Search Results (158)

Estrogen receptor alpha (ERα) plays a vital role in the development and progression of breast cancer by regulating the expression of genes associated with cell proliferation in breast tissue. ERα inhibition is a key strategy in the prevention and treatment of breast cancer. Previous research modified chalcone compounds into pyrazoline benzenesulfonamide derivatives (Modifina) which show activity as an ERα inhibitor. This study aimed to design novel pyrazoline benzenesulfonamide derivatives (PBDs) as ERα antagonists using in silico approaches. Structure-based and ligand-based drug design approaches were used to create drug target molecules. A total of forty-five target molecules were initially designed and screened for drug likeness (Lipinski’s rule of five), cytotoxicity, pharmacokinetics and toxicity using a web-based prediction tools. Promising candidates were subjected to molecular docking using AutoDock 4.2.6 to evaluate their binding interaction with ERα, followed by molecular dynamics simulations using AMBER20 to assess complex stability. A pharmacophore model was also generated using LigandScout 4.4.3 Advanced. The molecular docking results identified PBD-17 and PBD-20 as the most promising compounds, with binding free energies (ΔG) of −11.21 kcal/mol and −11.15 kcal/mol, respectively. Both formed hydrogen bonds with key ERα residues ARG394, GLU353, and LEU387. MM-PBSA further supported these findings, with binding energies of −58.23 kJ/mol for PDB-17 and −139.46 kJ/mol for PDB-20, compared to −145.31 kJ/mol, for the reference compound, 4-OHT. Although slightly less favorable than 4-OHT, PBD-20 demonstrated a more stable interaction with ERα than PBD-17. Furthermore, pharmacophore screening showed that both PBD-17 and PBD-20 aligned well with the generated model, each achieving a match score of 45.20. These findings suggest that PBD-17 and PBD-20 are promising lead compounds for the development of a potent ERα inhibitor in breast cancer therapy. Full article

Background/Objectives: Oncogenic KRAS drives ~30% of solid tumours, yet the only approved G12C-specific drugs benefit ≈ 13% of KRAS-mutant patients, leaving a major clinical gap. We sought mutation-agnostic natural ligands from Ziziphus lotus, whose stereochemically rich phenolics may overcome this limitation by occupying the SI/II (Switch I/Switch II) groove and locking KRAS in its inactive state. Methods: Phytochemical mining yielded five recurrent phenolics, such as (+)-catechin, hyperin, astragalin, eriodictyol, and the prenylated benzoate amorfrutin A, benchmarked against the covalent inhibitor sotorasib. An in silico cascade combined SI/II docking, multi-parameter ADME/T (Absorption, Distribution, Metabolism, Excretion, and Toxicity) filtering, and 100 ns explicit solvent molecular dynamics simulations. Pharmacokinetic modelling predicted oral absorption, Lipinski compliance, mutagenicity, and acute-toxicity class. Results: Hyperin and astragalin showed the strongest non-covalent affinities (−8.6 kcal mol⁻¹) by forging quadridentate hydrogen-bond networks that bridge the P-loop (Asp30/Glu31) to the α3-loop cleft (Asp119/Ala146). Catechin (−8.5 kcal mol⁻¹) balanced polar anchoring with entropic economy. ADME ranked amorfrutin A the highest for predicted oral absorption (93%) but highlighted lipophilic solubility limits; glycosylated flavonols breached Lipinski rules yet remained non-mutagenic with class-5 acute-toxicity liability. Molecular dynamics trajectories confirmed that hyperin clamps the SI/II groove, suppressing loop RMSF below 0.20 nm and maintaining backbone RMSD stability, whereas astragalin retains pocket residence with transient re-orientation. Conclusions: Hyperin emerges as a low-toxicity, mutation-agnostic scaffold that rigidifies inactive KRAS. Deglycosylation, nano-encapsulation, or soft fluorination could reconcile permeability with durable target engagement, advancing Z. lotus phenolics toward broad-spectrum KRAS therapeutics. Full article

