RSC medicinal chemistry最新文献

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of coronavirus disease (COVID-19) since its emergence in December 2019. As of January 2024, there has been over 774 million reported cases and 7 million deaths worldwide. While vaccination efforts have been successful in reducing the severity of the disease and decreasing the transmission rate, the development of effective therapeutics against SARS-CoV-2 remains a critical need. The main protease (Mpro) of SARS-CoV-2 is an essential enzyme required for viral replication and has been identified as a promising target for drug development. In this study, we report the identification of novel Mpro inhibitors, using a combination of deep reinforcement learning for de novo drug design with 3D pharmacophore/shape-based alignment and privileged fragment match count scoring components followed by hit expansions and molecular docking approaches. Our experimentally validated results show that 3 novel series exhibit potent inhibitory activity against SARS-CoV-2 Mpro, with IC₅₀ values ranging from 1.3 μM to 2.3 μM and a high degree of selectivity. These findings represent promising starting points for the development of new antiviral therapies against COVID-19.

A series of novel phenothiazine-containing imidazo[1,2-a]pyridine derivatives were designed and synthesized under metal-free conditions in excellent yield. These derivatives were effectively transformed further into N-alkyl, sulfoxide, and sulfone derivatives. Derivatives were deployed against human microtubule affinity regulating kinase (MARK4), some molecules play crucial roles in cell-cycle progression such as G1/S transition and regulator of microtubule dynamics. Hence, molecules have shown excellent MARK4 inhibitory potential. Molecules with excellent IC₅₀ values were selected for further studies such as ligand interactions using fluorescence quenching experiments for the binding constant. The highest binding constant was calculated as K = 0.79 × 10⁵ and K = 0.1 × 10⁷ for compounds 6a and 6h, respectively. Molecular docking, cell cytotoxicity, mitochondrial reactive oxygen species measurement and oxidative DNA damage were also studied to understand the mechanism of action of the molecules on cancer cells. It was found that the designed and synthesized compounds played anti-cancer roles by binding and inhibiting MARK4 protein.

Cancer is a complex disease and the second leading cause of death globally, and breast cancer is still a leading cause of cancer death in women. Tamoxifen is the most commonly used drug for breast cancer (ER-positive) treatment and chemoprevention, saving the lives of millions of patients every year. In addition, the tamoxifen template has been explored extensively for the development of selective estrogen receptor modulators (SERMs) applicable in breast cancer, osteoporosis, and postmenopausal symptom treatment. Numerous anticancer drugs, including tamoxifen, are in use, but the complexity and heterogeneous nature of cancer complicate the effect of conventional targeted drugs, leading to adverse reactions and resistance. One of the significant approaches to overcome these shortcomings is drug hybrids, generated by covalently linking two or more active pharmacophores. These drug hybrids are remarkably effective in acting on multiple drug targets with higher selectivity and specificity. In recent years, several tamoxifen hybrids have been discovered as potential candidates for cancer treatment. The review highlights the recent progress in developing anticancer hybrids, including organometallic, fluorescent, photocaged, and novel ligand-based tamoxifen hybrids. It also demonstrates the significance of merging various pharmacophores with tamoxifen to produce more potent, precise, and effective anticancer agents. The study offers valuable knowledge to researchers working on cancer research with the hope of enhancing drug potency and reducing drug toxicity to improve cancer patients' lives.

The concept of positron emission tomography (PET) based imaging was developed more than 40 years ago. It has been a widely adopted technique for detecting and staging numerous diseases in clinical settings, particularly cancer, neuro- and cardio-diseases. Here, we reviewed the evolution of PET and its advantages over other imaging modalities in clinical settings. Primarily, this review discusses recent advances in the synthesis of ¹⁸F radiolabeled biomolecules in light of the widely accepted performance for effective PET. The discussion particularly emphasizes the ¹⁸F-labeling chemistry of carbohydrates, lipids, amino acids, oligonucleotides, peptides, and protein molecules, which have shown promise for PET imaging in recent decades. In addition, we have deliberated on how ¹⁸F-labeled biomolecules enable the detection of metabolic changes at the cellular level and the selective imaging of gross anatomical localization via PET imaging. In the end, the review discusses the future perspective of PET imaging to control disease in clinical settings. We firmly believe that collaborative multidisciplinary research will further widen the comprehensive applications of PET approaches in the clinical management of cancer and other pathological outcomes.

Correction for ‘Aptamer AS1411 interacts with the KRAS promoter/hnRNP A1 complex and shows increased potency against drug-resistant lung cancer’ by Yuejie Zhu et al., RSC Med. Chem., 2024, https://doi.org/10.1039/d3md00752a.

Functional dyspepsia (FD) is a gastrointestinal disorder characterized by postprandial fullness, upper abdominal bloating, and early satiation. Peripheral acetylcholinesterase (AChE) inhibitors such as acotiamide have shown efficacy in FD treatment, but their limited affinity towards the enzyme has hindered their effectiveness. Conversely, AChE inhibitors developed for Alzheimer's disease have high potency but exhibit strong central activity, making them unsuitable for FD treatment. In this study, we developed potent AChE inhibitors based on a donepezil and a phthalimide scaffold that contain additional amine groups. Our compounds demonstrate IC₅₀ values in the low to mid-nanomolar range. Computational modelling was employed to determine important molecular interactions with AChE. The compounds show low membrane permeability, which indicates a significantly reduced central activity. These findings suggest that the developed inhibitors could potentially serve as promising treatments for functional dyspepsia.

