Search Results (232)

Background/Objectives: Fraxetin (7,8-dihydroxy-6-methoxycoumarin), a coumarin constituent of Cortex Fraxini (Qinpi) used in traditional Chinese medicine, is metabolised mainly by UGT1A9, but its potential to inhibit UGT enzymes and cause herb–drug interactions (HDIs) is largely unstudied. Methods: Fraxetin and four related coumarins were screened against 11 recombinant human UGTs; isoforms inhibited ≥80% underwent full kinetic analysis with 4-methylumbelliferone as probe. Binding was examined by molecular docking on AlphaFold structures with PLIP, triplicate 100 ns molecular dynamics, and MM/GBSA and MM/PBSA free-energy calculations, and interaction risk by FDA 2020 in vitro–in vivo extrapolation (IVIVE). Results: Fraxetin alone inhibited both UGT1A1 and UGT1A9 by >80% and was characterised in detail, acting as a mainly competitive mixed-type inhibitor (UGT1A1 IC₅₀ 15.99 μM, K_i 8.32 μM; UGT1A9 IC₅₀ 8.44 μM, K_i 5.90 μM). A structure–activity comparison identified a dual-element pharmacophore comprising the C-6 methoxy group and the 7,8-dihydroxycoumarin aglycone. MM/GBSA favoured UGT1A9 over UGT1A1 (ΔΔG = −4.06 kcal/mol, p = 0.005), concordant with the kinetic ranking. IVIVE predicted a borderline systemic signal (R₁ > 1.02) but an intestinal R_1,gut approximately five- to seven-fold above the high-risk threshold of 11 after capping the luminal concentration at fraxetin aqueous solubility. Conclusions: This is the first characterisation of fraxetin as a moderate-potency inhibitor of UGT1A1 and UGT1A9 and points to a previously under-recognised herb–drug interaction risk concentrated in the intestinal lumen rather than systemically; the finding constitutes an interaction signal requiring clinical confirmation rather than an established risk. Full article

Methyl methacrylate (MMA)-based materials are widely used in temporary and permanent prosthetic dentistry; the prolonged presence of these materials in the oral cavity and potential residual monomer release can affect local biological responses. This study aimed to evaluate the biocompatibility and toxicity profiles of MMA, the monomeric unit of polymethyl methacrylate (PMMA), a key component of dental materials used in temporary prosthetic restorations. Molecular docking simulations were performed using CB-Dock2 and Autodock vina, while protein–protein interaction (PPI) analysis was performed using STRING and Cytoscape. In addition, Swiss ADME Target Prediction, toxicity prediction, and enrichment analyses were used to characterize the biological significance of selected targets in more detail. Molecular docking studies revealed promising interactions of MMA with valuable biomolecular targets relevant to biocompatibility. The toxicity profile revealed aspects of MMA that could be improved. Pharmacophore modeling, highlighting the importance of carbonyl and hydroxyl groups as pharmacophoric properties, revealed compounds with suitable biocompatibility profiles. Consequently, it emphasizes the interactions of MMA with biomolecules and safety considerations. It can guide the design and optimization of biocompatible materials as an exploratory avenue for future developments in dental biomaterials. Full article

Hypertension is one major risk factor of cardiovascular diseases, and RAS plays vital role during the development of hypertension. To obtain a novel antihypertensive peptide, Coix glutelin was hydrolyzed by trypsin and further separated by Sephadex G10. Based on 751 identified sequences, pharmacophore mapping, molecular docking, and in silico proteolysis were applied to screen and optimize the candidate sequence. Finally, a novel peptide, ENWAAL, was generated with IC₅₀ of 210.57 μM, which acted with ACE in a competitively inhibitory pattern. The in vivo antihypertensive effect was evaluated in SHRs. Significant improvements were observed in hypertension-related characteristics, including blood pressure, cardiac structure and function, and serum angiotensin II (Ang II) level. In the brain, quantitative real-time PCR analysis revealed significant downregulation of angiotensin II type 1 receptor (AT1R) mRNA expression, concomitant with upregulation of angiotensin-converting enzyme 2 (ACE2) and MAS receptor. The protein expression of ACE and AT1R in the ENWAAL group also significantly decreased. This study can provide a candidate antihypertensive drug targeting RAS. Full article

