Medicinal Chemistry Research最新文献

The genus Plectranthus sensu lato is known to produce abietanes, which exhibit significant potency against Gram-positive bacteria. It is hypothesized that abietanes exert their antibacterial effects by disrupting microbial cell walls. Recent studies have classified Plectranthus s.l. abietanes into six distinct groups. However, the impact of this chemical diversity on the response of abietanes against Gram-positive bacteria remains unexamined. Therefore, a structure-activity relationship study on abietanes from species of Plectranthus sensu stricto and Coleus was conducted to identify active fragments or pharmacophores in abietane-type diterpenoids that could be responsible for their activity against the Gram-positive bacteria Staphylococcus aureus. The study followed a bio-guided approach and included chemical profiling of the extracts, performed using NMR spectroscopy, and comparative analysis, using LC-MS in both positive and negative ionization modes. Results revealed all six classes of abietanes occurred as major constituents of the extracts, with distinctive chemical markers differentiating between Plectranthus s.s. and Coleus species. Oxidation of the B-ring in acylhydrobenzoquinones was identified as a key factor contributing to the strong antibacterial activity of Plectranthus s.l. derived compounds against S. aureus. Analysis of 28 species of Plectranthus s.l. revealed four main clusters based on the accumulation of various abietane classes. The active acylhydrobenzoquinones were a defining factor in the separation of one of the groups of plants while another cluster in both Plectranthus s.s. and Coleus separated based on flavonoid contents. It would be of interest to examine how this trend might be broadened to encompass all species within each genus.

Single-target ligands have insufficient effectiveness in treating Alzheimer’s disease (AD), leading to the development of new pharmacological strategies, particularly multi-target-directed ligands (MTDLs) that tackle the multifactorial nature of the impairment. Among these, dual inhibition of acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) represents a promising approach for enhancing therapeutic outcomes. Here, analogs of 4-methylbenzyl 5-arylthiophene-2-carboxylates (5a–5h) were identified as dual inhibitors of AChE and MAO-B. In vitro evaluations demonstrated that 5a-5d exhibited the most promising inhibition potential towards targeted enzymes (AChE and MAO-B), having IC₅₀ values 0.72 ± 0.01 µM to 1.69 ± 0.04 µM for AChE and 0.19 ± 0.03 µM to 2.69 ± 0.10 µM for MAO-B. Docking analysis is consistent with the in vitro studies, critically unveiling bindings, commonly hydrogen interactions, π-Sulphur, π-π interaction, π-alkyl, and alkyl-alkyl ligand and enzyme binding interactions. These results underscore the promise of these dual inhibitors in tackling the complex pathology of AD.

Piperidone, a chemically versatile cyclic amine incorporating a ketone functional group, has emerged as a privileged scaffold in contemporary drug design owing to its synthetic adaptability and wide range of biological activities. This review provides a comprehensive overview of piperidone and piperidone-containing compounds that have been synthesized in laboratories, isolated from natural sources, or identified in marine organisms. Various synthetic strategies for constructing the piperidone scaffold are discussed, including multicomponent reactions, cycloadditions, organocatalytic methods, and microwave-assisted one-pot protocols. Piperidone derivatives exhibit a broad spectrum of biological activities, including antioxidant, anti-inflammatory, antimicrobial, antifungal, antiviral, neuroprotective, and, notably, anticancer effects across diverse cell lines. Interestingly, several derivatives exert their anticancer effects via more than one mechanism simultaneously, underscoring the importance of detailed structure-activity relationship (SAR) studies to delineate structural determinants responsible for specific modes of action. A deeper understanding of these mechanistic relationships could enable the rational design of novel piperidone-based molecules capable of targeting multiple pathways concurrently, thereby enhancing therapeutic efficacy. Moreover, investigating natural biosynthetic routes may facilitate scalable production of structurally complex piperidone derivatives, unlocking new opportunities in medicinal chemistry and drug development. Overall, this review highlights the significance of the piperidone scaffold as a key structural motif in rational drug design.

Glucose transporter 1 (GLUT1), the most extensively distributed member of the glucose transporter protein family, plays a pivotal role in regulating glucose metabolism and is indispensable for cellular growth, proliferation, and differentiation. Various metabolic disorders arise from the dysregulation of GLUT1 expression, which disrupts glucose homeostasis. The upregulation of GLUT1 has been identified in multiple cancer cells, facilitating tumor progression, metastasis, and resistance to treatment. Recent years have seen a surge in the discovery of GLUT1 inhibitors exhibiting improved selectivity and efficacy. Herein, we introduce the structure and biological function of GLUT1, GLUT1 related oncogenesis, and primarily focuses on recent advancements in the study of GLUT1 inhibitors over the last decade. Notably, this review is restricted to inhibitors that act through direct interaction with the GLUT1 protein, excluding agents that exert indirect effects via upstream signaling or metabolic regulation.

