Search Results (217)

One of the best-known flavonoid chrysin was coupled at position 7 with several trisubstituted phosphine derivatives with a flexible spacer, and their in vitro anticancer activities were investigated on 60 human tumor cell lines (NCI60) and on several gynecological cancer cells. The trisubstituted phosphines contained different substituents on the aromatic ring(s), e.g., methyl and methoxy groups or fluoro atoms. The phosphorus atom was substituted not only with aromatic rings but with cyclohexyl substituents. The ionic phosphonium building block is important because it allows the therapeutic agents to transfer across the cell membrane. Therefore, the pharmacophores linked to it can exert their effects in the mitochondria. Instead of the ionic phosphonium element, a neutral moiety, namely the triphenylmethyl group, was also added to the side chain, being sterically similar but without a charge and phosphorus atom. Most of the hybrids exhibited low micromolar growth inhibition (GI₅₀) values against the majority of the tested cell lines. Notably, conjugate 3f stood out, demonstrating nanomolar antitumor activity against the K-562 leukemia cell line (GI₅₀ = 34 nM). One selected compound (3i) with promising cancer selectivity elicited cell cycle disturbances and inhibited the migration of breast cancer. The tumor-selectivity of 3a and 3f was assessed based on their effects on non-tumor Chinese hamster ovary (CHO) cells using the CellTiter-Glo Luminescent Cell Viability Assay. Given their estimated half-maximal inhibitory concentration (IC₅₀) values on non-tumor CHO cells (2.65 µM and 1.15 µM, respectively), these conjugates demonstrate promising selectivity toward several cancer cell lines. The excellent results obtained may serve as good starting points for further optimization and the design of even more effective flavonoid- and/or phosphonium-based drugs. Full article

Background/Objectives: In this work, a series of six new indazole-benzimidazole hybrids (M1–M6) were designed, synthesized, and fully characterized. The design of these compounds was based on the combination of two pharmacophoric units, indazole and benzimidazole, both known for their broad spectrum of biological activities. Methods: The molecular hybridization strategy was planned to combine these scaffolds through an effective synthetic pathway, using 6-nitroindazole, two 2-mercaptobenzimidazoles, and 1,3- or 1,5-dihaloalkanes as key precursors, affording the desired hybrids in good yields and with enhanced biological activity. Quantum chemical calculations were performed to investigate the structural, electronic, and electrostatic properties of M1–M6 molecules using Density Functional Theory (DFT) at the B3LYP/6-311++G(d,p) level. The antimicrobial activity efficacy of these compounds was assessed in vitro against four Gram-positive bacteria (Staphylococcus aureus, Enterococcus faecalis, Bacillus cereus, and Lactobacillus plantarum), four Gram-negative bacteria (Salmonella enteritidis, Escherichia coli, Campylobacter coli, Campylobacter jejuni), and four fungal strains (Saccharomyces cerevisiae, Candida albicans, Candida tropicalis, and Candida glabrata) using ampicillin and tetracycline as reference standard drugs. Results: Among the series, compound M6 exhibited remarkable antimicrobial activity, with minimum inhibitory concentrations (MIC) of 1.95 µg/mL against S. cerevisiae and C. tropicalis, and 3.90 µg/mL against S. aureus, B. cereus, and S. enteritidis, while the standards Ampicillin (AmB) (MIC ≥ 15.62 µg/mL) and Tetracycline (TET) (MIC ≥ 7.81 µg/mL) exhibited higher MIC values. To gain molecular insights into the compounds, an in silico docking study was performed to determine the interactions of M1–M6 ligands against the antimicrobial target beta-ketoacyl-acyl carrier protein (ACP) synthase III complexed with malonyl-COA (PDB ID: 1HNJ). Molecular modeling data provided valuable information on the structure-activity relationship (SAR) and the binding modes influencing the candidate ligand-protein recognition. Amino acid residues, such as Arg249, located in the solvent-exposed region, were essential for hydrogen bonding with the nitro group of the 6-nitroindazole moiety. Furthermore, polar side chains such as Asn274, Asn247, and His244 participated in interactions mediated by hydrogen bonding with the 5-nitrobenzimidazole moiety of these compound series. Conclusions: The hybridization of indazole and benzimidazole scaffolds produced compounds with promising antimicrobial activity, particularly M6, which demonstrated superior potency compared to standard antibiotics. Computational and docking analyses provided insights into the structure–activity relationships, highlighting these hybrids as potential candidates for antimicrobial drug development. Full article