Tetrastigma erubescens, a native medicinal plant of Vietnam, has long been used in folk medicine to manage various diseases, including skin-related issues. However, limited research has been conducted on this herb’s bioactivities and chemical composition. This study aims to investigate the chemical constituents and evaluate the anti-tyrosinase activity and UV-A/UV-B absorption capacity of T. erubescens extracts, highlighting their potential as natural sources for skin-whitening and sun protection agents. In vitro assays demonstrated that the ethyl acetate (EA) extract of T. erubescens exhibited a significant UV-A and UV-B absorption capacity. Notably, this extract showed a strong anti-tyrosinase activity for the first time, with a maximum inhibition rate of 99.2% and an IC₅₀ value of 70.3 µg/mL. Based on the UHPLC and GCMS analysis, phenolic compounds (1–9) and ten volatile constituents (10–19) were identified in the EA extract of T. erubescens. Of these, almost all volatiles and some phenolics were reported for the first time in this genus. The molecular docking analysis revealed that all identified phytochemicals showed a comparable or greater binding affinity to both mushroom tyrosinase (docking scores: from −7.5 to −14.1 kcal/mol) and human tyrosinase (from −6.7 to −14.8 kcal/mol) than kojic acid (−8.7 and −8.6 kcal/mol, respectively). In addition, these identified compounds showed favorable drug-like properties and low toxicity risks via ADMET prediction and Lipinski’s Rule of Five analyses. The results obtained in this work suggest that the EA extract of T. erubescens is a promising natural source of bioactive compounds for cosmetic applications, particularly in whitening and sun protection formulations. Full article

Background/Objectives: Highly pathogenic coronaviruses (CoVs), including SARS-CoV, MERS-CoV, and SARS-CoV-2, continue to pose a significant threat to global public health. Therefore, this situation highlights the urgent need for effective broad-spectrum antiviral agents. Curcumin, a naturally occurring polyphenol known for its antiviral and anti-inflammatory properties, faces limitations such as poor bioavailability and rapid metabolic degradation, restricting its practical therapeutic application. Methods: To address these limitations, this study introduces a novel design strategy aimed at 42 new curcumin derivatives with improved pharmacokinetic profiles, specifically targeting the conserved coronavirus enzyme papain-like protease (PLpro). A comprehensive in silico evaluation was performed, including ADMET (Absorption, Distribution, Metabolism, Elimination, and Toxicity) analysis, molecular docking, molecular dynamics (MD) simulations, and Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) calculations. Results: Extensive pharmacokinetic and toxicological assessments (ADMET analyses) identified 19 derivatives exhibiting optimal drug-like characteristics according to Lipinski’s Rule of Five (Ro5). Molecular docking analyses demonstrated that these novel derivatives possess significantly enhanced binding affinities to PLpro enzymes from SARS-CoV, MERS-CoV, and SARS-CoV-2 compared to standard antiviral agents and natural curcumin. Further validation through MD simulations and MM/PBSA calculations confirmed the structural stability and robust interactions of the most promising derivatives within the SARS-CoV PLpro active site. Conclusions: The results of this study provide essential structural and functional insights, reinforcing the potential of these newly developed curcumin derivatives as potent, broad-spectrum antiviral agents effective against current and future coronavirus threats. Full article

Methoxycamalexins are close structural derivatives of the indolic phytoalexin Camalexin, which is a well-known drug lead with an antiproliferative and antioxidant profile. 6-methoxycamalexin, 7-methoxycamalexin, and 6,7-dimethoxycamalexin are natural bioactive products, and there is significant interest in the development of efficient methods for the synthesis of structurally related analogues. Herein, we describe an efficient and high-yielding method for the synthesis of variously substituted hydroxy-, bezyloxy, and methoxycamalexins. A set of methoxy-, hydroxy-, and benzyloxy-indoles were successfully amidoalkylated with N-acyliminium reagents derived in situ from the reaction of thiazole or methylthiazoles with Troc chloride. Eleven novel N-acylated analogues were synthesized, with yields ranging from 77% to 98%. Subsequent oxidative reactions with o-chloranil or DDQ led to 10 novel oxy-camalexins in 62–98% yield. This two-step approach allowed the synthesis of two 4,6-dimethoxy camalexins, which are difficult to obtain using published methods. The structure of the obtained products was unequivocally determined by ¹H-, ¹³C{¹H}-, HSQC-NMR, FTIR, and HRMS spectral analyses. An in silico assay was carried out on the obtained products to assess their general toxicity and physicochemical properties, including their compliance with Lipinski’s rule of five. The results indicate that all compounds have good potential to be developed as drugs or agrochemicals. Full article

