Search Results (623)

Quinoline is a bicyclic aromatic heterocycle composed of a fused benzene and pyridine ring, and it has held an important place in medicinal chemistry for nearly two centuries. F. Runge first isolated it from coal tar in 1834, and it was later found to form the structural core of well-known natural products such as quinine, camptothecin, and γ-fagarine. Its asymmetric electron distribution, amphoteric character, and ability to undergo both electrophilic and nucleophilic substitution confer considerable pharmacophoric versatility on the quinoline scaffold. This review covers the chemistry and therapeutic relevance of quinoline derivatives, with an emphasis on their pharmacological significance rather than on their synthesis alone. It begins with a brief account of the scaffold’s structural features and main synthetic routes, then examines the biological activities reported for quinoline-based compounds, including antibacterial, anticancer, anti-inflammatory, antimalarial, antiparasitic, antitubercular, antioxidant, and antiviral activities, together with structure–activity relationships discussed at the level of specific ligand–target interactions where data allow. The last section covers more recent directions in quinoline-based drug discovery, including PROTAC degraders, kinase inhibitors, and multitarget-directed ligands, an area not extensively addressed in earlier reviews of this scaffold. The literature surveyed here shows that quinoline derivatives continue to serve as a versatile scaffold for generating new leads, linking established synthetic chemistry with current mechanistic and computational approaches. The continued diversification of quinoline-based chemotypes and their biological mechanisms reinforces the importance of this scaffold as a versatile platform for medicinal chemistry and drug discovery. Full article

The genus Dalea (Fabaceae) comprises approximately 188 recognized species distributed mainly in arid and semi-arid regions of the American continent, where several species have been traditionally used in folk medicine for the treatment of gastrointestinal disorders, infections, inflammation, and other ailments. In recent years, Dalea species have attracted considerable scientific interest due to their remarkable diversity of secondary metabolites, particularly prenylated flavonoids, isoflavonoids, rotenoids, chalcones, stilbenes, and terpenoid-rich essential oils. Among these compounds, prenylated and geranylated flavonoids represent some of the most characteristic metabolites of the genus and are strongly associated with its reported biological activities. This review summarizes current knowledge regarding the taxonomy, distribution, traditional uses, phytochemical profile, pharmacological activities, and toxicological aspects of the genus Dalea. Although only about 19 species (approximately 10% of currently recognized species) have been subjected to phytochemical investigation, substantial knowledge gaps remain within the genus. Special emphasis is placed on prenylated phenolic compounds because of their structural diversity and broad spectrum of biological activities, including antibacterial, antifungal, antiparasitic, anti-inflammatory, neuroprotective, anticancer, anti-tyrosinase, and xanthine-oxidase-inhibitory effects. Despite promising pharmacological findings, most available evidence remains limited to in vitro evaluations, with relatively few studies including in vivo validation or mechanistic investigations. Furthermore, important challenges remain regarding toxicity, pharmacokinetics, metabolomic characterization, and sustainable production of bioactive metabolites. Overall, the available evidence highlights Dalea as a valuable source of bioactive compounds with potential pharmaceutical applications and supports the need for further interdisciplinary research focused on drug discovery and development. Full article

Antimicrobial resistance is a major global health challenge that has created an urgent need for new antibacterial agents capable of overcoming emerging resistance mechanisms. Among nitrogen-containing heterocycles, pyrrolidine has been widely investigated in medicinal chemistry due to its structural versatility, favourable physicochemical properties, and ability to enhance interactions with biological targets. This review provides a comprehensive and critical overview of pyrrolidine-based compounds investigated for antibacterial applications. Relevant studies describing clinically approved antibiotics, natural products, synthetic derivatives, hybrid molecules, and antibacterial adjuvants containing a pyrrolidine scaffold were collected, classified, and critically evaluated, with particular emphasis on structural features, antibacterial activity, and structure–activity relationships. The reviewed evidence demonstrates that the pyrrolidine moiety is present in several antibacterial drug classes, including carbapenems, cephalosporins, fluoroquinolones, lincosamides, streptogramins, and tetracyclines, where it contributes to improved target affinity, antibacterial potency, and pharmacokinetic behaviour. Numerous recently reported pyrrolidine derivatives have shown promising activity against clinically relevant, multidrug-resistant bacterial pathogens. The pyrrolidine scaffold is valuable for the design of next-generation antibacterial agents and resistance-modifying compounds, though further in vivo studies and pharmacological evaluation are required to support their clinical development. Full article

