The concurrent inhibition of DNA gyrase and topoisomerase IV (Topo IV) is a fundamental pharmacological approach to augment antibacterial effectiveness and significantly prevent the development of antibiotic resistance. A novel series of twelve methylene disalicylic acid-based derivatives was comprehensively designed, synthesized, and structurally confirmed. The inhibitory effects of the new compounds 6a-c and 8a-i on DNA gyrase and Topo IV were examined. Compounds 8g and 8h exhibited the most promising outcomes, with IC50 values of 0.96 ± 0.03 and 0.53 ± 0.01 μM against DNA gyrase, respectively, and 8.25 ± 0.32 and 11.02 ± 0.45 μM against Topo IV, respectively, in comparison to novobiocin at 0.78 ± 0.02 and 10.62 ± 0.46 μM, respectively. Compound 8h demonstrated the highest antibacterial efficiency against Gram-positive bacteria, with MIC values of 0.015 and 0.025 μg mL-1 against B. subtilis and S. aureus, respectively, in comparison to 0.010 and 0.030 μg mL-1 for ciprofloxacin, respectively. Compound 8g exhibited superior antibacterial efficacy against Gram-negative organisms, with a MIC of 0.050 μg mL-1 against E. coli and P. aeruginosa, compared to 0.060 μg mL-1 for ciprofloxacin. Compound 8h exhibits significant antibiofilm efficacy; at the MIC concentration, the biofilm inhibition rate reached 92%. Docking studies revealed that compounds 8g and 8h demonstrate enhanced binding affinity for E. coli DNA gyrase B and Topo IV compared to ciprofloxacin. These data jointly underscore 8g and 8h as attractive antibacterial candidates.

Abstract Simultaneous inhibition of DNA gyrase and topoisomerase IV (Topo IV) is a primary pharmacological strategy to enhance antibacterial efficacy and markedly reduce the emergence of antibiotic resistance. In this regard, a new set of twelve ciprofloxacin-based derivatives was rationally developed, synthesized, and structurally verified. The DNA gyrase and Topo IV inhibitory actions of the developed Compounds 6a-l were investigated. Compound 6 g showed the most promising results, with IC50 values of 1.75 ± 0.05 and 03.47 ± 0.14 µM against DNA gyrase and Topo IV, respectively, compared to ciprofloxacin at 02.13 ± 0.06 and 25.22 ± 1.27 µM, respectively. Compound 6 g demonstrated the highest antibacterial activity, with MIC values of 0.025, 0.025, and 0.125 µg/mL against E. coli, P. aeruginosa, and S. aureus, respectively. It exhibits comparable efficacy to ciprofloxacin against E. coli, a gram-negative bacterium, although it possesses only half the potency against P. aeruginosa and the gram-positive S. aureus. Compound 6 g exhibits a significant antibiofilm action; at the MIC level, the biofilm inhibition percentage was 96%. Docking analyses revealed that Compound 6 g displays enhanced binding affinity for E. coli DNA gyrase B and Topo IV compared to ciprofloxacin. Molecular dynamics simulations validated the exceptional stability of the 6 g–DNA gyrase B complex. In silico ADMET studies demonstrated satisfactory lipophilicity and metabolic characteristics. These findings collectively underscore 6 g as a viable antibacterial candidate.

C14H16N2O2S, triclinic, P 1 (no. 2), a = 7.4582(3) & Aring;, b = 8.5866(3) & Aring;, c = 12.0234(5) & Aring;, alpha = 103.646(3)degrees, beta = 103.474(3)degrees, gamma = 107.254(3)degrees, V = 675.43(5) & Aring;3, Z = 2, R gt (F) = 0.0514, wR ref (F2) = 0.1407, T = 160 K.

A novel series of quinolin-2-one/thiazole hybrids (6a-l) was designed, synthesized, characterized, and evaluated for their in vitro antiproliferative efficacy against three human cancer cell lines: HCT-116, MCF-7, and HepG-2. Most derivatives demonstrated good-to-moderate cytotoxic profiles. Among them, compound 6b emerged as the most potent lead candidate, with a mean IC50 of 4.20 µM, representing a 1.7-fold higher potency than the reference drug, sorafenib (IC50 = 6.80 µM). Specifically, compound 6b exhibited enhanced cytotoxicity against HCT-116 (IC50 = 5.20 µM) and MCF-7 (IC50 = 4.20 µM), and a two-fold higher potency against HepG-2 (IC50 = 3.20 µM) cells compared to sorafenib. Enzymatic assays revealed that 6b acts as an efficient multi-kinase inhibitor, effectively targeting EGFR (IC50 = 0.058 µM) and HER-2 (IC50 = 0.060 µM) with potencies comparable or superior to the standard controls erlotinib and lapatinib, while moderately inhibiting VEGFR-2 (IC50 = 0.51 µM). Safety screening against normal WI-38 cells showed low cytotoxicity (IC50 = 51.21 µM) and outstanding selectivity indices (SI > 10, > 12, and 16) for HCT-116, MCF-7, and HepG-2, respectively. Mechanistic investigations in HepG-2 cells confirmed that 6b induced a 6.9-fold increase in caspase-3/7 activity, triggering significant apoptosis. SAR analysis highlighted that a 6-methyl substitution on the quinoline core, an unsubstituted N-1 position, and a bulky 3-phenyl group on the thiazole ring are key structural prerequisites for optimal anticancer activity. These findings, along with docking investigation, highlight compound 6b as a promising multi-kinase therapeutic scaffold for further targeted oncological optimization.