The epidermal growth factor receptor (EGFR) enzyme plays a critical role in governing the cell cycle, positioning it as a promising target for the development of anticancer drugs. In this study, we endeavored to design and synthesize innovative EGFR inhibitors with potential applications in anticancer therapy. A novel series of compounds, namely 3-(4-(4-(1,3,4-oxadiazol-2-yl)-1H-imidazol-2-yl)phenyl)-1,2,4-oxadiazoles (30a–j), were meticulously designed using FBDD efforts and synthesized. The synthesized compounds underwent thorough characterization using ¹HNMR, ¹³CNMR, HRMS, and mass spectrum analyses. The in vitro anticancer activities of the newly developed compounds (30a–j) were evaluated against four human cancer cell lines such as prostate cancer (PC3 & DU-145), lung cancer (A549), and liver cancer (HEPG2) using the MTT method. The results, expressed as IC₅₀ values, demonstrated significant anticancer activity for several compounds, with five compounds (30a, 30b, 30c, 30i, and 30j) exhibiting superior potency compared to the established anticancer drug etoposide. Notably, compound 30a emerged as the most promising compound, displaying potent cytotoxicity. We also conducted a screening of the compounds on the normal Vero cell line, revealing a pronounced selectivity of the compounds against cancer cell lines, with no observable impact on the normal cell lines. Moreover, the synthesized compounds were investigated for their impact on enzyme EGFR activity. The findings revealed a robust inhibitory effect against the EGFR wild-type enzyme and a 10-fold inferior potency against the mutant form of EGFR. This observation underscores the potential of the new derivatives as effective EGFR^WT inhibitors with substantial anticancer efficacy. Further studies, including cell cycle analysis and apoptosis assays in HEPG2 cell lines, revealed cell cycle arrest at G1/G0 and G2 phases. We also evaluated the potential influence of compound 30a on the EGFR pathway using western blot analysis, revealing a significant inhibition of EGFR autophosphorylation in HEPG2 cells. In conclusion, our findings highlight the promise of these novel compounds as potent EGFR inhibitors, encouraging further investigation and development for the creation of novel and effective anticancer therapeutics.

Several scientific evidences report that a central role in the pathogenesis of Alzheimer's disease is played by the deposition of insoluble aggregates of β-amyloid proteins in the brain. Because Aβ is self-assembling, one possible design strategy is to inhibit the aggregation of Aβ peptides using short peptide fragments homologous to the full-length wild-type Aβ protein. In the past years, several studies have reported on the synthesis of some short synthetic peptides called β-sheet breaker peptides (BSBPs). Herein, we present the synthesis of novel (cell-permeable) N-methyl BSBPs, designed based on literature information on the structural key features of BSBPs. Three-dimensional GRID-based pharmacophore peptide screening combined with PT-WTE metadynamics was performed to support the results of the design and microwave-assisted synthesis of peptides 2 and 3 prepared and analyzed for their fibrillogenesis inhibition activity and cytotoxicity. An HR-MS-based cell metabolomic approach highlighted their cell permeability properties.

Raloxifene, a selective oestrogen receptor modulator (SERM), has demonstrated efficacy in the prevention and therapy of oestrogen receptor-positive (ER+) breast cancer, with some degree of effectiveness against triple-negative forms. This suggests the presence of oestrogen receptor-independent pathways in raloxifene-mediated anticancer activity. To enhance the potential of raloxifene against the most aggressive breast cancer cells, hybrid molecules combining the drug with a metal chelator moiety have been developed. In this study, we synthetically modified the structure of raloxifene by incorporating a 2,2′-bipyridine (2,2′-bipy) moiety, resulting in [6-methoxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl]-[4-(2,2′-bipyridin-4′-yl-methoxy)phenyl]methanone (bipyraloxifene). We investigated the cytotoxic activity of both raloxifene and bipyraloxifene against ER+ breast adenocarcinomas, glioblastomas, and a triple-negative breast cancer (TNBC) cell line, elucidating their mode of action against TNBC. Bipyraloxifene maintained a mechanism based on caspase-mediated apoptosis but exhibited significantly higher activity and selectivity compared to the original drug, particularly evident in triple-negative stem-like MDA-MB-231 cells.

Mycobacterium tuberculosis (Mtb) type II NADH dehydrogenase (NDH-2) transports electrons into the mycobacterial respiratory pathway at the cost of reduction of NADH to NAD⁺ and is an attractive drug target. Herein, we have synthesised a series of 2-mercaptobenzothiazoles (C1–C14) and evaluated their anti-tubercular potential as Mtb NDH-2 inhibitors. The synthesised compounds C1–C14 were evaluated for MIC₉₀ and ATP depletion against Mtb H37Ra, M. bovis, and Mtb H37Rv mc² 6230. Compounds C3, C4, and C11 were found to be the active molecules in the series and were further evaluated for their MIC₉₀ against Mtb-resistant strains and for their bactericidal potential against Mtb H37Rv mc²6230. The Peredox-mCherry-expressing Mtb strain was used to examine whether C3, C4, and C11 possess NDH-2 inhibitory potential. Furthermore, cytotoxicity analysis against HepG2 displayed a safety index (SI) of >10 for C3 and C4. To get an insight into the mode of interaction at NDH-2, we have performed computational analysis of our active compounds.