The oral cavity represents an extremely complex and dynamic microbial ecosystem capable of rapidly adapting to antimicrobial stress. These characteristics make it a promising environment for the identification of novel bioactive molecules with therapeutic potential. At the same time, the increasing prevalence of resistant pathogens in dental and oral-maxillofacial infections highlights the limitations of current therapeutic strategies and the urgent need for new effective antibacterial agents. This review examines the central role of advanced analytical techniques, with particular emphasis on mass spectrometry, in the discovery and characterization of bioactive metabolites and biomarkers relevant to future antibacterial discovery and to the understanding of biological responses to pathogens or therapeutic interventions. It discusses how the integration of metabolomics approaches, imaging mass spectrometry, and bioinformatics platforms is transforming the antibacterial discovery process by accelerating the identification of active compounds and improving the understanding of microbial interactions within the oral cavity. Overall, this work provides an up-to-date overview of current knowledge regarding the oral microbiome as a source of bioactive molecules and biomarkers. It highlights how emerging analytical technologies are opening new perspectives for the development of innovative therapeutic strategies against resistant oral infections. Full article

The rapid emergence and dissemination of antimicrobial resistance (AMR) among bacterial pathogens, particularly the ESKAPE group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.), represents one of the most pressing global public health challenges, contributing to increased morbidity, mortality, and healthcare costs. The limited development of new antibiotic classes over the past two decades has intensified the search for structurally novel antimicrobial agents and adjuvants capable of overcoming multidrug resistance. Natural products continue to serve as an invaluable source of anti-infective drug leads owing to their remarkable structural diversity and broad spectrum of biological activities. Mangrove ecosystems, located at the interface of terrestrial and marine environments, harbor highly diverse microbial communities, including fungi that have evolved under extreme environmental conditions and produce a wide range of unique secondary metabolites. Beyond their ecological significance, mangrove-associated fungi have emerged as prolific producers of bioactive compounds with promising antibacterial activity against multidrug-resistant pathogens. This review comprehensively summarizes recent advances (2018–2026) in the discovery of antibacterial metabolites from mangrove-associated fungi active against ESKAPE pathogens, which discusses their structural diversity, reported antimicrobial activities, and emerging strategies for accelerating natural product discovery, including genome mining, metabolomics, OSMAC, adaptive laboratory evolution, and artificial intelligence-assisted approaches. A total of 139 chemically distinct metabolites (Compounds 1–139) isolated from mangrove-associated fungi are critically reviewed, highlighting their potential as promising leads for the development of next-generation antimicrobial agents against ESKAPE pathogens. Full article

The escalating crisis of bacterial antimicrobial resistance necessitates the discovery of novel antibacterial agents with distinct mechanisms of action. Ursolic acid (UA), a naturally abundant pentacyclic triterpenoid, serves as a promising scaffold for structural modification. In this study, a series of 26 novel UA derivatives (A1–A7 and B1–B19) were designed and synthesized by introducing various substituents at the C-28 carboxyl group via a chloroacetyl chloride linker. Their antibacterial activities were evaluated against S. aureus, S. epidermidis, E. coli, and P. aeruginosa using the microbroth dilution method. Among them, compound B1 exhibited the most potent activity, with a minimum inhibitory concentration (MIC) of 37.5 μg/mL against S. aureus and 75 μg/mL against E. coli. Antibacterial kinetic and time-kill curve assays confirmed the sustained bactericidal effect of B1. Furthermore, B1 significantly inhibited biofilm formation in both S. aureus and E. coli in a time-dependent manner. Molecular docking studies revealed that B1 binds spontaneously to the S. aureus SarA protein through three hydrogen bonds and π-π stacking interactions, providing a structural basis for its antibacterial and anti-biofilm activities. This study demonstrates that piperazine-modified UA derivative B1 is a promising antibacterial candidate and offers a new strategy for the structural optimization of ursolic acid. Full article