Abstract C 14 H 16 N 2 O 2 S, triclinic, P 1 ̅ $̅{1}$ (no. 2), a = 7.4582(3) Å, b = 8.5866(3) Å, c = 12.0234(5) Å, α = 103.646(3) ° , β = 103.474(3) ° , γ = 107.254(3) ° , V = 675.43(5) Å 3 , Z = 2, R gt ( F ) = 0.0514, wR ref ( F 2 ) = 0.1407, T = 160 K.

C15H23N3S, orthorhombic, Pbca (no. 61), a = 10.0075(1) & Aring;, b = 11.8795(1) & Aring;, c = 23.8519(2) & Aring;, V = 2835.61(4) & Aring;(3), Z = 8, R-gt(F) = 0.0321, wR(ref)(F-2) = 0.0932, T = 160 K.

DNA gyrase and topoisomerase IV are promising targets for the development of novel antibacterial therapies. We introduce the design, synthesis, and biological evaluation of a novel series of quinoline-2-one derivatives as potential dual inhibitors exhibiting antibacterial and antiproliferative properties. All novel compounds were assessed in vitro for their efficacy against E. coli DNA gyrase and topoisomerase IV. Compounds 4b, 4d, and 4e demonstrated the highest potency against both enzymes, with IC50 values of 0.97, 1.37, and 0.89 & micro;M for DNA gyrase, comparable to Novobiocin's IC50 value of 0.78 & micro;M, and IC50 values of 8.25, 9.05, and 7.12 & micro;M for topoisomerase IV, indicating enhanced potency relative to Novobiocin (IC50 = 10.62 & micro;M). Compounds 4b and 4e had superior antibacterial activity compared to ciprofloxacin against Gram-negative organisms P. aeruginosa and E. coli; however, their efficacy was inferior to ciprofloxacin against Gram-positive strains S. aureus and B. subtilis. Furthermore, compounds 4b, 4d, and 4e exhibited notable antiproliferative activity, with mean IC50 values of 12.90, 22.01, and 8.78 & micro;M, respectively, compared to doxorubicin's mean IC50 value of 6.10 & micro;M. Assays of apoptotic markers demonstrate that 4e is highly efficient at triggering apoptosis and exhibits favorable pharmacokinetic features.

The development of novel microtubule-targeting medicines (MTAs) remains a crucial strategy in cancer treatment, as they combat drug resistance and systemic toxicity. A novel series of thiazole-based derivatives was synthesized, characterized, and evaluated as antitubulin agents endowed with antiproliferative action. An IC50 experiment was performed to assess the efficacy of novel compounds 9a-o in suppressing tubulin activity. The antiproliferative effects of the most potent compounds were evaluated. The levels of initiator caspases (Caspase-8 and Caspase-9) and executioner caspase (Caspase-3) were examined to ascertain the degree of apoptosis. Additionally, the expression levels of the mitochondrial regulatory proteins Bax and Bcl-2 were examined to ascertain the importance of the intrinsic apoptotic pathway. Compound 9k exhibited significant inhibition of tubulin with an IC50 of 1.56 µM and showed potent activity against HeLa (cervical), HCT-116 (colorectal), and A-549 (lung) cancer cell lines. The apoptotic assays revealed that 9k effectively triggered the apoptotic cascade, leading to a ninefold increase in Caspase-3 and a significant twenty-onefold rise in Caspase-9, surpassing the effects of the reference Staurosporine. Caspase-8 was activated by an elevenfold increase, primarily via the intrinsic pathway. This was confirmed by a substantial change in the mitochondrial "rheostat": 9k induced a 38-fold increase in pro-apoptotic Bax and a 5-fold decrease in anti-apoptotic Bcl-2. Molecular docking studies showed that 9k exhibited a favorable binding mode consistent with its tubulin-inhibition profile. In silico ADMET predictions further supported 9k as a drug-like lead with acceptable oral exposure and a beneficial P-gp-related transporter profile. The enhanced apoptotic effects of 9k compared with Staurosporine make 9k an attractive lead candidate for further development as an anti-cancer drug targeting the colchicine-binding site.