Background: Extrapolation of intrinsic clearance from in vitro systems such as liver microsomes or hepatocytes is an established approach to predict clearance in preclinical species and in humans. A common discussion in the literature is whether the predictive accuracy of such extrapolations is influenced by the chemotype and whether these methods are also applicable to compounds studied in early drug discovery programs. Compounds in such programs are frequently lipophilic and show low solubility and low free fraction in plasma, which may pose challenges to the extrapolation of clearance different from those of the final clinical candidates. A similar discussion has been raised about compounds residing beyond the traditional small-molecule property space, such as PROTACs© and other molecules incompatible with Lipinski’s rule-of-five. Methods: To further enlighten the field on these matters, we present a study comparing the predictive accuracy between mouse hepatocytes and microsomes for a set of molecules (N = 211) from the Merck Healthcare drug discovery pipeline. This set was dominated by compounds belonging to class 2 and 4 of the extended clearance classification systems (ECCS). It contained a similar proportion of molecules compliant with the Lipinski rule-of-five (N = 127) and molecules lacking such compliance (N = 84). Results: This study showed no or little differences in predictive accuracy nor bias between the two groups, with an average fold error close to 1, an absolute average fold error of just over 2, and around 50% being within 2-fold and >90% being within 5-fold of the predicted unbound clearance in both in vitro systems. Furthermore, no significant differences in accuracy were observed for compounds with an extremely low free fraction (down to 0.05%) in plasma. Conclusions: The accuracy of in vitro–in vivo extrapolation of female CD-1 mouse clearance was not affected by the physicochemical properties. Full article

Breast cancer is one of the leading causes of cancer-related mortality in women worldwide, highlighting the importance of effective therapies. This study evaluates the interaction between camptothecin, a potent anticancer agent, and two key receptors implicated in breast cancer progression: HER2 (human epidermal growth factor receptor 2) and EGFR (epidermal growth factor receptor), using molecular docking. The results reveal a stronger binding affinity between camptothecin and HER2 than EGFR, in contrast to neratinib, which demonstrated affinity exclusively for HER2. Camptothecin exhibits significant hydrophobic and pi-alkyl interactions with HER2, whereas its interactions with EGFR are primarily mediated by hydrogen bonds. Molecular dynamics (MD) simulations of the camptothecin-HER2 complex indicate stable binding, with minimal fluctuations observed over 100 nanoseconds, confirming the stability of the ligand–receptor interaction. Pharmacokinetic evaluations, based on Lipinski’s rule of five, demonstrate that camptothecin adheres to essential drug-likeness parameters, suggesting favorable bioavailability. Furthermore, the analysis comparing the pharmacological properties of camptothecin with other well-known anticancer compounds, such as neratinib, shows that camptothecin exhibited superior compliance with drug-likeness rules. Despite its low solubility, the binding stability and pharmacokinetic profile suggest its potential as an effective therapeutic agent for breast cancer, particularly when combined with drug delivery systems that enhance solubility. This work underscores the importance of receptor-specific ligand interactions in drug design and highlights the need for further studies into camptothecin’s clinical applications, especially in HER2-positive breast cancer treatment. Full article

This study reports the synthesis, characterization, and antifungal evaluation of a series of pyridoxal and salicylaldehyde derivatives, using synthetic methodologies such as radical cyclizations and click chemistry. Compounds 6a and 6b, featuring a fused dihydrobenzoxepine-pyridine scaffold, demonstrated effective fungicidal activity with MIC values of 19 µg/mL against Cryptococcus neoformans 2807. Similarly, compound 6b exhibited notable activity with a MIC of 75 µg/mL against Candida auris PUJ-HUSI 537. Both compounds outperformed fluconazole (FLC) in these strains. In silico ADMET profiling revealed favorable pharmacokinetic properties, including blood–brain barrier penetration and drug-likeness parameters consistent with Lipinski’s rule of five. Cytotoxicity assays on human fibroblasts confirmed the low toxicity of compound 6a at the tested concentrations. These results highlight the potential of the fused dihydrobenzoxepine-pyridine scaffold as a promising antifungal candidate for further investigations. Full article