Marine organisms from deep-sea environments have attracted considerable attention in drug discovery because they produce structurally diverse natural products. However, Norwegian deep-sea ecosystems remain largely unexplored in terms of natural product chemistry and bioactivity. In this study, a deep-sea sponge belonging to the genus Phakellia was selectively collected using a low-impact, remotely operated vehicle approach from the Mohn’s Treasure area in the Norwegian Sea at a depth of 2858 m, representing one of the deepest sponge samples investigated in Norwegian waters to date. Chemical investigation of this specimen resulted in the isolation of three new glycosylated fatty acid amides, phakelliosides A–C (1–3), together with two known compounds, 11-(S)-myxillin B (4) and 11-(S)-myxillin C (5), which were isolated as pure individual compounds from natural sources for the first time, with their absolute configurations unambiguously established. These compounds were isolated using a combination of chromatographic techniques, and the structures of the isolated compounds were elucidated by comprehensive spectroscopic analyses, including 1D and 2D NMR and UHPLC–HRMS data. The absolute configurations were determined by optical rotation analysis following acid hydrolysis. Compounds 1–5 were subjected to preliminary antibacterial screening against Enterococcus faecalis, Staphylococcus aureus, Streptococcus agalactiae, Escherichia coli, and Pseudomonas aeruginosa at 100 µg/mL. Under the screening conditions, compound 3 produced the lowest OD₆₀₀ value against E. faecalis (OD₆₀₀ = 0.154), whereas generally higher OD₆₀₀ values were observed against the Gram-negative strains. To the best of our knowledge, this is the first report describing the preliminary antibacterial screening of glycosylated fatty acid amides isolated from Norwegian deep-sea organisms. These findings expand current knowledge of the chemical diversity of natural products associated with Norwegian deep-sea sponges. The biosynthetic origin of these metabolites remains unresolved and warrants further investigation. Full article

Antimicrobial resistance is outpacing antibacterial innovation, yet most explanations for the shrinking pipeline emphasize downstream economic and regulatory attrition. This review identifies an underexamined upstream bottleneck: the unreliable recognition of genuine chemical novelty when a natural-product hit is first encountered. It advances a unifying framework—false novelty—that treats two conventionally separate failures—the rediscovery of known metabolites and the structural misassignment of genuinely new ones—as coordinate manifestations of a single diagnostic failure, an integration rarely made explicit. Eleven independently verified cases from 2019 to 2025, spanning three rediscoveries and eight misassignments, demonstrate that both failures persist under modern instrumentation. Their persistence, therefore, appears to reflect inconsistent workflow adoption more than a lack of technical capability, since dereplication and computational structure-verification tools mature enough to intercept both are already available. The review translates this diagnosis into a resource-conscious, three-checkpoint verification workflow that matches each failure mode to an appropriate remedy at the discovery stage, where correction is cheapest. Recognizing novelty earlier offers a tractable route to conserving scarce discovery-stage resources. Full article

