Chemical Biology & Drug Design最新文献

The versatile basic structure of piperazine allows for the development and production of newer bioactive molecules that can be used to treat a wide range of diseases. Piperazine derivatives are unique and can easily be modified for the desired pharmacological activity. The two opposing nitrogen atoms in a six-membered piperazine ring offer a large polar surface area, relative structural rigidity, and more acceptors and donors of hydrogen bonds. These properties frequently result in greater water solubility, oral bioavailability, and ADME characteristics, as well as improved target affinity and specificity. Various synthetic protocols have been reported for piperazine and its derivatives. In this review, we focused on recently published synthetic protocols for the synthesis of the piperazine and its derivatives. The structure–activity relationship concerning different biological activities of various piperazine-containing drugs has also been highlighted to provide a good understanding to researchers for future research on piperazines.

Cisplatin-based chemotherapy is frequently employed as the primary therapeutic approach for advanced lung cancer. Nevertheless, a significant proportion of patients may develop resistance to cisplatin, leading to diminished efficacy of chemotherapy. Through analysis of Gene Expression Omnibus databases, TSPAN6 has been identified as a key factor in conferring resistance to cisplatin, attributed to its activation of the NF-κB signaling pathway. Knockdown of TSPAN6 using siRNA resulted in decreased expression levels of NF-κB in A549 cells. This indicates that TSPAN6 may have dual effects on lung cancer cisplatin resistance and could serve as a promising therapeutic target for individuals with cisplatin resistance.

Staphylococcus aureus has the ability to invade cortical bone osteocyte lacuno-canalicular networks (OLCNs) and cause osteomyelitis. It was recently established that the cell wall transpeptidase, penicillin-binding protein 4 (PBP4), is crucial for this function, with pbp4 deletion strains unable to invade OLCNs and cause bone pathogenesis in a murine model of S. aureus osteomyelitis. Moreover, PBP4 has recently been found to modulate S. aureus resistance to β-lactam antibiotics. As such, small molecule inhibitors of S. aureus PBP4 may represent dual functional antimicrobial agents that limit osteomyelitis and/or reverse antibiotic resistance. A high throughput screen recently revealed that the phenyl-urea 1 targets PBP4. Herein, we describe a structure–activity relationship (SAR) study on 1. Leveraging in silico docking and modeling, a set of analogs was synthesized and assessed for PBP4 inhibitory activities. Results revealed a preliminary SAR and identified lead compounds with enhanced binding to PBP4, more potent antibiotic resistance reversal, and diminished PBP4 cell wall transpeptidase activity in comparison to 1.

Ferroptosis is a novel form of programmed cell death that is triggered by iron-dependent lipid peroxidation. Brusatol (BRU), a natural nuclear factor erythroid 2-related factor 2 inhibitor, exhibits potent anticancer effects in various types of cancer. However, the exact mechanism of BRU in the treatment of hepatocellular carcinoma (HCC) remains unknown. The anticancer effects of BRU in HCC were detected using cell counting kit-8 and colony formation assays and a xenograft model. RNA sequencing (RNA-seq) and bioinformatics analyses of HCC cells were utilized to elucidate the mechanism underlying the effects of BRU in HCC. The levels of reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), and Fe²⁺ were measured using assay kits. The expression of activating transcription factor 3 (ATF3) was tested using RT-qPCR, western blotting, and immunofluorescence staining. The role of ATF3 in BRU-induced ferroptosis was examined using siATF3. BRU significantly inhibited HCC cell proliferation, both in vitro and in vivo. BRU activated the ferroptosis signaling pathway and increased ATF3 expression. Furthermore, ATF3 knockdown impeded BRU-induced ferroptosis. BRU suppressed HCC growth through ATF3-mediated ferroptosis, supporting BRU as a promising therapeutic agent for HCC.

Click chemistry is widely used for the efficient synthesis of 1,4-disubstituted-1,2,3-triazole, a well-known scaffold with widespread biological activity in the pharmaceutical sciences. In recent years, this magic ring has attracted the attention of scientists for its potential in designing and synthesizing new antifungal agents. Despite scientific and medical advances, fungal infections still account for more than 1.5 million deaths globally per year, especially in people with compromised immune function. This increasing trend is definitely related to a raise in the incidence of fungal infections and prevalence of antifungal drug resistance. In this condition, an urgent need for new alternative antifungals is undeniable. By focusing on the main aspects of reaction conditions in click chemistry, this review was conducted to classify antifungal 1,4-disubstituted-1,2,3-triazole hybrids based on their chemical structures and introduce the most effective triazole antifungal derivatives. It was notable that in all reactions studied, Cu(I) catalysts generated in situ by the reduction in Cu(II) salts or used copper(I) salts directly, as well as mixed solvents of t-BuOH/H₂O and DMF/H₂O had most application in the synthesis of triazole ring. The most effective antifungal activity was also observed in fluconazole analogs containing 1,2,3-triazole moiety and benzo-fused five/six-membered heterocyclic conjugates with a 1,2,3-triazole ring, even with better activity than fluconazole. The findings of structure–activity relationship and molecular docking of antifungal derivatives synthesized with copper-catalyzed azide–alkyne cycloaddition (CuAAC) could offer medicinal chemistry scientists valuable data on designing and synthesizing novel triazole antifungals with more potent biological activities in their future research.