Our review focuses on methanesulfonamide-containing compounds, a well-characterized class of high-affinity blockers of the hERG potassium channel, which plays a critical role in cardiac repolarization by mediating the cardiac I_Kr. These compounds, which include notable class III antiarrhythmic drugs such as dofetilide and d-sotalol, block the hERG channel in its open state by binding within the inner vestibule. This interaction is particularly strong with some residues and the compounds form hydrogen bonds with others. This binding results in high-affinity inhibition with slow dissociation kinetics, frequently leading to drug trapping and prolonged action potential duration (APD). This can predispose patients to arrhythmias, including Torsades de Pointes. Beyond cardiac drugs, there are several non-cardiac methanesulfonamide drugs that also block the hERG channel. This causes pro-arrhythmic side effects despite their primary indications. The clinical significance of these effects, especially in patients with impaired drug elimination, is that accumulation increases the risk of arrhythmia. The objective of forthcoming research endeavors is to mitigate hERG affinity, with the aim of reducing pro-arrhythmic risks while maintaining therapeutic efficacy. This means structural modifications that seek to remove or modify the methanesulfonamide group. Machine learning also emerged as promising tool for exploring drug–protein interactions. It is evident that the methanesulfonamide moiety plays a pivotal role in the structural basis of hERG blockade. However, it should be noted that this moiety does not necessarily represent a universal pharmacophore. This observation underscores the necessity for a nuanced approach in drug development, aimed at achieving a balance between efficacy and safety. Full article

Phytocompounds undoubtedly are structurally diverse and play a crucial role in the development of novel therapeutic agents. 2-Hydroxy-4-methoxybenzaldehyde (HMB), from Hemidesmus indicus, is a potent antibacterial agent. Yet its pharmacophore has not been mechanistically defined. Here, we deconstructed HMB through a panel of structural derivatives to delineate the core structural determinants driving activity against foodborne pathogens. Structure–activity analysis revealed that the core benzaldehyde structure, rather than HMB itself, is the minimal active pharmacophore, with specific functional substitutions modulating antibacterial activity and membrane affinity. Integrating an experimental membrane assay with molecular dynamics simulations provided the first atomistic insight into how these derivatives interact with bacterial membrane lipids, demonstrating that substituent-driven modulation of hydrogen bonding dictates antibacterial potency. Specifically, electron-withdrawing groups enhanced membrane penetration and depolarization, particularly in Gram-positive pathogens. Time–kill kinetics and functional assays confirmed bactericidal action via membrane disruption rather than DNA interaction. Crucially, the active derivatives exhibited negligible cytotoxicity toward mammalian Vero cells, confirming their potential as selective and safe natural preservatives. This work provides a mechanistic blueprint for designing benzaldehyde-based antibacterials to combat antimicrobial resistance. Full article

A DABCO-catalyzed one-pot synthesis of a novel pentacyclic heterocycle featuring an unprecedented benzo[4,5]imidazo[1,2-a]chromeno[3,2-e]pyridine scaffold from 2-(cyanomethyl)benzimidazole and 3-trifluoroacetyl-4-phenyl-4H-chromene has been developed. This hybrid architecture merges three privileged pharmacophores—benzimidazole, chromene, and pyridine—into a rigid, nearly planar π-extended system decorated with trifluoromethyl and nitrile groups. The structure of 8-phenyl-13a-(trifluoromethyl)-13aH-benzo[4,5]imidazo[1,2-a]chromeno[3,2-e]pyridine-6-carbonitrile was unambiguously confirmed through NMR spectroscopy and X-ray diffraction analysis. A plausible mechanism involves Michael addition, hemiaminal formation, ring opening, recyclization, and oxidation. Full article

Background: 8-Hydroxyquinoline and phthalimide are two significant heterocyclic scaffolds in medicinal chemistry due to their pharmacological profiles. Hybridizing these pharmacophores and further modifying them via modified Mannich reactions provides a strategy to improve their physicochemical parameters and selectivity toward multidrug-resistant (MDR) cancer cells. Objectives: To synthesize a series of 8-hydroxyquinoline–phthalimide hybrids and their Mannich base derivatives and evaluate their cytotoxic activity and resistance-selective properties against sensitive Colo205 and resistant Colo320 cancer cell lines. Methods: Four hybrid compounds were synthesized by reacting 5-amino-8-hydroxyquinoline with different phthalic anhydride derivatives. Twelve fine-tuned derivatives were prepared by using the modified Mannich reaction. Cytotoxic activity was measured using the MTT assay, and relative resistance (RR) was calculated to determine selectivity toward the resistant cell line. P-glycoprotein (Pgp) ATPase activity was evaluated for the most active compounds. Results: All derivatives displayed cytotoxic activity, with higher potency toward the resistant Colo320 cell line. Compounds 2 and 4 showed the strongest activity against both cell lines (IC₅₀ down to 4.88 µM). Compounds 5, 8a, 9a, and 9c retained potent activity against Colo320 (IC₅₀ = 9.89–22.79 µM). Incorporating a CH₂–N group at position C7 substantially enhanced the selectivity for MDR cells. Compounds 9c, 9a, and 8a exhibited the highest selectivity, with RR values of 0.29, 0.33, and 0.35, respectively. Compounds 2, 4, 5, 8a, and 9a showed inhibitory effects on Pgp ATPase activity. Conclusions: The newly synthesized HQ–phthalimide hybrids represent promising candidates for targeting MDR in colorectal cancer, with Mannich modification enhancing the selectivity toward resistant cells. Full article