Background: Among natural products, vanillin (Van), a major component of Vanilla planifolia, exhibits multiple bioactivities, including antimicrobial effects. Methods: In this study, Van, its analogues o-vanillin (oVan), iso-vanillin (iVan), ethylvanillin (eVan), and a library of newly synthesized derivatives were evaluated against Helicobacter pylori strains with distinct antibiotic susceptibilities. Time-kill kinetics, antibacterial spectrum, and viability in a normal gastric cell line GES-1, were also assessed. Results: Van showed minimal or no activity (MIC and MBC > 128 µg/mL), whereas structural modifications markedly improved anti-H. pylori activity, with MIC values as low as 4 µg/mL. Compounds 16V, 20oV, and 29eV were among the most potent (MIC₉₀ = 4–16 µg/mL). Activity depended on both the vanilloid core and substituent type. The compounds were inactive against representative Gram-negative and Gram-positive bacteria (MIC > 128 µg/mL). Selected compounds preserved viability in GES-1 cells. Hierarchical clustering, artificial neural clustering, and principal component analysis identified potency-related architectural motifs and strain-specific activity. Docking against H. pylori urease suggested that several compounds, particularly 16V, may interact with the enzyme, providing preliminary support for a possible involvement of this target. Conclusions: Systematic modification of the vanilloid scaffold generated selective and relatively non-cytotoxic anti-H. pylori hit compounds and confirmed the value of natural metabolites in antibacterial drug discovery. Full article

Background/Objectives: Antibiotic-resistant Pseudomonas aeruginosa and limited experimental validation capacity motivate efficient prioritization of antibacterial candidates from large chemical libraries. Quantitative structure–activity relationship (QSAR) benchmarks often binarize disk diffusion inhibition-zone (IZ) measurements, obscuring activity gradients and imposing threshold dependence. We examined whether continuous-IZ modeling provides complementary retrospective prioritization relative to calibrated binary classification in a highly imbalanced dataset. Methods: In this retrospective matched-data evaluation, we revisited a published ChEMBL-derived P. aeruginosa disk diffusion dataset using preserved training and locked external validation partitions. A calibrated support vector classifier using Molecular ACCess System keys (SVC/MACCS) provided conservative binary active calls. RegressionStack combined source-descriptor extreme gradient boosting (XGBoost) and ElasticNet regressors, Morgan-fingerprint random forest and gradient-boosting regressors, and a MACCS-key XGBoost regressor through an XGBoost meta-regressor to predict continuous IZ. Results: On the locked external set (n = 1130; 87 actives), SVC/MACCS achieved a positive predictive value (PPV) = 0.619, receiver operating characteristic area under the curve (ROC-AUC) = 0.857, precision–recall area under the curve (PR-AUC) = 0.479, and enrichment factor at 1% (EF@1%) = 7.58. RegressionStack achieved a mean absolute error (MAE) = 3.20 mm, ROC-AUC = 0.896, PR-AUC = 0.545, and EF@1% = 9.74. Neither paired permutation tests (ROC-AUC, p = 0.501; PR-AUC, p = 0.442) nor paired bootstrap confidence intervals resolved these differences. The y-randomization analyses supported non-random signals; scaffold-grouped validation retained early enrichment but showed reduced broader performance. The consensus-positive tier contained 27 actives among 35 nominations (PPV = 0.771). At measured IZ ≥ 30 mm, MAE increased to 9.46 mm, and all 30 compounds were underpredicted. Conclusions: Continuous-target modeling retained the IZ scale during training and generated a threshold-flexible predicted-IZ prioritization coordinate complementary to, but not statistically superior to, calibrated binary classification. The methodological contribution is a matched-data evaluation of complete workflows and their nomination behavior under the same partitions, yielding a retrospective compound-tiering scheme. Because the pipelines differed in architecture and molecular representation, their differences cannot be attributed solely to endpoint formulation. The workflows were not prospectively evaluated on compounds lacking pre-existing IZ measurements, and whether retrospective enrichment improves experimental hit discovery or reduces screening workload remains to be established. Full article

