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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.

Many studies have pointed to GABA-A receptors as a promising therapeutic target for promoting recovery after stroke, owing to their neuroprotective efficacy and the enhancement of synaptic GABAergic currents. However, identifying nanomolar-affinity ligands that evade P-glycoprotein–mediated efflux can pose a significant challenge. To overcome this barrier, we developed a structure-based machine learning workflow integrating molecular docking, which screened over 160 000 virtual analogs and identified eight synthetically accessible molecules. The synthesized compounds exhibited K_i values at the GABA-A receptor ranging from 50 to 1600 nM, with the most promising being 4d (K_i = 62 ± 11 nM) and 4h (K_i = 50 ± 3 nM), both of which confirmed PAM efficacy at GABA-A receptors. Both ligands exhibited neuroprotective activity by attenuating glutamate-induced Ca²⁺ overload, preserving mitochondrial membrane potential and enhancing cell viability following oxygen–glucose deprivation in HT-22 neurons. In MDR1-MDCKII bidirectional assays, compound 4d (azetidine derivative) exhibited symmetric permeability (efflux ratio = 0.94), while 4h (bicyclic amino alcohol) was identified as a P-gp substrate (efflux ratio = 2.04), suggesting that eliminating a single hydrogen-bond donor at the amide tail is critical for minimizing efflux. Collectively, this study identifies compound 4d as a potent, low-efflux GABA-A receptor PAM with neuroprotective properties, supporting its further investigation.

The human 2-oxoglutarate-dependent oxygenase Jumonji-C domain-containing protein 6 (JMJD6) catalyzes post-translational C-5 lysyl residue hydroxylation in multiple proteins. Aberrant JMJD6 catalysis is associated with the upregulation of androgen receptor splice variant 7 (AR-V7), which confers resistance towards antiandrogens used for prostate cancer treatment; JMJD6 is thus a promising cancer target. To date, few small-molecule JMJD6 inhibitors are reported, likely in part reflecting a lack of robust assays to monitor effects of small molecules on catalysis by isolated JMJD6. The use of solid-phase extraction coupled to mass spectrometry assays is described to screen scaffolds for the development of selective JMJD6 inhibitors. The results reveal that the reported JMJD6 inhibitors WL12, SKLB325, and Compound 7p manifest relatively inefficient JMJD6 inhibition in vitro. By contrast, some, but not all, clinically used inhibitors of the human hypoxia-inducible factor-α prolyl hydroxylase domain-containing proteins (PHDs) efficiently inhibit isolated JMJD6, in particular Enarodustat and Desidustat. The results identify attractive scaffolds for the development of selective, cell permeable JMJD6 inhibitors and suggest that JMJD6 inhibition is a potential off-target effect of PHD inhibitors in clinical use.

The inflammatory cascade of acute kidney injury (AKI) is mainly mediated by TLR-4/NF-κB signaling pathway that ultimately leads to increased release of proinflammatory cytokines. This study aims to discover novel anti-inflammatory candidates targeting proinflammatory cytokines in AKI. Ten novel coumarin-ferulate cyclic conjugates (1–10) are synthesized (by oxidative coupling of coumarin derivatives and ethyl ferulate) and characterized (mass and nuclear magnetic resonance spectroscopy). All compounds are tested for cytotoxicity and proinflammatory cytokines inhibition properties using RAW 264.7 cells stimulated with lipopolysaccharide (Enzyme Linked Immuno-Sorbent Assay). The compounds 3 and 5 show excellent inhibition of TNF-α, IL-6, and IL-1β secretions and also inhibite IL-1β protein levels (western blot). Compounds 3 and 5 are then evaluated (50 mg kg⁻¹ oral dose; C57BL/6 mice) in an oxalate-induced nephropathy model. Results show significant renal protection in compound-treated animals, as evidenced by a significant decrease in the blood urea nitrogen and creatinine, IL-1β protein expression (western blot), and mRNA levels of TNF-α and IL-1β (real-time polymerase chain reaction)). A decrease in the overall percentage of live immune cells and kidney resident macrophages in renal tissues is also observed (flow cytometry). Additionally, histopathological studies (H&E staining) show a significant decrease in renal tissue damage (tubular injury index). This findings suggest that these new anti-inflammatory conjugates have a strong renal protective effect.

Proteolysis-targeting chimeras (PROTACs) have emerged as an excellent strategy for targeted protein degradation by the ubiquitin-proteasome system. Traditional inhibitors suppress the enzymatic activity, but the PROTACs utilize the method of total degradation of protein, promising prolonged and target-specific therapeutic efficacy. Histone deacetylases (HDACs) are epigenetic regulators, implicated in most cancers, neurodegeneration, and other inflammatory diseases. Therefore, HDAC-PROTAC development provides a unique approach to overcome the limitations of conventional HDAC inhibitors, including off-target effects, short duration of action, and resistance mechanisms. Recent advancements in HDAC-PROTACs lead to the design of selective degraders for specific isoforms of HDACs, including HDAC3, HDAC4, HDAC6, and HDAC8, representing superior efficacy in preclinical studies. This review highlights the progress of HDAC-targeting PROTACs, focusing on structural optimization, selectivity enhancements, and therapeutic applications with their degradation potential. However, various challenges include poor pharmacokinetics and bioavailability, and limited in vivo validation for further safety, efficacy analysis. Further research and optimization efforts will be pivotal in translating HDAC-PROTACs into clinically viable therapies for cancer and other epigenetic disorders.