Resistance to single-target kinase inhibitors is increasing, necessitating the development of multi-target-directed medications that can simultaneously affect different carcinogenic pathways. The objective of this investigation was to develop, synthesize, and evaluate the pharmacological properties of a novel set of compounds that are derived from benzimidazole and thereby inhibit both EGFR and BRAF(V600E). Compounds 8c, 8d, and 8f were identified as the most potent candidates in in vitro enzymatic and antiproliferative investigations. Compound 8d exhibited the most potent dual inhibitory activity, with IC50 values of 7.17 nM against EGFR and 45.50 nM against BRAF(V600E). These values were comparable to those of the reference medications vemurafenib (IC50 = 41.38 nM) and erlotinib (IC50 = 5.40 nM). Mechanistic studies have shown that compounds 8d and 8f strongly induce apoptosis, primarily through the intrinsic (mitochondrial) pathway, as evidenced by significant activation of caspase-9 and caspase-3. The experimental results were confirmed by molecular docking studies, which showed that compound 8d exhibits strong binding affinity for both the EGFR and BRAF(V600E) kinase domains. The in silico ADME profiling and drug-likeness analysis revealed that compound 8d exhibits high gastrointestinal absorption and adheres to Lipinski's rule of five, supporting its potential as an oral therapy.

Two halogenated N '-(adamantan-2-ylidene)benzohydrazide derivatives bearing chloro- and fluoro-substituted phenyl rings were synthesized and comprehensively investigated to elucidate their structural, supramolecular, and biological properties. Single-crystal X-ray diffraction revealed the presence of multiple crystallographically independent molecules and diverse intermolecular interactions, including N-H & sdot;& sdot;& sdot;N/O hydrogen bonds, C-H & sdot;& sdot;& sdot;O/ N, C-H & sdot;& sdot;& sdot;Cl/F, and C-H & sdot;& sdot;& sdot;pi contacts, which collectively govern the solid-state architectures. Hirshfeld surface analysis and PIXEL/DFT-based interaction energy evaluations highlight the dominant role of electrostatic and dispersion forces in stabilizing the crystal packing. QTAIM analysis further confirms the closed-shell nature of the intermolecular interactions and provides quantitative insight into their relative strengths. The compounds were evaluated for antiproliferative activity, revealing enhanced activity for the fluoro-substituted derivative. To rationalize the biological findings, molecular docking and 100 ns molecular dynamics simulations were performed against the epidermal growth factor receptor (EGFR) kinase domain. Both compounds exhibit stable binding within the EGFR active site, with favourable hydrophobic interactions and binding free energies, while the fluoro-substituted analogue displays superior binding affinity compared to the chloro derivative and the reference inhibitor erlotinib. Overall, this study demonstrates that halogen substitution and adamantane incorporation synergistically influence supramolecular assembly and EGFR-targeted antiproliferative potential, providing valuable insights for the rational design of hydrazide-adamantane-based anticancer agents.

Cyclooxygenase-2 (COX-2) and lipoxygenases (LOXs), two enzymes involved in arachidonic acid metabolism, have been linked to various cancers. As a result, it was exciting to develop dual COX-2/5-LOX inhibitors for promoting the development of new treatments. This study examines the synthesis and in vitro pharmacological properties of pyrimidine-sulfonamide derivatives. Compounds 4c, 4g, 4j, 4m, and 4o were the most effective COX-2 inhibitors and showed substantial inhibitory activity against 5-LOX. Compound 4c demonstrated significant inhibition of COX-2 (IC50 = 0.11 ± 0.01 µM) and 5-LOX (IC50 = 0.46 ± 0.02 µM) with comparable efficacy to celecoxib (IC50 = 0.08 ± 0.0004 µM) and surpassing the standard Zileuton (IC50 = 0.69 ± 0.03 µM). Additionally, compound 4c had the highest potency as a soluble epoxide hydrolase (sEH) inhibitor, with an IC50 of 4.30 ± 0.19 µM, demonstrating 1.6-fold lower potency than the reference AUDA but 5-fold greater potency than celecoxib. Compounds 4c, 4g, and 4j showed promising antiproliferative activity, with compound 4c being the most potent against the pancreatic (Panc-1) cancer cell line, and compound 4j the most effective against the breast MCF-7 cancer cell line. Their efficacy against these two cell lines exceeded that of the reference compounds celecoxib, sorafenib, and doxorubicin. Docking analysis of compound 4c showed a good fit within the active sites of both COX-2 and human sEH.