Risdiplam is the first approved small-molecule therapy for spinal muscular atrophy (SMA), a severe, progressive neuromuscular disorder. In addition to its clinical significance, risdiplam is of a great interest for organic and medicinal chemistry due to its complex molecular architecture. Its structure incorporates three highly substituted heterocyclic fragments—imidazo[1,2-b]pyridazine, pyrido[1,2-a]pyrimidin-4-one, and 4,7-diazaspiro[2.5]octane—that serve as both versatile synthetic building blocks and critical pharmacophoric elements for drug design and discovery. The increasing scientific interest in risdiplam has led to numerous publications and patent applications that describe alternative synthetic methodologies. Recently, our group has also developed and introduced efficient, scalable manufacturing routes for the preparation of the target substance and the key intermediates of its synthesis. This mini-review systematically analyzes a plethora of risdiplam assembly strategies and synthetic approaches, covering developments from 2013 to the present. Full article

Cytisine, a naturally occurring alkaloid and partial agonist of nicotinic acetylcholine receptors (nAChRs), has long been used as a smoking cessation aid and serves as the pharmacophore for varenicline. Recent research has expanded its therapeutic scope to neurodegenerative and neurological disorders, motivating the development of new cytisine derivatives. Among these, N-propargylcytisine combines the biological activity of the parent compound with the synthetic versatility of the terminal alkyne group. Herein, we report the synthesis and characterization of N-propargylcytisine, and its symmetrical dimer linked through 1,3-diyne moiety obtained via a copper-mediated Glaser–Hay oxidative coupling. The products were analyzed by NMR, FT-IR, and mass spectrometry, confirming the introduction of the propargyl moiety and the formation of the diyne bridge. Solvatochromic study of both compounds were performed using UV-VIS absorption spectroscopy in solvents of varying polarity, including protic solvents capable of hydrogen bonding. The 1,3-diyne motif, commonly found in bioactive natural products, endows the resulting dimer with potential for further derivatization and biological evaluation. This study demonstrates the utility of the Glaser–Hay reaction in the functionalization of alkaloid scaffolds and highlights the prospects of N-propargylcytisine derivatives in drug discovery targeting the central nervous system. Full article

Parkinson’s disease is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons, resulting in multiple motor and cognitive impairments. Among the hypotheses proposed for its etiology, oxidative stress mediated by the enzyme monoamine oxidase B (MAO-B) stands out, as it is directly associated with dopamine metabolism. In this context, the search for molecules with potential antiparkinsonian activity and low toxicity, particularly those of natural origin, has been extensively investigated using computational approaches. In the present study, a pharmacophore-based virtual screening was carried out on molecules belonging to the alkaloid and flavonoid groups, followed by the evaluation of their pharmacokinetic, toxicological, and biological activity profiles, as well as ligand–receptor interaction analysis through molecular docking. The results indicated that palmatine, genistein, ZINC00597214, and ZINC72342127 exhibited superior performance compared to the other analyzed structures, considering all evaluated criteria. Therefore, this study, through in silico methodologies, demonstrated the antiparkinsonian potential of several chemical structures, attributable to their inhibitory activity on the MAO-B enzyme. Further experimental investigations, both in vitro and in vivo, are necessary to more comprehensively characterize the properties of these molecules, with the ultimate goal of developing new therapeutic strategies for the treatment of Parkinson’s disease. Full article

Background/Objectives: Severe malaria, mainly caused by Plasmodium falciparum, remains a significant therapeutic challenge due to increasing drug resistance and adverse effects. Flavonoids, known for their wide range of bioactivities, offer a promising route for antimalarial drug discovery. The aim of this study was to elucidate key structural features associated with antimalarial activity in flavonoids and to develop accurate, interpretable predictive models. Methods: Curated databases of flavonoid structures and their activity against P. falciparum strains and enzymes were constructed. Molecular fingerprinting and decision tree analyses were used to identify key pharmacophoric groups. Subsequently, molecular descriptors were generated and reduced to build multiple classification and regression models. Results: These models demonstrated high predictive accuracy, with test set accuracies ranging from 92.85% to 100%, and R² values from 0.64 to 0.97. Virtual screening identified novel flavonoid candidates with potential inhibitory activity. These were further evaluated using molecular docking and molecular dynamics simulations to assess binding affinity and stability with Plasmodium proteins (FabG, FabZ, and FabI). The predicted active ligands exhibited stable pharmacophore interactions with key protein residues, providing insights into binding mechanisms. Conclusions: This study provides highly predictive models for antimalarial flavonoids and enhances the understanding of structure–activity relationships, offering a strong foundation for further experimental validation. Full article