The prevalence of human intestinal helminth parasitic infections is extensive, with over half of the global population estimated to suffer from these infections. Traditionally, various plant species, including Ricinus communis L. (Euphorbiaceae), are used to treat helminth infections. In this study, ricinoleic acid was isolated from the base hydrolysate of the petroleum ether seed extract of R. communis using column chromatography and transformed into ricinoleic acid methyl ester through esterification. The extract, ricinoleic acid and its methyl ester were evaluated for their anthelmintic activities against the model organism Caenorhabditis elegans. The results revealed that at a concentration of 1 mg/mL, ricinoleic acid and its methyl ester killed 97.40% and 97.83% of C. elegans worms, respectively. Molecular docking studies of ricinoleic acid on succinate dehydrogenase (SDH), glucose-6-phosphate 1-dehydrogenase (G6PD), and tubulin beta-2 chain (TBB2C) revealed that ricinoleic acid has a more favorable interaction with succinate dehydrogenase (−5.408 kcal/mol) compared to glucose-6-phosphate 1-dehydrogenase (−3.758 kcal/mol) and tubulin beta-2 chain (−1.444 kcal/mol). Furthermore, Absorption, Distribution, Metabolism, and Excretion (ADME) analyses unveiled that ricinoleic acid adheres to Lipinski’s rule of five, positioning it as a potential compound to treat helminths. The current study demonstrated that R. communis seed oil possesses genuine anthelmintic activity against C. elegans, which is likely due to ricinoleic acid. Full article

As a part of our ongoing search for bioactive constituents of Artemisia capillaris, we isolated 4-O-caffeoyl-2-C-methyl-d-threonic acid (PPT-14). This is a rare caffeic acid ester derivative that is reported here for the first time in the Artemisia species, which is the third occurrence in any plant species worldwide. In this study, we evaluated the anti-diabetic potential of PPT-14 using in vitro and in silico approaches. PPT-14 demonstrated significant inhibitory activity against two crucial enzymes linked to diabetes progression and complications: protein tyrosine phosphatase 1B (PTP1B) and aldose reductase (AR). These had IC₅₀ values of 64.92 and 19.50 µM, respectively. Additionally, PPT-14 exhibited free radical scavenging activity with 2,2-diphenyl-2-picrylhydrazyl (IC₅₀ 14.46 µM). Molecular docking and 200 ns molecular dynamics simulations confirmed that there were stable binding interactions with the key residues of PTP1B and AR, highlighting strong affinity and dynamic stability. Pharmacokinetic analyses revealed favorable water solubility, adherence to Lipinski’s Rule of Five, and minimal interactions with cytochrome P450 enzymes, indicating the drug-like potential of PPT-14. Toxicity studies confirmed its safety profile, showing no genotoxicity, hepatotoxicity, or significant toxicity risks, with an acceptable oral LD₅₀ value of 2.984 mol/kg. These findings suggest that PPT-14 could be a promising multitarget lead compound for ameliorating diabetes and its associated complications. Full article

Background/Objectives: Pteridine reductase 1 (PTR1) has been one of the prime targets for discovering novel antileishmanial therapeutics in the fight against Leishmaniasis. This enzyme catalyzes the NADPH-dependent reduction of pterins to their tetrahydro forms. While chemotherapy remains the primary treatment, its effectiveness is constrained by drug resistance, unfavorable side effects, and substantial associated costs. Methods: This study addresses the urgent need for novel, cost-effective drugs by employing in silico techniques to identify potential lead compounds targeting the PTR1 enzyme. A library of 1463 natural compounds from AfroDb and NANPDB, prefiltered based on Lipinski’s rules, was used to screen against the LmPTR1 target. The X-ray structure of LmPTR1 complexed with NADP and dihydrobiopterin (Protein Data Bank ID: 1E92) was identified to contain the critical residues Arg17, Leu18, Ser111, Phe113, Pro224, Gly225, Ser227, Leu229, and Val230 including the triad of residues Asp181-Tyr194-Lys198, which are critical for the catalytic process involving the reduction of dihydrofolate to tetrahydrofolate. Results: The docking yielded 155 compounds meeting the stringent criteria of −8.9 kcal/mol instead of the widely used −7.0 kcal/mol. These compounds demonstrated binding affinities comparable to the known inhibitors; methotrexate (−9.5 kcal/mol), jatrorrhizine (−9.0 kcal/mol), pyrimethamine (−7.3 kcal/mol), hardwickiic acid (−8.1 kcal/mol), and columbamine (−8.6 kcal/mol). Protein–ligand interactions and molecular dynamics (MD) simulation revealed favorable hydrophobic and hydrogen bonding with critical residues, such as Lys198, Arg17, Ser111, Tyr194, Asp181, and Gly225. Crucial to the drug development, the compounds were physiochemically and pharmacologically profiled, narrowing the selection to eight compounds, excluding those with potential toxicities. The five selected compounds ZINC000095486253, ZINC000095486221, ZINC000095486249, 8alpha-hydroxy-13-epi-pimar-16-en-6,18-olide, and pachycladin D were predicted to be antiprotozoal (Leishmania) with Pa values of 0.642, 0.297, 0.543, 0.431, and 0.350, respectively. Conclusions: This study identified five lead compounds that showed substantial binding affinity against LmPTR1 as well as critical residue interactions. A 100 ns MD combined with molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) calculations confirmed the robust binding interactions and provided insights into the dynamics and stability of the protein–ligand complexes. Full article