The species Inula helenium belongs to the genus Inula (Asteraceae) and exhibits antibacterial and anti-inflammatory properties. It is used in respiratory and skin diseases. Its bioactivity is attributed to its eudesmanolide components, mainly to alantolactone and isoalantolactone. These components were isolated in high purity from the plant’s dried roots, either via multiple column chromatography separations or via repeated recrystallization. Two more eudesmanolides structurally similar to their parent compounds were isolated, namely 11,13-dihydro-alantolactone and 11,13-dihydro-isoalantolactone. The secondary metabolites and their derivatives were characterized in detail, for the first time, via NMR spectroscopy, GC-MS, and HRMS. Synthetic modification of the natural component structure was considered necessary for structure–activity relationship studies and biological tests. Thus, each compound was converted to its nitrile and then to the corresponding acid, or to its azide derivative and then corresponding amine. Antioxidant studies were conducted on the parent compounds, their derivatives, and the methanolic and hexane plant extracts using the DPPH radical method. The study revealed a strong antioxidant capacity of the methanolic extract. Acaricidal studies of both natural products and synthetic analogs against Varroa destructor and the comparison of their activity with the parent natural product costic acid, as well as one of its synthetic congeners, indicated that the “from nature to synthesis and vice versa” approach led to active compounds as well as to meaningful conclusions regarding the “pharmacophore” groups in the structural framework of the acaricides. Full article

Background: Melanin protects skin and hair from the effects of ultraviolet (UV) radiation damage, which contributes to all forms of skin cancer, including melanoma. Human melanocytes produce two main types of melanin: eumelanin provides effective photoprotection, and pheomelanin offers less protection against UV-induced skin damage. The agouti signaling protein (ASIP) antagonizes the melanocortin-1 receptor (MC1R), hinders melanocyte signaling, and shifts pigmentation toward pheomelanin, promoting UV vulnerability. In this study, we aim to discover compounds that inhibit ASIP–MC1R interaction and effectively preserve eumelanogenic signaling. Methods: The ASIP–MC1R interface-based pharmacophore model from ASIP is implicated in MC1R receptor protein engagement. We performed virtual screening with a validated pharmacophore model for ~4000 compounds curated from ZINCPharmer and applied drug-likeness filters, viz. ADMET and toxicity profiling tests. Further, the screened candidates were targeted for docking to the ASIP C-terminal domain corresponding to the MC1R-binding moiety. Top compounds underwent a 100-nanosecond (ns) run of molecular dynamics (MD) simulations to assess complex stability and persistence of key contacted residues. Results: Sequential triage, including pharmacophore, ADME–toxicity (ADMET), and docking/ΔG, yielded a focused group of candidates against ASIP antagonists with a favorable fit value. The MD run for 100 ns supported pose stability at the targeted pocket. Based on these predictions and analyses, compound ZINC14539068 was screened as a new potent inhibitor of ASIP to preserve α-MSH-mediated signaling of MC1R. Conclusions: Our in silico pipeline identifies ZINC14539068 as a potent inhibitor of ASIP at its C-terminal interface. This compound is predicted to disrupt ASIP–MC1R binding, thereby maintaining eumelanin-biased signaling. These findings motivate experimental validation in melanocytic models and in vivo studies to confirm pathway modulation and anti-melanoma potential. Full article