Here we presented the synthesis of two groups of heterocyclic benzimidazole derivatives—methanimines 4a–c and hydrazones 6a–c. In vitro biological activity screening of the compounds was performed on isolated encapsulated muscle larvae of Trichinella spiralis. All tested compounds showed higher efficacy than albendazole, with compound 4a demonstrating activity comparable to ivermectin. Structure–activity relationship (SAR) analysis revealed that methanimines 4a–c, containing a thiophene moiety, were more effective than their hydrazone counterparts, highlighting the beneficial synergy between benzimidazole and thiophene pharmacophores. However, replacing the -N=CH- linker in compound 4a with -NH-N=CH- (as in compound 6a) led to a 23% reduction in activity, suggesting that methaniamines possess superior larvicidal potency under equivalent structural conditions. The ability of the studied compounds to interfere with the tubulin polymerization was studied spectrophotometrically on purified porcine brain. Of note, the tested benzimidazoles 4a–b and 6a–b had no discernible effect on tubulin polymerization. An in silico study of the physicochemical and pharmacokinetic characteristics of the novel synthesized heterocyclic benzimidazoles showed that they were characterized by a significant degree of drug-likeness and optimal properties for antineurotrichinellosis agents. Full article

Background: Casein kinase 1 epsilon (CK1ε) plays a critical role in cancer progression by activating oncogenic signaling pathways, making it a target for cancer therapy. However, no inhibitors are currently available for clinical use, highlighting the need for novel therapeutic candidates. Methods: This study aimed to identify potential CK1ε inhibitors. To achieve this, a modified version of a previously reported pharmacophore model was applied to an ultra-large database of over 100 million compounds for virtual screening. Hits were filtered based on drug-likeness and pH-dependent pharmacophore compliance and then grouped according to their structural core. A representative compound from each structural group underwent molecular dynamic (MD) simulations and binding free energy calculations to predict its stability and affinity, allowing extrapolation of the results to the entire set of candidates. Results: Pharmacophore matching initially identified 290 compounds. After energy minimization, and an assessment of drug-likeness and pharmacophore compliance, we selected 29 structurally related candidates. MD simulations showed that most of the compounds representative of structural groups had stable binding modes, favorable intermolecular interactions, and free energies comparable to those of previously reported CK1ε inhibitors. An analysis of additional members of the most promising structural group showed that two 2,4-diaminopyrimidine-based compounds likely inhibit CK1ε. Conclusions: These findings provide structural insights into the design of CK1ε inhibitors, supporting compound optimization and the eventual development of targeted cancer therapeutics. Full article

Histone deacetylases (HDACs) are key regulators of gene expression, influencing chromatin remodeling and playing a crucial role in various physiological and pathological processes. Aberrant HDAC activity has been linked to cancer, neurodegenerative disorders, and inflammatory diseases, making these enzymes attractive therapeutic targets. HDAC inhibitors (HDACis) have gained significant attention, particularly those containing zinc-binding groups (ZBGs), which interact directly with the catalytic zinc ion in the enzyme’s active site. The structural diversity of ZBGs profoundly impacts the potency, selectivity, and pharmacokinetics of HDACis. While hydroxamic acids remain the most widely used ZBGs, their limitations, such as metabolic instability and off-target effects, have driven the development of alternative scaffolds, including ortho-aminoanilides, mercaptoacetamides, alkylhydrazides, oxadiazoles, and more. This review explores the structural and mechanistic aspects of different ZBGs, their interactions with HDAC isoforms, and their influence on inhibitor selectivity. Advances in structure-based drug design have allowed the fine-tuning of HDACi pharmacophores, leading to more selective and efficacious compounds with improved drug-like properties. Understanding the nuances of ZBG interactions is essential for the rational design of next-generation HDACis, with potential applications in oncology, neuroprotection, and immunotherapy. Full article