Single-crystal X-ray diffraction and supramolecular analysis were performed for three bioactive triazole-3-thione derivatives 1–3 featuring an adamantan-1-yl, (4-arylpiperazin-1-yl)methyl, and an arylideneamino moieties as the main substituents. Although all compounds share this molecular scaffold, differences in the substitution pattern of the aryl rings attached to the piperazine and arylideneamino fragments lead to distinct crystal packing motifs. The supramolecular arrangement was interpreted in terms of directional interactions such as C–H···O, C–H···N, C–H···F, and C–H···π, whose role in the supramolecular architecture was evaluated using electrostatic potential maps and Hirshfeld surface analysis. Among the three structures, compound 2 is the only one crystallizing in a non-centrosymmetric space group as a consequence of the lack of the inversion centers observed in compounds 1 and 3. In the case of compound 3, the incorporation of fluorine atoms gives rise to multiple C–H···F contacts that define a unique packing behavior and highlight the impact of fluorination on the solid-state organization.

IntroductionIn cancer therapy, inhibiting tubulin polymerization is a key approach for modifying microtubule dynamics required for cell survival and proliferation. Microtubule destabilizing agents (MDAs), also known as tubulin polymerization inhibitors, prevent tubulin heterodimers from forming microtubules, resulting in catastrophic cellular collapse.MethodsA novel series of thiazole-based compounds 8a-o was developed to inhibit tubulin polymerization and assess for its antiproliferative efficacy against the NCI 60 cell line. The structures of the newly synthesized compounds were confirmed using 1H NMR, 13C NMR, and elemental microanalyses. All 15 compounds (8a-o) were assessed for antiproliferative action at a single dosage (10 μM) and analyzed against the comprehensive 60-cell panel at five concentrations (0.01, 0.1, 1, 10, and 100 μM).Results and DiscussionThe results from the one-dose and five-dose studies demonstrate that 8b, 8c, 8d, 8m, and 8o are the most prominent antiproliferative agents, exhibiting the most favourable low-micromolar GI50 values across various cell lines, frequently advancing to low-micromolar TGI, and, in numerous sensitive cell lines, achieving LC50 values within the single-digit micromolar range. Compounds 8b, 8d and 8m showed significant anti-tubulin activity, with IC50 values ranging from 3.86 to 7.19 μM, compared to the reference CA-4 (IC50 = 2.40 μM). In the MCF-7 breast cancer cell line, compound 8m drove a significant accumulation of cells in the G2/M phase, increasing from 13.74% to 45.35%. G2/M arrest is frequently associated with DNA damage or the inhibition of microtubule dynamics, which aligns with Western blot results demonstrating a decrease in tubulin (50 kDa) expression following treatment with 8m. Apoptotic and necrotic experiments indicate that 8m stimulates a defined programmed cell death pathway rather than inducing non-specific toxic necrosis. Molecular docking corroborated their binding at the colchicine site, while in silico ADMET profiling indicated a promising drug-like profile for compound 8m.

A new series of dihydropyrimidine-5-carbonitrile/1,2,4-oxadiazole hybrids (10a-l) was developed as dual inhibitors of EGFR and VEGFR-2. The structures of the newly synthesized compounds were confirmed using 1H NMR, 13C NMR, and elemental analysis. The novel compounds were evaluated for their antioxidant and antiproliferative apoptotic characteristics. Compounds 10e, 10k, and 10l demonstrated the most potent antiproliferative activity and exhibited more efficacy than the reference erlotinib against both Panc-1 (pancreatic) and MCF-7 (breast) cancer cell lines. Compounds 10k and 10l exhibited the highest potency as EGFR and VEGFR-2 inhibitors, with IC50 values of 57 nM and 61 nM against EGFR, respectively, and IC50 values of 21 nM and 26 nM for VEGFR-2, respectively. Moreover, compounds 10k and 10l demonstrated promising apoptotic activity through the overexpression of caspases-3, 8, and 9, as well as Bax and p53, and the downregulation of the anti-apoptotic protein Bcl-2. Additionally, compounds 10k and 10l exhibited notable antioxidant activity at 10 μM, demonstrating DPPH radical scavenging rates of 72.5% and 69.8%, respectively. An integrated computational study was conducted to validate the dual kinase inhibitory potential of compound 10k and 10i against EGFR and VEGFR-2. Compound 10k and 10i established strong hydrogen bonds with Met769 in EGFR and Glu885 in VEGFR-2, achieving interaction energies of -8.21 and -7.42 kcal mol-1, respectively. Molecular dynamics simulations over 100 ns confirmed that the 10k-kinase complexes remained highly stable, showing minimal conformational fluctuations throughout the simulation. Compound 10i also exhibited stable dynamics and favorable interactions; however, 10k consistently maintained stable binding conformations. These results highlight 10k as the most dynamically stable and potent dual EGFR/VEGFR-2 inhibitor in the series. DFT analysis revealed a moderate HOMO-LUMO gap (3.86 eV), chemical hardness (1.93 eV), and a dipole moment of 6.4 debye, which correlates with favorable reactivity and polarity for kinase engagement. ADME profiling highlighted drug-likeness, acceptable bioavailability, and selective CYP inhibition. Altogether, these findings validate 10k as a promising dual EGFR/VEGFR-2 inhibitor with strong structural and pharmacokinetic potential.