The present review article thoroughly analyses natural products and their derived phytoconstituents as a rich source of plausible anticancer drugs. The study thoroughly explores the chemical components derived from various natural sources, thus emphasizing their unique structural characteristics and therapeutic potential as an anticancer agent. The review contains the critical chemical constituents' in-depth molecular mechanisms, their source's chemical structures and the categories. The review also comprises an exhaustive and comprehensive analysis of different chemical spacing parameters of the anticancer agents derived from natural products. It compares them with USFDA-approved synthetic anticancer drugs up to 2020, thus providing a meaningful understanding of the relationship between natural and synthetic compounds portraying the anticancer assets. The review also delves more deeply into the chemical analysis of the heterocyclic moieties from the natural product arena, illustrating the anticancer mechanisms. The present article is, therefore, expected to serve as a valuable resource for natural product and medicinal chemists, encouraging and promoting an integrated approach to exploit the potential of natural products in drug discovery development and translational research, which have a prerequisite of bench to bedside approach. The work could guide researchers toward innovative approaches for the ever-evolving field of anticancer drug discovery.

The severe acute respiratory syndrome coronavirus (SARS-CoV-2) pandemic has triggered a significant impact on global public health security, it is urgent to develop effective antiviral drugs. Previous studies have found that binding to ACE2 is a key step in the invasion of SARS-CoV-2 into host cells, so virus invasion can be inhibited by blocking ACE2, but there are few reports on this kind of specific inhibitor. Our previous study found that Harringtonine (HT) can inhibit the entry of SARS-CoV-2 spike pseudovirus into ACE2^h cells, but its relatively high cytotoxicity limits its further development. Amino acid modification of the active components can increase their solubility and reduce their cytotoxicity. Therefore, in this study, seven new derivatives were synthesized by amino acid modification of its core structure Cephalotaxine. The target compounds were evaluated by cell viability assay and the SARS-CoV-2 spike pseudovirus entry assay. Compound CET-1 significantly inhibited the entry of pseudovirus into ACE2^h cells and showed less cytotoxicity than HT. Molecular docking results showed that CET-1 could bind TYR83, an important residue of ACE2, just like HT. In conclusion, our study provided a novel compound with more potential activity and lower toxicity than HT on inhibiting the SARS-CoV-2 spike pseudovirus infection, which makes it possible to be a lead compound as an antiviral drug in the future.

The leaves of Araucaria cunninghamii are known to be nonedible and toxic. Previous studies have identified biflavones in various Araucaria species. This study aimed to investigate the in vitro cytotoxicity of the isolated compounds from Araucaria cunninghamii after metabolomics and network pharmacological analysis. Methanol extract of Araucaria cunninghamii leaves was subjected to bioassay-guided fractionation. The active fraction was analyzed using LC-HRMS, through strategic database mining, by comparing the data to the Dictionary of Natural Products to identify 12 biflavones, along with abietic acid, beta-sitosterol, and phthalate. Eight compounds were screened for network pharmacology study, where in silico ADME analysis, prediction of gene targets, compound-gene-pathway network and hierarchical network analysis, protein–protein interaction, KEGG pathway, and Gene Ontology analyses were done, that showed PI3KR1, EGFR, GSK3B, and ABCB1 as the common targets for all the compounds that may act in the gastric cancer pathway. Simultaneously, four biflavones were isolated via chromatography and identified through NMR as dimeric apigenin with varying methoxy substitutions. Cytotoxicity study against the AGS cell line for gastric cancer showed that AC1 biflavone (IC₅₀ 90.58 μM) exhibits the highest cytotoxicity and monomeric apigenin (IC₅₀ 174.5 μM) the lowest. Besides, the biflavones were docked to the previously identified targets to analyze their binding affinities, and all the ligands were found to bind with energy ≤−7 Kcal/mol.