RSC medicinal chemistry最新文献

Novel thiazole analogs 3a, 3b, 4, 5, 6a-g, 8a, 8b, 9a-c, 10a-d and 11 were designed and synthesized as molecular mimetics of sunitinib. In vitro antitumor activity of the obtained compounds was investigated against HepG2, HCT-116, MCF-7, HeP-2 and HeLa cancer cell lines. The obtained data showed that compounds 3b and 10c are the most potent members toward HepG2, HCT-116, MCF-7 and HeLa cells. Moreover, compounds 3a, 3b, 6g, 8a and 10c were assessed for their in vitro VEGFR-2 inhibitory activity. Results proved that compound 10c exhibited outstanding VEGFR-2 inhibition (IC₅₀ = 0.104 μM) compared to sunitinib. Compound 10c paused the G0-G1 phase of the cell cycle in HCT-116 and MCF-7 cells and the S phase in HeLa cells. Additionally, compound 10c elevated caspase-3/9 levels in HCT-116 and HeLa cells, leading to cancer cell death via apoptosis. Furthermore, compound 10c showed a significant reduction in tumor volume in Swiss albino female mice as an in vivo breast cancer model. Docking results confirmed the tight binding interactions of compound 10c with the VEGFR-2 binding site, with its binding energy surpassing that of sunitinib. In silico PK studies predicted compound 10c to have good oral bioavailability and a good drug score with low human toxicity risks.

Device-related infections (DRIs) from bacterial/fungal biofilms that form on surfaces are a major cause of death in first-world countries. DRIs and the increasing prevalence of antibiotic resistant strains require development of new antimicrobials for improved antimicrobial prophylaxis. New antimicrobial prophylaxis practices necessitate novel agents to combat a broad spectrum of both fungi and bacteria, to be less toxic to patients, and to be locally administrable to prevent perturbations to a patient's microbiome. A class of antimicrobials that we have previously developed to fit these criteria is ceragenins. Here we describe the design, synthesis, and characterization of a new series of ceragenins that is composed of and degrades into endogenous compounds: cholic acid, B alanine, and glycerides. From this series we identify an optimized bioresorbable ceragenin that has comparable antimicrobial activities to other ceragenins, degrades rapidly through the action of lipase and at pH 7.2, and has a similar mechanism of action to previously developed ceragenins.

Hypoxia is a hallmark of the glioblastoma multiforme microenvironment and represents a promising therapeutic target for cancer treatment. Herein, we report nitroaromatic-based triazene prodrugs designed for selective activation by tumoral endogenous reductases and release of the cytotoxic methyldiazonium ion via a self-immolative mechanism. While compounds bearing a 2-nitrofuran bioreductive group were more efficiently activated by nitroreductases, 4-nitrobenzyl prodrugs 1b, 1d and 1e elicited a more pronounced cytotoxic effect against LN-229 and U-87 MG glioblastoma cell lines under hypoxic conditions when compared to temozolomide (TMZ), the golden standard for glioblastoma treatment. This cytotoxic response aligns with the increased apoptosis levels in LN-229 cells and senescence induction in U-87 MG cells, promoted by prodrugs 1d and 1e, under hypoxic conditions. These results highlight the potential of these hypoxia-activated nitroaromatic-based triazene prodrugs for selective delivery of the cytotoxic methyldiazonium ion and support further optimization to provide a safer alternative for glioblastoma treatment.

Prodrugs are masked drugs that first become pharmacologically active after undergoing a structural change in vivo. They are designed to improve physicochemical/biopharmaceutical drug properties and increase site specificity. The prodrug approach is important when developing brain-targeting drugs due to the presence of the brain barriers that seriously limit the brain entry of highly polar, multifunctional drug entities. While several excellent reviews summarize the structural modifications facilitating transport across the brain barriers, a summary of mechanisms used for the activation of the prodrug in the brain is missing. Given the high need for innovative discoveries in brain drug development, we here review the most important tools being developed since 2000 for CNS prodrug activation.

Twelve 2,4-bis-substituted quinazoline-based compounds were synthesized and screened for antiproliferative and tubulin polymerization enhancing potential. In the series, compound A4V-3 substituted with an imidazole ring displayed IC₅₀ values of 4.25 μM, 2.65 μM, and 9.95 μM, and A4V-5 with a benzotriazole substitution displayed IC₅₀ values of 3.45 μM, 7.25 μM, and 8.14 μM against MCF-7, HCT-116 and SHSY-5Y cancer cells, respectively. In the mechanistic studies involving cell cycle analysis, apoptosis assay and JC-1 studies, compound A4V-3 was found to arrest the cells in the G₂/M phase of the cell cycle and induce mitochondria-mediated apoptosis. In addition, compound A4V-3 displayed significant tubulin polymerization-enhancing potential. 2,4-Bis-substituted quinazoline-based compounds showed appreciable drug-like characteristics and can be developed as potent anticancer agents.