Ralstonia solanacearum is an important pathogen causing bacterial wilt in pepper (Capsicum annuum L.). The concurrent infection of R. solanacearum and root-knot nematodes (Meloidogyne spp.) exacerbates the severity of bacterial wilt in pepper. Utilizing plant endophytic bacteria to control these mixed diseases is a viable strategy. Waltheria indica L. (Sterculiaceae) is a traditional medicine plant. A total of 209 endophytic bacteria were isolated from W. indica, and Pseudomonas aeruginosa W-126 showed an efficient antagonistic effect against R. solanacearum. Based on active compound tracking principles, a compound was isolated through silica gel column chromatography and preparative HPLC combined with TLC analysis. It was identified as phenazine-1-carboxamide (PCN) by spectral techniques (ESI-MS, ¹H-NMR, ¹³C-NMR). PCN displayed excellent inhibitory activity against R. solanacearum, with an EC₅₀ of 64.16 μg/mL in vitro. In addition, it showed certain nematocide activity, with an LC₅₀ value of 118.63 μg/mL at 72 h. PCN also showed certain inhibitory activity against five other phytopathogenic bacteria. The structure−activity relationship indicated that the phenazine skeleton and acylamide groups were the key pharmacophores for the activity of phenazine-related compounds against R. solanacearum. PCN controlled the complex diseases of R. solanacearum and M. incognita in a pot experiment, with respective 51.41 and 39.80% inhibitory rates. The exploration of secondary metabolites of biocontrol bacteria can provide reference for the development of novel and efficient pesticides. Full article

Background/Objectives: Metastatic prostate cancer remains a major clinical challenge, with limited therapeutic options. Doxycycline, a tetracycline antibiotic with anti-inflammatory properties, has shown potential as an adjunctive therapy. This study aimed to evaluate its efficacy in reducing prostate-specific antigen (PSA) levels and improving quality of life in patients receiving standard treatment for metastatic prostate cancer. Methods: This phase II, double-blind, randomized controlled trial included 45 participants (aged 57–81 years) assigned to doxycycline (100 mg daily) or a placebo for six months. The primary outcome was the percentage change in PSA levels at 3 and 6 months. Secondary outcomes included quality of life (EQ-5D-5L), cognitive function (Mini-Mental State Examination), and glucose levels. Additionally, a structure–activity relationship (SAR) analysis was performed through an extensive bibliographic review to identify pharmacophores responsible for doxycycline’s biological activity, particularly its tetracyclic core. The SAR analysis included tetracyclines and derivatives, androgen-targeting agents, and other pharmacologically relevant molecules used in prostate cancer therapy. Statistical analysis was conducted using multivariate logistic regression. Results: At six months, the doxycycline group showed a median PSA reduction of 60% compared to 10% in the placebo group (p = 0.043). A ≥50% reduction in PSA levels was observed in 71.4% of patients receiving doxycycline versus 20.8% in the placebo group (p = 0.001), with an adjusted relative risk of 10.309 (95% CI: 2.359–45.055, p = 0.002). Quality of life improved, with 7.1% of doxycycline-treated patients reporting poor quality of life compared to 42.9% in the placebo group (p = 0.028). A slight improvement in cognitive function was also noted (p = 0.037). SAR analysis suggested that the tetracyclic ring of doxycycline may play a crucial role in its observed biological effects. Conclusions: Doxycycline demonstrates potential as an adjunctive therapy in metastatic prostate cancer by reducing PSA levels and improving quality of life. The SAR analysis supports the hypothesis that its tetracyclic structure may be responsible for its therapeutic effects. Further large-scale trials are warranted to confirm these findings. Full article

This paper describes the first detailed NMR analysis of the borylated intermediates and target compounds for a small library of pyrrolidine iminosugars of l-gulose absolute stereochemical configuration. The iminosugars were functionalised via N-alkylation to bear a boronate ester or boronic acid groups. The addition of the organic boron pharmacophore allows to further explore the chemical space around and in the active sites, where the boron atom has the capability to make reversible covalent bonds with enzyme nucleophiles and other nucleophiles. We discuss the concurrent complex equilibrium processes of mutarotation and borarotation as studied by NMR. Full article