The progressive development of resistance in Neisseria gonorrhoeae to almost all available antibiotics has made it crucial to develop novel approaches to tackling multi-drug resistance (MDR). One of the primary causes of antibiotic resistance is the over-expression of the MtrCDE efflux pump protein, making this protein a vital target for fighting against antimicrobial resistance (AMR) in N. gonorrhoeae. This study was aimed at evaluating the potential MtrCDE efflux pump inhibitors (EPIs) and their stability in treating gonorrhoea infection. This is significant because finding novel EPIs would allow for the longer maintenance of antibiotics at therapeutic levels, thereby prolonging the susceptibility of currently available antibiotics. A virtual screening of the selected Helichrysum populifolium compounds (4,5-dicaffeoylquinic acid, apigeninin-7-glucoside, and carvacrol) was conducted to evaluate their potential EPI activity. An integrated computational framework consisting of molecular docking (MD), molecular mechanics generalized born, and surface area solvation (MMGBSA) analysis, molecular dynamics simulations (MDS), and absorption, distribution, metabolism, and excretion (ADME) properties calculations were conducted. Of the tested compounds, 4,5-dicaffeoylquinic acid revealed the highest molecular docking binding energies (−8.8 kcal/mol), equivalent MMGBSA binding free energy (−54.82 kcal/mol), indicative of consistent binding affinity with the MtrD protein, reduced deviations and flexibility (root mean square deviation (RMSD) of 5.65 Å) and, given by root mean square fluctuation (RMSF) of 1.877 Å. Carvacrol revealed a docking score of −6.0 kcal/mol and a MMGBSA computed BFE of −16.69 kcal/mol, demonstrating the lowest binding affinity to the MtrD efflux pump compared to the remaining test compounds. However, the average RMSD (4.45 Å) and RMSF (1.638 Å) of carvacrol-bound MtrD protein showed no significant difference from the unbound MtrD protein, except for the reference compounds, implying consistent MtrD conformation throughout simulations and indicates a desirable feature during drug design. Additionally, carvacrol obeyed the Lipinski rule of five which confirmed the compound’s drug-likeness properties making it the most promising EPI candidate based on its combined attributes of a reasonable binding affinity, sustained stability during MDS, its obedience to the Lipinski rule of five and compliance with drug-likeness criteria. An in vitro validation of the potential EPI activities of H. populifolium compounds confirmed that 4,5-dicaffeoylquinic acid reduced the expulsion of the bis-benzimide dye by MtrCDE pump, while carvacrol showed low accumulation compared to other compounds. While 4,5-dicaffeoylquinic acid demonstrated the highest binding affinity in computational analysis and an EPI activity in vitro, it showed lower stability compared to the other compounds, as indicated in MDS. This leaves carvacrol, as a better EPI candidate for the management of gonorrhoea infection. Full article