Tubulin inhibition remains a well-established strategy in anticancer therapy, mediated primarily through three binding sites on the α-β tubulin heterodimers: taxane, vinca, and colchicine binding site (CBS). Although several clinically approved drugs target the taxane and vinca sites, their efficacy is often compromised by multidrug resistance. In contrast, CBS remains an underexploited yet highly promising target, as no anticancer drug has been approved that specifically binds this site. Flavonoids, a diverse class of naturally occurring polyphenols, share structural features with colchicine and have emerged as potential CBS inhibitors with favourite safety profiles. Reported tubulin-inhibiting flavonoids encompass polymethoxylated (PMF), polyhydroxylated (PHF), and synthetic or semi-synthetic derivatives, with the most potent compounds exhibiting sub micromolar IC₅₀ values. PMFs generally display stronger activity than PHFs, likely due to enhanced lipophilic interactions within the CBS pocket. Synthetic modifications extending beyond the traditional methoxy and hydroxy substituents have further improved potency. Computational modelling and X-ray crystallographic analyses consistently reveal that flavonoids and colchicine share a similar binding orientation at the CBS supporting their potential as scaffolds for rational anticancer drug design. This review highlights the biochemical, structural, and mechanistic features of flavonoids targeting CBS and discusses their promise as leads for novel CBS inhibitors.

The therapeutic target tubulin, which is of great clinical significance, was previously believed to be an undegradable protein by PROTAC technology. Based on the fact that tubulin-targeting agents have been successfully developed as chemotherapeutic drugs in cancer treatment for decades, it is anticipated that research on tubulin PROTACs will address the limitations of tubulin inhibitor, including resistance and toxicity, as well as revitalize this “old” target. Herein, a series of novel tubulin degraders were designed and synthesized by connecting CA-4 with CRBN ligands through linkers of varied lengths and compositions. One active degrader C02 was identified, which achieved a DC₅₀ value of 1.73 μM and 1.38 μM for α- and β-tubulin respectively in A549 cells. Further biological evaluation has shown that C02 could trigger the degradation of the αβ-tubulin in a ubiquitin-proteasome dependent manner. In addition, C02 was discovered to arrest cell cycle at G2/M phase, induced ROS accumulation, inhibited migration and eventually apoptosis of cancer cells.

Malignant melanoma, a heterogeneous neoplasm arising from melanocytes, is driven by mutations in critical signaling pathways, including MAPK and PI3K-AKT. Despite the improvement in patient outcomes achieved through targeted therapies such as BRAF inhibitors, the persistence of drug resistance poses a significant challenge. This underscores the necessity for the development of novel small molecule therapeutics and combination treatment strategies. Currently, several strategies show promise in addressing drug resistance, including the targeting of RAF dimers, modulation of MAPK pathway components such as SOS1/SHP2 and ERK, regulation of cyclins, and the integration of these approaches with immunotherapy. This review highlights recent advancements in small molecule therapeutics for melanoma, focusing on those targeting key pathogenic proteins and their combination strategies. It also explores future directions in precision medicine based on molecular profiling and drug resistance mechanisms, aiming to provide a theoretical foundation for research and clinical applications.

A series of new bis-1,3,4-oxadiazoles was synthesized by reacting the corresponding dicarboxylic acid bishydrazides with dialkyl chloroethynyl phosphonate. The resulting compounds were tested against a range of test cultures: Staphylococcus aureus ATCC6538; Pseudomonas aeruginosa 0387; and Candida utilis LIA-01. All synthesized compounds exhibited antistaphylococcal activity and fungistatic action. The cytotoxicity and antiviral activity of the obtained compounds against the influenza A (H1N1) virus was studied in vitro. Two of seven compounds under investigation (28%) have demonstrated high anti-viral activity against influenza virus A/Puerto Rico/8/34 (H1N1) with selectivity indices of 15 and 24.

Heat shock proteins (HSPs) play a major role in cell survival in response to stress. Cancer cells in particular rely on these chaperone proteins to facilitate their proliferation and survival. Heat shock factor 1 (HSF1), a transcription factor, sits at the center of this pathway controlling downstream HSP regulation. HSF1, itself, is upregulated in response to heat or stress. As a result, cancer cells have elevated levels of HSF1 relative to healthy cells, and therefore the inhibition of HSF1 has potential to be a promising cancer treatment. HSF1 acts by binding to DNA thus triggering downstream regulation. This study describes the use of a fluorescence polarization assay that interrogates the DNA-binding domain of HSF1. This FP assay was used to demonstrate the suitability toward high throughput screening and the discovery of a new scaffold for HSF1 inhibition.