This study aims to design improved inhibitors targeting the thymidylate kinase (TMK) of Mycobacterium tuberculosis (Mtb), the causative agent of infectious disease tuberculosis that is associated with high morbidity and mortality in developing countries. TMK is an essential enzyme for the synthesis of bacterial DNA. We have performed computer-aided molecular design of MtbTMK inhibitors by modification of the reference crystal structures of the lead micromolar inhibitor TKI1 1-(1-((4-(3-Chlorophenoxy)quinolin-2-yl)methyl)piperidin-4-yl)-5-methylpyrimidine-2,4(1H,3H)-dione bound to TMK of Mtb strain H37Rv (PDB entries: 5NRN and 5NR7) using the computational approach MM-PBSA. A QSAR model was prepared for a training set of 31 MtbTMK inhibitors with published inhibitory potencies (${\mathrm{I}\mathrm{C}}_{50}^{\mathrm{e}\mathrm{x}\mathrm{p}}$) and showed a significant correlation between the calculated relative Gibbs free energies of the MtbTMK–TKIx complex formation and the observed potencies. This model was able to explain approximately 95% of the variation in the in vitro inhibition data and validated our molecular model of MtbTMK inhibition for the subsequent design of new TKI analogs. Furthermore, we have confirmed the predictive capacity of this complexation QSAR model by generating a 3D QSAR PH4 pharmacophore-based model. A satisfactory correlation was also obtained for the validation PH4 model of MtbTMK inhibition (R² = 0.84). We have extended the hydrophobic m-chloro-phenoxyquinolin-2-yl group of TKI1 that can occupy the entry into the thymidine binding cleft of MtbTMK by alternative larger hydrophobic groups. Analysis of residue interactions at the enzyme binding site made it possible to select suitable building blocks to be used in the preparation of a virtual combinatorial library of 28,900 analogs of TKI1. Structural information derived from the complexation model and the PH4 pharmacophore guided the in silico screening of the library of analogs and led to the identification of new potential MtbTMK inhibitors that were predicted to be effective in the low nanomolar concentration range. The QSAR complexation model predicted an inhibitory concentration ${\mathrm{I}\mathrm{C}}_{50}^{\mathrm{p}\mathrm{r}\mathrm{e}}$ of 9.5 nM for the best new virtual inhibitor candidate TKI 13_1, which represents a significant improvement in estimated inhibitory potency compared to TKI1. Finally, the stability of the MtbTMK–inhibitor complexes and the flexibility of the active conformation of the inhibitors were assessed by molecular dynamics for five top-ranking analogs. This computational study resulted in the discovery of new MtbTMK inhibitors with predicted enhanced inhibitory potencies, which also showed favorable predicted pharmacokinetic profiles. Full article

The hydroxylated perhydroquinoxaline 14 was designed by conformational restriction of the prototypical κ receptor agonist U-50,488 and the introduction of an additional polar group. The synthesis of 14 comprised ten reaction steps starting from diethyl 3-hydroxyglutarate (4). The first key step was the diastereoselective establishment of the tetrasubstituted cyclohexane 7 by the reaction of dialdehyde 6 with benzylamine and nitromethane. The piperazine ring was annulated by the reaction of silyloxy-substituted cyclohexanetriamine 8 with dimethyl oxalate. The pharmacophoric structural elements characteristic for κ receptor agonists were finally introduced by functional group modifications. The structure including the relative configuration of the tetrasubstituted cyclohexane derivative (2r,5s)-7a and the perhydroquinoxaline 9 was determined unequivocally by X-ray crystal structure analysis. The hydroxylated perhydroquinoxaline 14 showed moderate κ receptor affinity (K_i = 599 nM) and high selectivity over μ, δ, σ₁, and σ₂ receptors. An ionic interaction between the protonated pyrrolidine of 14 and D138 of κ receptor anchors 14 in the κ receptor binding pocket. Full article

Background/Objectives: Leishmaniasis is one of the 20 Neglected Tropical Diseases according to the WHO, affecting approximately 12 million people in four continents, generating serious public health problems. The lack of therapeutic options, associated with toxicity and the emergence of resistance to the few available drugs, makes it urgent to develop new drug options. In this context, the aims of this work are to expand the knowledge about the pharmacophore group responsible for the antileishmanial potential of 2-aminothiophene derivatives. Thus, new compounds were synthesized containing chemical modifications at the C-3, C-4, and C-5 positions of the 2-aminothiophene ring, in addition to the S-Se bioisosterism. Methods: Dozens of 2-AT and 2-aminoselenophen (2-AS) derivatives were sequentially synthesized through applications of the Gewald reaction and were then evaluated in vitro for their activities against L. amazonensis and for cytotoxicity against macrophages. Results: Several series of compounds were synthesized, and it was possible to identify some substitution patterns favorable to the activity generating compounds with IC₅₀ values below 10 µM, such as the non-essentiality of the presence of a carbonitrile group at C-3; the importance of the presence and size of cycloalkyl/piperidinyl chains at C-4 and C-5 in modulating the activity; and the increase in activity without affecting the safety of the S/Se bioisosteric substitution. Conclusions: Taken together, these findings reaffirm the great potential of 2-aminothiophenes to generate antileishmanial drug candidates and offers contributions to the drug design of compounds with an even more promising profile for the problem of leishmaniasis. Full article