Small-molecule probes are powerful tools for studying biological systems and can serve as lead compounds for developing new therapeutics. Especially, nitrogen heterocycles are of considerable importance in the pharmaceutical field. These compounds are found in numerous bioactive structures. Their synthesis often requires several steps or the use of functionalized starting materials. This review describes the use of vicinal diamines generated from modified short peptides to access substituted diaza- and triazacyclic compounds. Small-molecule diaza- and triazacyclic compounds with different substitution patterns and embedded in various molecular frameworks constitute important structure classes in the search for bioactivity. The compounds are designed to follow known drug likeness rules, including “Lipinski’s Rule of Five”. The screening of diazacyclic and traizacyclic libraries has shown the utility of these classes of compounds for the de novo identification of highly active compounds, including antimalarials, antimicrobial compounds, antifibrotic compounds, potent analgesics, and antitumor agents. Examples of the synthesis of diazacyclic and triazacyclic small-molecule libraries from vicinal chiral polyamines generated from modified short peptides and their application for the identification of highly active compounds are described. Full article

Antimicrobial chemotherapeutic failure as a result of pathogenic resistance stain is great concern across the globe, there is need to search for an effective antimicrobial agent from synthetic sources to overcome emergent of microbial resistant in clinical practice. The phenylhydrazone derivatives were scientifically found to have wide application in the field of drug discovery due to their anticancer, anti-tubercular, antibacterial, and antifungal activities. The (E)-Substituted-N-(phenylhydrazones) derivatives were obtained by a condensation reaction between substituted acetophenone and substituted phenyl hydrazine through a one-step reaction, resulting of five (5) novel compounds such as HS1 (E)-1-(1-(4-bromophenyl)ethylidene)-2-(2,4-dinitrophenyl)hydrazine), HS2(E)-1-(1-(4-bromophenyl)ethylidene)-2-(4-nitrophenyl)hydrazine), HS3(E)-1-(4-nitrophenyl)-2-(1-(3-nitrophenyl)ethylidene)hydrazine), HS4(E)-1-(2,4-dinitrophenyl)-2-(1-(3-nitrophenyl)ethylidene)hydrazine), and HS5 (E)-1-(1-(3-nitrophenyl)ethylidene)-2-phenylhydrazine) and the in-silico prediction of physicochemical properties were found within Lipinski’s rule of five and the synthesized compounds were established by structurally elucidations on the basis of FTIR, 1D and 2D NMR spectral analysis and the newly synthesized compounds were then subjected to antimicrobial assessment for an in vitro test evaluation using the inhibition zone technique, minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and minimum fungicidal concentration (MFC). Full article

The threatening phenomenon of antibiotic failure in the future determines the intensive research of antibacterial active compounds, which are promising candidates as antibiotics. Quinolines, with only the representative in clinical practice being Nitroxoline^TM, are, in addition to being effective beta-lactams, macrolides, tetracyclines, and other antibiotic categories, forgotten antibiotics. The antibacterial efficiency of Nitroxoline^TM and 2-aminoquinolin-8-ol on eight selected highly resistant bacterial species that are the most problematic (Klebsiella ssp., Enterococcus ssp., Pseudomonas aeruginosa, Acinetobacter baumannii, and Staphylococcus aureus) could lead to higher solubility and thus bioavailability and increased antibacterial effects. In the first phase, the basic salts of Nitroxoline^TM, with sodium hydroxide, benzylamine, 4-(aminomethyl)pyridine, and other primary amines, were synthesized. In the second phase, the corresponding acidic salts of 2-aminoquinolin-8-ol were synthesized with the following acids: oxalic acid, pyrazine-2,3-dicarboxylic acid, chelidonic acid, quinaldic acid, 3,5-dinitrosalycilic acid, quinoline-2-carboxylic acid, quinoline-3-carboxylic acid, kynurenic acid, and xanthurenic acid. Nitroxoline^TM and 2-aminoquinolin-8-ol both demonstrated moderate antibacterial effects, with the average value for the eight mentioned bacterial strains being 16 mg/L (84 μM) and 50 mg/L (301 μM), respectively. The synthetized salts of both quinolinols demonstrated significantly higher solubility and slightly increased antibacterial activity. The identity and purity of the prepared products were determined by NMR and IR spectroscopy. The MW values of both quinolinols are relatively low and offer better use of the largest molecule limit, defined by Lipinski’s rule of five at 500 g/M. The options of amines and acids offer the achievement of quaternary salts with improved antibacterial activity. Full article