ChemMedChem最新文献

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.

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.

Schistosomiasis affects hundreds of millions of people worldwide, yet its chemotherapeutic treatment is based on the only drug available-praziquantel (PZQ). The development of alternative treatment options is urgent, not only due to the threat of drug resistance, but also because the drawbacks of PZQ, such as its inactivity against juvenile stages, contribute to its incomplete cure rates, thus requiring repeated treatment. This study presents the design, synthesis, characterization, and biological evaluation of 10 novel organometallic derivatives of the old schistosomicide, niridazole. The in vitro characterization of the derivatives on different life stages of Schistosoma mansoni showed that the activity profile of niridazole could be modified and extended. One ferrocenoyl derivative showed promising activity against all life cycle stages of S. mansoni. Two ferrocenyl and one ruthenocenyl derivatives also displayed higher potency against adult schistosomes than niridazole. In conclusion, valuable information could be gained on the structure–activity relationship of the different organometallic modifications, which could be used to design a second generation of derivatives with further improved activity profiles.

A series of cyano- and amidino-substituted derivatives of N3-methyl-imidazo[4,5-b]pyridines is designed and synthesized to investigate their biological activity. The previously published synthetic methods for the synthesis of targeted derivatives are further optimized to obtain higher yields. In order to investigate how the number, the position, and the type of amidine groups affect biological activity, targeted compounds are substituted with amidine groups on opposite sides of molecules. All compounds demonstrated moderate to strong antiproliferative activity in vitro against tested cancer cell lines with good selectivity against HeLa cancer cell lines. 6-Benzonitril-substituted compound 12 showed pronounced antiproliferative activity against HeLa (IC₅₀ 0.7 µM) and MCF7 (IC₅₀ 0.6 µM) cancer cell lines. Compound 19 bearing two imidazolinyl amidine groups also showed selective activity against MCF7 (IC₅₀ 0.6 µM) cancer cell line. Spectroscopic investigation of the interaction of the most active derivatives with calf thymus-DNA is monitored by UV/Vis, emission, and circular dichroism spectroscopy. The lead compound 19 is shown to bind in the minor groove of DNA, suggesting a possible mechanism of action in tumor cells. The compounds are also tested for their antibacterial activity in vitro, but they showed no antibacterial activity against the tested bacterial strains.

Marine sponges of the genus Oceanapia are prolific producers of bioactive secondary metabolites. Four known bifunctional sphingolipids are isolated: isorhizochalin (1), rhizochalin (2), rhizochalin C (3), and oceanapiside (4) from Oceanapia ramsayi sponges. These compounds are derivatized to form aglycones (1b-4b), perbenzoates (1c–4c), and bis-oxazoline (2e). The compounds and their derivatives are investigated for their cytotoxicity against three breast cancer cell lines (HCC70, MDA-MB-231, MCF7). All four sphingolipids are cytotoxic with significant selectivity indices (SI) for the three breast cancer cells. Compound 1 has high selectivity against the HCC70 cell line, 4 against the MDA-MB-231 cells, and aglycon 4b against both the MDA-MB-231 and MCF7 cell lines, respectively, demonstrating the functional importance of the sugar units and terminal amino-alcohol stereochemistry. Compounds 1–4 also show promising antibacterial activity against Staphylococcus aureus, Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, and the multiple antibiotic-resistant Klebsiella pneumoniae test strains, with compound 2 exhibiting the greatest activity. Derivatization diminished potency, indicating that the sugar moiety and stereochemistry are functionally important for antibacterial activity.

In the pursuit of novel therapeutic agents for cancer treatment, a series of styryl-spirooxindole-based carboxamide derivatives are designed and synthesized, targeting dual inhibition of tubulin polymerization and VEGFR-2 kinase. Among the synthesized compounds, 9j demonstrates remarkable potency against A549 (lung cancer) cell line with an IC₅₀ value of 0.89 ± 0.14 μM. The efficacy of 9j is significantly surpassed by that of the standard drugs colchicine (IC₅₀ = 1.66 ± 0.16 μM) and sunitinib (IC₅₀ = 2.98 ± 0.4 μM). Furthermore, compound 9j exhibits 66% growth inhibition in HUVEC cells with an IC₅₀ value of 1.2 ± 0.2 μM, as assessed by the MTT assay. Mechanistic studies confirm the apoptotic activity of compound 9j, as evidenced by its ability to induce mitochondrial dysfunction and promote apoptosis. Further, the apoptosis is quantified through Annexin V/PI dual staining assay. Additionally, enzymatic assays highlight the dual inhibitory activity of 9j against tubulin polymerization (IC₅₀ = 1.1 μM) and VEGFR-2 kinase (IC₅₀ = 0.95 ± 0.5 μM). In continuation, the anti-angiogenic effect of 9j is also evaluated by CAM assay. Moreover, molecular docking studies also reveal critical binding interactions within the active sites of both targets. Pharmacokinetic evaluations using QikProp and SwissADME tools further underscore the drug-like properties of compound 9j, strengthening its potential as a lead molecule. This comprehensive study indicates that compound 9j is a promising lead in the realm of dual-targeting anti-cancer strategies, warranting further development and optimization.