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Kaposi's sarcoma-associated herpesvirus (KSHV) is a gamma-herpesvirus linked to several malignancies, including Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. Among its numerous encoded proteins, the latency-associated nuclear antigen (LANA) plays a pivotal role in the maintenance of viral latency and oncogenesis. This manuscript focuses on therapeutic strategies aimed at targeting LANA to prevent KSHV-associated diseases. Following the concept of proteolysis-targeting chimeras (PROTACs), heterobifunctional compounds are designed and synthesized, which are able to bind LANA as well as specific E3 ligases. To achieve induction of targeted protein degradation, formation of functional ternary complexes as well as uptake into cells is required, which necessitates optimization of multiple compound parameters in parallel. Hence, the conjugates are tested using an assay pipeline tailored for PROTAC drug discovery by checking properties such as binding affinities, formation of ternary complexes, and in vitro absorption, distribution, metabolism, excretion (ADME) data. Restricted permeation as the reason for lack of intracellular target degradation is especially identified.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway activates the immune response upon detection of cytosolic dsDNA and is a key regulator of innate immunity. Overactivation of cGAS-STING has been implicated in numerous inflammatory diseases, and inhibition of cGAS-STING signaling has attracted significant interest as a therapeutic approach to attenuate aberrant inflammation. Proteolysis-targeting chimeras (PROTACs) have become popular modalities for catalyzing the degradation of proteins of interest, thus inhibiting their function. Herein, the design, synthesis, and characterization of noncovalent catalytic STING PROTACs based on a known diphenyl-dihydroisoquinolone STING inhibitory chemotype are reported. The lead from this series (BH690L) exhibits an effective concentration for half-maximal degradation (DC₅₀) of 11.3 nM and a maximum level of degradation observed for a given concentration of PROTAC (D_max) of 0.67, and elicits suppression of downstream markers of inflammation.

Inhibitors of the 90- kDa heat shock protein (Hsp90) family, especially Hsp90β, have been a sought-after therapeutic strategy for the treatment of cancer, neurological disorders, and other diseases. Furthermore, recent studies suggest that their coadministration with other therapies can enhance efficacy. pan-Inhibition of the cytosolic Hsp90α and Hsp90β isoforms has proven to be problematic, since the on-target toxicities have resulted in the failure of most Hsp90 inhibitors that entered clinical trials. Consequently, such outcomes highlight the demand for isoform-selective inhibitors that overcome these detriments. Previously, we reported that subtle modifications to the solvent-exposed region of Hsp90β-selective inhibitors can significantly impact affinity and selectivity. Consequently, nineteen additional analogs were synthesized and evaluated for their ability to bind the cytosolic Hsp90 isoforms, as well as elucidate further structure–activity relationships (SAR) at this region of the molecule. The work herein reveals the extent to which appendages with steric bulk are tolerated, as well as the importance of heteroatoms to maintain high Hsp90β affinity and selectivity. Biological evaluation of these compounds supports the selective inhibition of Hsp90β in cellulo, which is encouraging for the continued exploration of Hsp90 isoform-selective inhibitors for therapeutic applications.

Owing to the importance of tracing new routes in the development of macromolecular prodrugs, in the present work, two potential macromolecular ester prodrugs (i.e., 12a and 13a) of selective cyclooxygenase-2 (COX-2) inhibitor 7b are designed and synthesized. In the design, two different oligo(ethylene glycol)-based spacers are linked through a ferulate residue to the backbone hyaluronic acid (HA) showing a medium molar mass value (i.e., Mw = 270 kDa). The spacers are designed to differ in the sensitivity to the hydrolytic conditions so that the chemical hydrolysis of ferulate ester bond in 12a is assumed to produce the corresponding ferulic acid derivative 12b. On the other hand, the same reaction in 13a leading to ferulate derivative 13b could be accompanied by the hydrolysis of the second ester bond with the release of the selective COX-2 inhibitor 7b. The COX inhibitory activity of the newly synthesized compounds is evaluated in vitro, and macromolecular ester prodrugs 12a and 13a are found to be completely inactive together with hydrolysis product 12b. Conversely, these in vitro studies reveal the intriguing COX-2 inhibitory activity and selectivity of ferulate derivative 13b related to macromolecular ester prodrug 13a. Therefore, to obtain information on the hydrolysis process in different environments, hydrolysis studies are performed on macromolecular ester prodrug 13a by using ¹H NMR and UHPLC-MS techniques. These studies show that severe hydrolytic conditions (i.e., aqueous NaOH solutions) promote the rapid release of potent and selective COX-2 inhibitor 7b, whereas in ammonium acetate buffer the release is slower. Overall, these results lead to envision possible applications of the design approach to the development of macromolecular ester prodrugs of all the drug molecules bearing hydroxyl groups in their structures.

Chemical libraries are essential in drug discovery, providing a vast variety of compounds for screening and exploration. Previously, through collective efforts of chemoinformaticians and chemists, the group has created two libraries: the essential eIMS containing 578 in-stock compounds on plates ready for high throughput screening and a companion virtual library vIMS, containing 821.069 compounds derived from the scaffolds of the eIMS compounds, and decorated with substituents from customized collection of R-groups. In this article, validation of this library design approach is aimed, which is built on scaffold-based structuring and decoration guided by chemists’ expertise. Specifically, its effectiveness is evaluated in comparison to the widely adopted reaction- and building block-based approach. Using Enamine REAL Space library, two scaffold-focused datasets are developed and the make-on-demand chemical space containing the same scaffolds are systematically compared. The results showed similarity between the two, but with limited strict overlap. Interestingly, a significant portion of the R-groups are not identified as such in the make-on-demand library. Synthetic accessibility analysis of the compound sets indicated overall low to moderate synthetic difficulty. These findings confirm the value of the scaffold-based method for generating focused libraries, offering high potential for lead optimization in drug discovery.