A strategy for constructing trifluoromethylated spiroisoxazolones has been developed. This approach relies on the 1,3-dipolar cycloaddition of CF₃-substituted nitrile imines, generated in situ from trifluoroacetyl hydrazonoyl bromides and K₂CO₃, with the exocyclic double bond of 4-benzylidene-3-methylisoxazol-5(4H)-ones. The reaction provides a series of trifluoromethylated spiro(isoxazolone-pyrazoline) derivatives in moderate to high yields (up to 93%). The protocol exhibits broad substrate compatibility with respect to aromatic substituents on both reaction partners. To the best of our knowledge, the introduction of a trifluoromethyl group at the 3-position of the pyrazoline ring via nitrile imine cycloaddition chemistry has not been previously reported. The resulting products incorporate a valuable CF₃-substituted pyrazoline pharmacophore spiro-fused to an isoxazolone core and may be of interest for medicinal chemistry programs. Full article

Carboxyxanthones containing carboxylic acid groups linked to lipophilic aromatic rings resemble the key pharmacophoric features of many nonsteroidal anti-inflammatory drugs (NSAIDs). This structural similarity makes them attractive scaffolds for the development of new anti-inflammatory agents. This study describes the production, cytocompatibility, and anti-inflammatory potential of ten carboxyxanthones (1–10) and two intermediates (11–12) by evaluating their effects on key pro-inflammatory mediators, namely interleukin 6 (IL-6) and prostaglandin E2 (PGE₂). As these compounds are produced by distinct mechanisms, their multi-target potential will be evaluated. Carboxyxanthones were obtained by multi-step pathways using different synthetic approaches through classical benzophenone or diaryl ether intermediates synthesis followed by intramolecular acylation. To the best of our knowledge, the synthesis of carboxyxanthones 3 and 5 is described herein for the first time. All tested compounds were cytocompatible with lipopolysaccharide (LPS)-stimulated macrophages. The most notable carboxyxanthones were 3, 4, 7, and 8, which were able to significantly reduce IL-6 production by approximately 60%. Molecular docking simulations between compounds 1–12 and cyclooxygenase-2 were conducted to characterize the structural features underlying molecular recognition, and to identify the most promising candidates for subsequent PGE₂ assays. Carboxyxanthones 3, 5, and 6, as well as intermediate 12, were predicted to be the best. In the human in vitro inflammation model used, carboxyxanthone 6 exhibited the most potent and consistent inhibitory effect on PGE₂ production. At the highest concentration tested (100 µM), it presented an efficacy comparable to that of celecoxib. Carboxyxanthones 3 and 5 demonstrated a biphasic effect, decreasing and increasing PGE₂ production at lower (5, 12.5, and 25 µM) and higher (50 and 100 µM) concentrations, respectively. These results highlight the potential of carboxyxanthones as promising modulators of inflammatory pathways, paving the way for further studies aimed at elucidating their mechanisms of action, optimizing structural features, and assessing their safety and therapeutic potential in relevant disease models. Full article

Introduction: Globally, microbial infections are projected to be among the leading causes of death by 2050 due to rising drug resistance. Antimicrobials are vital for treating both animals and humans worldwide. However, their overuse and misuse accelerate drug resistance, posing a serious threat to public health. Coumarin is a naturally occurring compound contributing health-beneficial features in drug discovery. Its high solubility in organic solvents, high bioavailability, simple structure, low toxicity, and low molecular weight make it an ideal candidate for combining with other pharmacophores to develop new therapeutic agents. This compound exhibits several biological activities, including antimicrobial, anticancer, anti-inflammatory, antidiabetic, neuroprotective, and anticoagulant effects, motivating medicinal researchers to hybridize it with other compounds to enhance its pharmacological efficacy. Hybridization of different pharmacophores via suitable linkers, including cleavable and non-cleavable ones, is a promising approach in drug development, resulting in new therapeutics with improved biological activity. Therefore, the hybridization of coumarin with other pharmacophores has become an interesting paradigm for medicinal scientists. Aim: This review aims to summarize the existing scientific literature on coumarin-based hybrid compounds with antimicrobial capabilities and discuss the structure–activity relationship (SAR) of these hybrids to potentially guide future research on and development of coumarin-based drugs for microbial treatment. Material and Methods: The review focuses on open-access literature about coumarin hybrid drugs available through searching tools such as Google, Google Scholar, ScienceDirect, and Scopus, published from 2024 to 2025. Results: Coumarin hybrids exhibit promising antimicrobial activity, particularly against S. aureus and C. albicans. The SAR reveals that halogenation, bulky aromatics, nitro, and hydroxyl groups enhance the interaction of the coumarin rings with amino acid residues. Conclusions: The reported coumarin hybrids showed a promising antimicrobial activity, with structural modifications influencing their activity. Hence, more studies, including more pre-clinical and clinical evaluations, are recommended for these hybrid compounds. Full article