Background/Objectives: Plant secondary metabolites remain an invaluable source of novel antibacterial phytochemicals in the fight against antibiotic resistance. The medicinal plant Solidago gigantea Ait. (giant goldenrod) is an invasive species in Europe and represents an abundant, yet largely underexplored reservoir of such bioactive compounds. The primary aim of this study was to perform a non-targeted, effect-directed screening, detection, bioassay-guided isolation, structure elucidation, and microbiological assessment of the antibacterial constituents present in the inflorescences of S. gigantea. Methods: Thin-layer chromatography coupled with direct bioautography (TLC–DB) assay using Bacillus subtilis was utilized for the non-targeted, effect-directed analysis of antibacterial components and the evaluation of in vitro antibacterial activity. Successive preparative flash column chromatography, semi-preparative reversed-phase high-performance liquid chromatography (RP-HPLC), and thin-layer chromatography–mass spectrometry (TLC–MS) were employed for the bioassay-guided fractionation and isolation. The structures of the isolated compounds were elucidated using one- and two-dimensional nuclear magnetic resonance (NMR) spectroscopy and high-resolution tandem mass spectrometry (HRMS/MS). The presence of known antibacterial compounds was established via reversed-phase ultra-high-performance liquid chromatography coupled with high-resolution electrospray ionization tandem mass spectrometry (RP-UHPLC–HR-ESI-MS/MS). Results: Two previously undescribed cis-clerodane diterpenoids, the isomeric solidagoic acid L (1) and solidagoic acid M (2), were isolated, identified, and characterized from the ethyl acetate extract of S. gigantea inflorescences. Both compounds exhibited in vitro antibacterial activity against the Gram-positive B. subtilis, confirmed via TLC–DB. In addition, 23 known compounds with antibacterial activity, including 17 clerodane diterpenes, four hydroxylated polyunsaturated fatty acids, and two unsaturated monoacylglycerols, were detected. All of these are reported for the first time in the inflorescences of this plant species. Conclusions: With further optimization, the isolated compounds may represent promising leads for antibacterial drug development. Our findings demonstrate the potential of non-targeted, bioassay-guided approaches for the discovery of novel plant-derived bioactive natural products. Full article

Background: Antimicrobial resistance among Gram-positive veterinary pathogens has increased the need for more rational and experimentally grounded strategies to prioritize tylosin derivatives for antibacterial development. This study aimed to develop and externally a calibrated, decision-oriented screening workflow for tylosin-derived antibacterial analog prioritization against Staphylococcus aureus and Streptococcus agalactiae. Methods: Publicly available minimum inhibitory concentration (MIC) data were used to construct organism-specific multilayer perceptron models. Model performance was evaluated using a five-fold out-of-fold framework. Calibrated activity probabilities were then combined with precision-oriented thresholds and similarity-based applicability-domain constraints to define prospective Go/No-Go decisions. To examine external transferability, six synthesized tylosin derivatives (A1–A6) were prospectively predicted and subsequently tested using in vitro MIC assays. Results: Internal validation showed stronger and more stable performance for S. aureus than for S. agalactiae. However, closed-loop external validation revealed distinct organism-specific decision behaviors. For S. aureus, the workflow assigned Go decisions to five compounds and included the only experimentally active analog, A6, but also generated several false Go decisions for inactive analogs. For S. agalactiae, all six compounds were classified as No-Go under the primary decision rule, whereas MIC testing showed that four analogs were experimentally active, indicating conservative under-selection in a low-data extrapolation setting. Conclusions: Calibrated probabilities and applicability-domain analysis can improve the transparency and diagnostic value of antibacterial prioritization, but they do not guarantee robust external activity prediction when training-set coverage, threshold transferability, or chemical-space representation is limited. Overall, this study provides an early-stage, risk-aware closed-loop decision-support framework for tylosin-derived analog prioritization and highlights the need for iterative model updating, probability recalibration, and larger external validation before such workflows are used as high-confidence prospective screening tools in veterinary antibacterial discovery. Full article

