compounds with high inhibitory potencies were identified, their antiparasitic activity remained limited, probably due to insufficient cell permeability. Here, we present our efforts to improve it through the N-terminal introduction of basic or hydrophobic moieties and/or cyclization. Compared to our previous reference compounds 1/2 (Ac-Ile/Cpg-Thr-Ala-AlaCO-Asp-Glu (Oall)-NH₂), we identified analogues with improved Pf-/PvSUB1 inhibition (IC₅₀ values in the 10-20 nM range) and parasite growth inhibition (up to 98 % at 100 μM). The increase in potency was mainly observed when increasing the overall hydrophobicity of the compounds. Conjugation to the cell penetrating peptide octa-arginine was also favorable. Finally, the crystal structure of PvSUB1 in complex with compound 15 has been determined at 1.6 Å resolution. Compared to compound 1, this structure extended to the P5 residue and revealed two additional hydrogen bonds.

Macrocyclic supramolecular materials play an important role in encapsulating anticancer drugs to improve the anticancer efficiency and reduce the toxicity to normal tissues through host-guest interactions. Among them, pillar[n]arenes, as an emerging class of supramolecular macrocyclic compounds, have attracted increasing attention in drug delivery and drug-controlled release due to their high biocompatibility, excellent host-guest chemistry, and simplicity of modification. In this review, we summarize the research progress of pillar[n]arene-based supramolecular nanodrug delivery systems (SNDs) in recent years in the field of tumor therapy, including drug-controlled release, imaging diagnostics and therapeutic modalities. Furthermore, the opportunities and major limitations of pillar[n]arene-based SNDs for tumor therapy are discussed.

Presented herein is the chemical construction of unprecedented 3,4-trans-3,6-anhydro hexofuranose frameworks. The disfavored 3,6-anhydro hexofuranosides were effectively established by Pd-catalyzed debenzylative intramolecular acetalation for the first time. The critical roles of benzyl protection and Pd as catalyst were demonstrated. Various 3,4-trans-3,6-anhydro sugars including sauropunol E was first obtained in satisfactory yields. Pharmaceutical investigation of the sauropunol E and its analogues revealed their potential application as anti-inflammatory agents.

Membrane proteins, a principal class of drug targets, play indispensable roles in various biological processes and are closely associated with essential life functions. Their study, however, is complicated by their low solubility in aqueous environments and distinctive structural characteristics, necessitating a suitable native-like environment for molecular analysis. Nanodisc technology has revolutionized this field, providing biochemists with a powerful tool to stabilize membrane proteins and significantly enhance their research possibilities. This review outlines the substantial advancements in nanodisc methodologies and applications from 2018 to 2024. We cover the development of various nanodisc models, as well as structural and functional studies of membrane proteins that utilize nanodiscs, highlighting their medical applications.