RSC medicinal chemistry最新文献

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.

Resistance of oestrogen receptor-positive (ER+) breast cancer, the most prevalent type of breast cancer accounting for ∼70% of all cases, to current therapies necessitates the study of alternative strategies. One promising strategy is the multi-targeting approach using dual aromatase-steroid sulfatase inhibitors (DASIs). Herein, we describe the development of DASIs using a common benzofuran pharmacophore. Triazole benzofuran sulfamates were found to have low nM aromatase (Arom) inhibitory activity but no steroid sulfatase (STS) inhibitory activity (IC₅₀ > 10 μM); by contrast, benzofuran ketone sulfamates demonstrated low nM STS inhibitory activity but no Arom inhibitory activity (IC₅₀ > 1 μM). The addition of a methyl group at the 3rd position of the benzofuran ring in the benzofuran ketone sulfamate 19 (R¹ = CH₃) had a notable effect, resulting in dual aromatase and STS inhibitory activities with the 4-chloro derivative 19b (Arom IC₅₀ = 137 nM, STS IC₅₀ = 48 nM) and 4-methoxy derivative 19e (Arom IC₅₀ = 35 nM, STS IC₅₀ = 164 nM) optimal for dual inhibition. Arom/STS inhibition results combined with molecular dynamics studies provided a clear rationale for the activity observed.

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.

Small molecules targeting activating mutations within the epidermal growth factor receptor (EGFR) are efficacious anticancer agents, particularly in non-small cell lung cancer (NSCLC). Among these, lazertinib, a third-generation tyrosine kinase inhibitor (TKI), has recently gained FDA approval for use in combination with amivantamab, a dual EGFR/MET-targeting monoclonal antibody. This review delves into the discovery and development of lazertinib underscoring the improvements in medicinal chemistry properties, especially in comparison with osimertinib. Analysis of its structure-activity relationships (SAR), as outlined in the patent literature, reveals the structural diversity explored enroute to the candidate molecule. The resulting structure of lazertinib is distinguished among other TKIs due to the combination of the hydrophobic phenyl and hydrophilic amine substituents on the pyrazole. The structural basis for the selectivity against the T790M mutation is enabled by the substituted pyrazole moiety, which facilitates both van der Waals and H-bonding interactions with the EGFR kinase domain. Insights from this case study offer lessons that can inform the future design of kinase inhibitors with improved safety and efficacy profiles for cancer treatment and other diseases.

The sphingosine-1-phosphate-5 (S1P₅) receptor is one of the five membrane G protein-coupled receptors that are activated by the lysophospholipid, sphingosine-1-phosphate, resulting in regulation of many cellular processes. S1P₅ receptors are located on oligodendrocytes and are proposed to influence oligodendrocyte physiology. Understanding S1P₅ modulation during processes such as remyelination could have potential applications for demyelinating CNS disorders such as multiple sclerosis (MS). Herein, we report the synthesis and preliminary evaluation of a series of fluorinated 6-arylaminobenzamides as positron emission tomography (PET) ligands of S1P₅. Pharmacokinetic screening and binding evaluation using a [³⁵S]GTPγS assay led to the discovery of TEFM78, a selective and high affinity agonist of S1P₅. Radiosynthesis of [¹⁸F]TEFM78 allowed pilot PET imaging studies in an animal model, which showed that [¹⁸F]TEFM78 can cross the blood brain barrier with good uptake in rat brain and spinal cord.

Topical delivery of therapeutics on the skin can effectively alleviate skin symptoms of psoriasis and reduce systemic toxicity. However, the low delivery efficiency caused by the stratum corneum barrier limits the therapeutic impact. Here, we reported an oligopeptide hydrogel that encapsulates cell-penetrating-peptide (CPP)-decorated curcumin-loaded nanoemulsions (Cur-CNEs) to enhance the skin penetration of curcumin for topical treatment of psoriasis. After being applied to the skin of psoriatic mice, the Cur-CNE embedded oligopeptide hydrogel (Cur-CNEs/Gel) provided a prolonged residue time of Cur-CNEs on the skin lesion. The fluidic and elastic properties of the nanoemulsions enabled them to effectively pass through the interstitial spaces of the stratum corneum, while the CPP decoration further enhanced skin penetration and cellular uptake of Cur-CNEs. The Cur-CNEs/Gel exhibits effective alleviation of the symptoms of psoriasis in mice and provides a promising strategy for topical treatment of psoriasis.

The development and characterization of quaternary phosphonium compounds (QPCs) have long benefitted from their incorporation into a cornerstone reaction in organic synthesis - the Wittig reaction. These structures have, more recently, been developed into a wide variety of novel applications, ranging from phase transfer catalysis to mitochondrial targeting. Importantly, their antimicrobial action has demonstrated great promise against a wide variety of bacteria. This review aims to provide an overview of recent development in non-polymeric biocidal QPC structures, highlighting their synthetic preparation, and comparing their antimicrobial performance. Discussions of similarities and dissimilarities to QACs are included, both in bioactivity as well as likely mechanism(s) of action. The observed potential of QPCs to eradicate Gram-negative pathogens via a novel mechanism is highlighted, as there is an urgent need to address the declining biocide arsenal in modern infection control.