Canarii Fructus (Canarium album) is a rich source of polyphenols with significant potential for functional food applications. This review summarizes recent advances in the composition, extraction technologies, biological activities, and utilization prospects of Canarii Fructus polyphenols (CFPs). More than 30 polyphenolic compounds have been identified, with gallic acid and ellagic acid as the major constituents, accounting for approximately 38.8% and 14.3% of the total phenolics, respectively. The fruit contains about 300 mg/100 g fresh weight of phenolic compounds. Emerging extraction technologies, including ultrasound-assisted extraction, microwave-assisted extraction, and ultrasound–microwave-assisted extraction (UMAE), have improved extraction efficiency, with UMAE achieving yields of up to 6.33% within 4.4 min. Unlike previous studies focusing primarily on phytochemical characterization or pharmacological activities, this review provides a comprehensive food-oriented perspective by integrating chemical diversity, extraction strategies, molecular mechanisms, bioavailability challenges, and functional food applications of CFPs. CFPs exhibit antioxidant, anti-inflammatory, antiviral, antibacterial, antitumor, anti-aging, hepatoprotective, and metabolic regulatory activities through pathways including Nrf2/ARE, NF-κB, PI3K/Akt, and AMPK. Representative bioactivities include α-glucosidase inhibition (IC₅₀ = 9.914 × 10⁻³ μg/mL) and regulation of lipid metabolism via AMPK activation. Particular attention is given to emerging approaches, including green extraction technologies, nanodelivery systems, and AI-assisted target discovery. Current limitations related to low bioavailability, unclear structure–activity relationships, and insufficient in vivo evidence are also discussed. Overall, CFPs represent a promising natural resource for the development of functional foods and nutraceuticals. Full article

Xanthotoxin (8-methoxypsoralen) belongs to the group of naturally occurring furanocoumarin (furocoumarin) compounds and is a product of plant secondary metabolism. Analysis of the available literature indicates that xanthotoxin exhibits a broad spectrum of pharmacological activities, including anti-inflammatory, antioxidant, immunomodulatory, and antibacterial effects. Xanthotoxin has been shown to stimulate autophagy via inhibition of the AKT/mTOR pathway, as well as to block cell migration by modulating RIG-1 and NF-κB signaling. Moreover, its effects on JNK/MAPK, PI3K/AKT, Calcium–CaMYK/PYK2, and other signaling cascades have been confirmed. Among its most promising properties is the ability to inhibit ABC transporters, thereby preventing the reduction of chemotherapeutic agent concentrations within tumor cells and enhancing their intracellular accumulation. Thus, the aim of this study was to evaluate xanthotoxin as a potential anticancer agent. The literature review was based on publications indexed in Google Scholar, Scopus, Web of Science, and PubMed and published between 2010 and 2026. Studies describing the biological properties of xanthotoxin, its toxicity, anticancer mechanisms of action, and modulation of ABC transporters were included. This literature review summarizes the pharmacological profile of xanthotoxin, and its biological activities and therapeutic potential, as well as its antitumor effects in various cancer cell lines. The available evidence may provide a foundation for the future development of xanthotoxin as a lead compound for anticancer drug discovery. Full article

For nearly a century, since the discovery of penicillin by Alexander Fleming, we have used covalent inhibitors as antimicrobial drugs. The success of penicillin in treating microbial infections led to numerous other antibiotics containing β-lactam, the reactive warhead that forms the covalent adduct, exemplified by later-generation cephalosporins with approvals into 2020. In parallel, early non-β-lactam covalent agents also emerged, extending covalent mechanisms beyond β-lactam antibacterials to antifungal, antiparasitic, and antiviral applications. Despite the successes of covalent mechanisms of action, there are still considerable safety concerns due to the possibility of off-target covalent adducts which may lead to significant side effects. This review provides an overview of non-β-lactam covalent antimicrobials across all major pathogen classes, organized by their warhead class, covalency, and resistance mechanisms, and outlines design and clinical-level mitigation strategies. We trace the field from the serendipitous discovery of penicillin to the intentional design of new drugs, with a discussion of changes in perception and evolution of technology that enable modern covalent drug design. Full article