Bile acids provide a versatile platform for the design of biologically active compounds due to their amphiphilic structure, biocompatibility, and capacity for diverse chemical modifications. Among them, lithocholic acid is a promising scaffold for designing and revealing new antiviral agents. A novel lithocholic acid-based 3-spiro-1,2,4-trioxolane was synthesized by Griesbaum co-ozonolysis of methyl 3-O-methyl-oximino-lithocholate and 4-(trifluoromethyl)-cyclohexanone, and its structure was confirmed by 2D NMR and X-ray crystallographic analysis. Lithocholic acid derivatives were evaluated for cytotoxicity and anti-influenza activity against A/Puerto Rico/8/34 (H1N1), showing that steroid 1,2,4-trioxolane 3 exhibited the highest potency (IC₅₀ 4.3 µM, SI 11) compared to the parent methyl-3-oxo-lithocholate 1 (IC₅₀ > 84 µM, SI 1). In silico ADME predictions revealed several favorable drug-like properties, including a highly three-dimensional structure (Fsp³ = 0.97), significant lipophilicity (LogP = 7.54), and the presence of key pharmacophores such as a peroxide moiety and a trifluoromethyl group. Taken together, a stereospecific synthesis of a lithocholic acid 3-spiro-1,2,4-trioxolane by Griesbaum co-ozonolysis was realized and the first evidence of anti-influenza activity in the steroid-1,2,4-trioxolane series was found. Full article

Dermatophytes can cause infections of the skin, hair and nails. This study aims to investigate the thiosemicarbazides with nitroimidazole moiety against Trichophyton spp. The activity of fourteen thiosemicarbazide derivatives was evaluated against Trichophyton spp. The minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC) showing 50% and 90% reduction in fungal growth after 4–7 days of incubation (MFC₅₀ and MFC₉₀) were used. The 6 and 11 (MICs ≤ 125 µg/mL), followed by the 3, 5 and 7 containing a fluorophenyl group (MIC = 125 µg/mL, MFC = 125–250 µg/mL) exhibited the best activity and specifically T. mentagrophytes, respectively. Fluorine-containing derivatives (5–9) demonstrated 2–4-fold higher activity (MIC = 31.25–1000 µg/mL) against T. rubrum than T. mentagrophytes, than their chlorinated counterparts (2–4) with MIC = 62.5–500 µg/mL. The position of the fluorine atom within the phenyl ring was important, as observed for derivatives with fluorine in the meta position (3, 6), while the para position was associated with enhanced selectivity. A methoxy group in the meta position of the phenyl ring exhibited the strongest, broadest-spectrum activity. Notably, the introduction of the trifluoromethylphenyl moiety (pharmacophore) led to the disappearance of antifungal properties. Full article

Background: The synthesis and biological investigation of pyrrolidine (L-gulo) iminosugars bearing an organic boron pharmacophore in ortho and meta positions of an N-benzyl group is reported. This paper completes the structure–activity relationship data for this novel family of boron-bearing iminosugars. These can establish reversible intramolecular interactions via dative bonding from nucleophilic amino acid side chains to the empty p-orbital of the boron atom. Methods: Inhibitory activities against two panels of glycosidases and cancer cell lines were investigated to ascertain structure–activity relationship profiles for these novel iminosugar drug leads. Results: These iminosugars display selective, moderate-to-weak inhibitions (IC₅₀s = 116–617 μM) of β-D-galactosidase (bovine liver), and indications of inhibition of β-D-glucosidases (almond, bovine liver) (IC₅₀s = 633 and 710 μM) and α-D-glucosidases (rice, yeast, rat intestinal maltase) (IC₅₀s = 106–784 μM). The boronic acid group emerges as a useful pharmacophore for management of lysosomal storage disorders via the chaperone-mediated therapy approach. The cancer assays revealed that the A2780 ovarian carcinoma cell line is selectively inhibited by all compounds screened and the MIA-Pa-Ca2 pancreatic carcinoma cell line is selectively inhibited by most compounds. Growth inhibition and GI₅₀ values were most potent for the meta 7 side-product. Conclusions: Beyond the cancer cell line inhibition and dose-response capabilities, the real therapeutic potential of these borylated drugs lies in their switch on/switch off activation under boron neutron capture therapy (BNCT) radiotherapeutic conditions, thus providing an important area of application for borylated monosaccharides. Full article