N-Formyl peptide receptors (FPRs) are membrane receptors that are abundantly expressed in innate immune cells, including neutrophils and platelets, demonstrating potential new targets for immune system regulation and the treatment of inflammatory conditions. We report here the development and bio-physical validation of new FPR imaging agents as effective tools to track FPR distribution, localisation and functions, ultimately helping to establish FPR exact roles and functions in pathological and physiological conditions. The new series of probes feature a small molecule-based FPR address system conjugated to suitable fluorophores, resulting in highly specific FPR agents, including a partial agonist endowed with high affinity (i.e. low/sub-nanomolar potency) on FPR-transfected cells and human neutrophils. Preliminary imaging studies via multiphoton microscopy demonstrate that the probes enable the visualisation of FPRs in live cells, thus representing valid bio-imaging tools for the analysis of FPR-mediated signalling, such as the activation of neutrophils in inflammatory events.

Unveiling novel pathways for drug discovery forms the foundation of a new era in the combat against tuberculosis. The discovery of a novel drug, bedaquiline, targeting mycobacterial ATP synthase highlighted the targetability of the energy metabolism pathway. The significant potency of bedaquiline against heterogeneous population of Mycobacterium tuberculosis marks ATP synthase as an important complex of the electron transport chain. This review focuses on the importance and unique characteristics of mycobacterial ATP synthase. Understanding these distinctions enables the targeting of ATP synthase subunits for drug discovery, without aiming at the mammalian counterpart. Furthermore, a brief comparison of the structural differences between mycobacterial and mitochondrial ATP synthase is discussed. Being a complex multi-subunit protein, ATP synthase offers multiple sites for potential inhibitors, including the a, c, ε, γ, and δ subunits. Inhibitors targeting these subunits are critically reviewed, providing insight into the design of better and more potent chemical entities with the potential for effective treatment regimens.

Piglets afflicted with porcine epidemic diarrhea virus (PEDV) experience severe diarrhea and elevated death rates, leading to substantial financial losses in the pig farming sector. The objective of this study is to investigate the impact of saponins on PEDV within Vero cells by utilizing different methodologies to evaluate their anti-PEDV effect. By producing 40 saponins, we have discovered that No. 29, No. 31, No. 35, and No. 38 exhibit properties that make them effective against PEDV, serving as potential drugs. The findings showed that in a clear dose-dependent manner, the mRNA levels of PEDV were significantly inhibited in the high, middle, and low-dose groups of No. 29, No. 31, No. 35, and No. 38, when compared to the PEDV control. The four tested saponins significantly inhibited the levels of PEDV N contents and viral titers. Furthermore, concentration of cytotoxicity 50% (CC₅₀) values for No. 29, No. 31, No. 35, and No. 38 saponins were 37.13 μM, 52.86 μM, 44.98 μM, and 43.81 μM, respectively, demonstrating the safety of these medications in clinical environments. Collectively, these findings indicate that the four examined saponins could efficiently modulate the immune response against PEDV and hold promise for utilization in antiviral treatments.

In continuation of our efforts to develop new anticancer compounds, a new series of imidazo[1,5-a]pyridine-chalcone derivatives was designed, synthesized, characterized, and evaluated for its cytotoxicity against five human cancer cell lines, i.e., breast (MDA-MB-231), colon (RKO), bone (Mg-63), prostate (PC-3), and liver (HepG2) cell lines, as well as a normal cell line (HEK). Among the synthesized compounds, two exhibited promising cytotoxicity against the MDA-MB-231 cell line with IC₅₀ values of 4.23 ± 0.25 μM and 3.26 ± 0.56 μM. We also studied apoptotic induction of the compounds using annexin V-FITC/PI staining, and ROS-mediated mitochondrial damage was elucidated using DCFDA, followed by JC-1 staining. The potential activity of the compounds was further confirmed by immuno-fluorescence and molecular docking studies, which revealed the anticancer activity of active compounds through binding and microtubule disruption.

In this work, we developed potential multifunctional agents to combat Alzheimer's disease. According to our strategy, fragments of tacrine and donepezil were merged in a unique hybrid structure. After successfully synthesizing the compounds, they were evaluated for their dual AChE/BuChE inhibitor potential and neuroprotector response using a glutamate-induced excitotoxicity model. Most of the compounds showed promising activity. Among them, the hybrid with 2,5-dimetoxysubstitution (3b) was the most potent analogue, triggering dual potent AChE/BuChE inhibition with low nanomolar affinity (IC₅₀ ∼ 300 nM) and low toxicity to human liver cancer cells (HepG2). This analogue prevented the glutamate excitotoxic stimulus during pre/post treatment testing, maintained ATP levels, possessed an astrocytic protective response, and abolished the glutamate-induced excitotoxicity. Besides, the hit compound 3b exhibited suitable permeability in the blood-brain barrier (BBB) and low degradability in human blood-plasma. In addition, the docking studies suggested that the neuroprotectant response exhibited by 3b can be related to the direct blockage of the NMDA channel pore. Finally, an ideal neuropharmacokinetic profile was estimated for 3b. Overall, the designed conjugates provide a novel multifunctional molecular scaffold that can be used as a prototype drug in further investigations toward novel multipotent therapeutics for treating AD.