In this study, seven novel dihydroartemisinin–loxoprofen hybrids are designed and synthesized, which exhibits significantly enhanced anticancer activity compared to their parent compounds. Through antiproliferation assays, compound 5 is identified as the most potent agent, showing remarkable efficacy against acute myeloid leukemia (AML) cell lines, with IC₅₀ values of 0.013 μM for HL-60 cell, 0.048 μM for U937 cell, and 0.010 μM for THP-1 cell. The antitumor activity of compound 5 is more than tenfold higher than that of the parent compounds. Furthermore, fluorescence microscopy and flow cytometry analyses reveal that compound 5 induces apoptosis in HL-60 cells more effectively than the positive drug cytarabine. X-ray single-crystal diffraction analysis confirms the absolute configuration of these compounds. Molecular docking studies demonstrate strong binding affinities between all seven hybrid molecules and COX-2 (PDB ID: 5IKR) via hydrophobic interactions, hydrogen bonds, and π–π stacking with key residues. Evaluations in human normal liver THLE-2 cells show favorable selectivity indices (SI > 10), and in silico absorption, distribution, metabolism, and excretion (ADME) predictions indicate high gastrointestinal absorption, CYP3A4-mediated metabolism, and bioavailability of 8.15–9.36%. The results highlight the potential of dihydroartemisinin–loxoprofen hybrids as a promising research direction for AML treatment strategies.

As a continuation of the project aimed at searching for new chemotherapeuticagents against Chagas disease or American trypanosomiasis, new selenocyanate derivatives are designed, synthesized, and biologically evaluated against the clinically more relevant dividing amastigote form of Trypanosoma cruzi, the etiologic agent of this illness. Furthermore, as all the title compounds are fluorine-containing molecules, it seemed to be reasonable to explore the role of fluorine atoms in the aromatic system and to determine the optimal position at the terminal phenoxy group, and therefore, various regioisomers are prepared. The conformationally restricted selenocyates structurally related to WC-9Se exhibited improved antiparasitic activity compared to the lead drugs, Out to be extremely potent inhibitors of T. cruzi growth. In particular, (±)-5-(3-fluorophenoxy)-2-(selenocyanatomethyl)−2,3-dihydrobenzofuran exhibited an EC₅₀ value of 0.032 µM, which resulted in the most potent selenocyanate developed in the laboratory. The presence of the fluorine atom together with the rigidity of the molecules are beneficial for the anti-T. cruzi effect. The resulting antiparasitic activity provides further insight into the role of the selenocyanate group in its effective and putative anti-T. cruzi action.

Sulfonium salt 20b competitively targets α-glucosidase on intestinal villus cells, preventing the binding of maltose and sucrose to the enzyme. This inhibits the hydrolysis of α-1,4-glycosidic bonds and subsequent glucose production, thereby suppressing the postprandial rise in blood glucose levels. More details can be found in the Research Article by Weijia Xie and co-workers (DOI: 10.1002/cmdc.202500299).

An efficient and concise synthesis of tetrasubstituted α-phosphinyl α-amino acids (AAs) by hydrophosphinylation of α-ketimino esters under catalyst-free conditions is revealed. The strategy is simple, highly atom-economic and environmentally benign (E-factor = 0.03–0.38). Among the synthesized tetrasubstituted phosphinyl α-AA derivatives, compounds 3ab, 3ac, and 3ad exhibit potent anticancer activity in HepG2 (liver) and MCF7 (breast) cancer cells, whereas compound 3ah displays marked activity against A549 (lung) cancer cells. Notably, these compounds show more than twofold selectivity index toward MCF-7 cells compared to normal HEK-293 cells (kidney). Further, mechanistic studies reveal that these compounds effectively induce G1 or G2/M phase cell cycle arrest and promote significant apoptosis in a dose-dependent manner. Furthermore, compounds 3ab, 3ac, 3ad, and 3ah markedly downregulate the expression of anti-apoptotic genes (BCL-2 and Survivin), thereby enhancing their overall anticancer efficacy. These findings highlights the therapeutic potential of this class of compounds and encourage their further development as promising candidates for liver, breast, and lung cancer treatment.

In the pursuit of novel therapeutic agents with enhanced antimicrobial properties, a new series of hybrid compounds combining the tetrahydroindolones and dihydropyrimidinones scaffolds is designed and synthesized in good yields. The hybridization strategy aims to merge the distinct biological functionalities of each pharmacophore, leading to synergistic effects. The resulting compounds exhibit significant antibiofilm activity against resistant bacterial Staphylococcus aureus and Pseudomonas aeruginosa strains, indicating that the hybrid framework plays a crucial role in this enhanced performance. To assess the safety profile of the new molecules, toxicity studies are conducted using the Caenorhabditis elegans model. The study reveals no observable toxicity, even at elevated concentrations, suggesting a favorable therapeutic window. The combination of strong antibiofilm activity with nontoxic behavior underlines the antivirulence potential of these compounds, positioning them as promising adjuvants to conventional antibiotics in the fight against chronic bacterial infections.