C 17 H 16 Cl 2 N 2 O 4 , monoclinic, P 2 1 / c (no. 14), a = 8.0893(1) Å, b = 26.1791(3) Å, c = 8.2311(1) Å, β = 98.002(1)°, V = 1726.13(4) Å 3 , Z = 4, R gt ( F ) = 0.0343, w R ref ( F 2 ) = 0.0904, T = 160 K.

C 12 H 15 N 3 S 2 , monoclinic, P 2 1 / n (no. 14), a = 5.51310(10) Å, b = 15.4525(4) Å, c = 15.9261(4) Å, β = 99.844(2)°, V = 1336.79(5) Å 3 , Z = 4, R gt ( F ) = 0.0359, wR ref ( F 2 ) = 0.1009, T = 160 K.

Two N′-(adamantan-2-ylidene)-substituted benzohydrazide derivatives, namely, N′-(adamantan-2-ylidene)-2,4-dichlorobenzohydrazide (1) and N′-(adamantan-2-ylidene)-3,4,5-trimethoxybenzohydrazide (2), were successfully synthesized and thoroughly characterized. Single-crystal X-ray diffraction analysis revealed that both compounds form robust molecular dimers stabilized by multiple hydrogen bonds, including N–H···O/N and C–H···O/N/Cl/π interactions. In the dichloro-substituted compound, numerous C–H···Cl interactions contribute to the stabilization of various molecular dimers in the solid state. Conversely, the trimethoxy-substituted derivative features numerous C–H···O interactions, which stabilize distinct molecular dimeric arrangements. Furthermore, the dichloro compound exhibits a Cl···Cl halogen bond, while the trimethoxy derivative demonstrates a tetrel bond involving methoxy groups. The energetics of the molecular dimers observed in these structures were analyzed, and the intermolecular interactions were further explored using atoms in molecules theory. Furthermore, in vitro antiproliferative activity, molecular docking, and molecular dynamic simulations were conducted to gain deeper insights into their bioactivity.

This study presents a comprehensive experimental and computational investigation into the role of variable side-on X & ctdot;pi (X = O, S, Cl) interactions complementing conventional hydrogen-bonding in the molecular packing of four differently substituted 3-(adamantan-1-yl)-1-[(E)-(arylmethylidene)amino]thiourea derivatives (1-4). Single-crystal X-ray diffraction analyses reveal distinct molecular packing modes across the series: conventional hydrogen-bonding dominates in 1, while non-conventional non-covalent interactions involving the aryl rings are prominent in 2-4. Molecular electrostatic potential (MEP) surface analysis precisely maps electrophilic (amino N-H) and nucleophilic (thione-S, nitro-O, F, Cl atoms) regions, consistent with observed hydrogen-bonding patterns and revealing positive potentials over the aromatic rings (0.7 to 6.9 kcal mol-1) that rationalize lone-pair (LP)& ctdot;pi interactions. Combined quantum theory of atoms in molecules (QTAIM) and non-covalent interaction (NCI) plot analyses confirm the presence of LP & ctdot;pi contacts in 2 and 3 (S & ctdot;pi) and Cl & ctdot;pi interactions in 4, characterised by specific bond critical points and extended RDG isosurfaces. The Energy Decomposition Analysis (EDA) for LP & ctdot;pi-mediated dimers of 2-4 reveals that these interactions are predominantly stabilised by dispersion and correlation effects, with electrostatic contributions being minor. This joint crystallographic and computational approach elucidates how side-on X & ctdot;pi interactions contribute to crystal architecture, confirming their structure-directing role and offering insights for rational crystal engineering.

Two structurally related 2,4-disubstituted pyrimidine-5-carbonitrile derivatives were synthesized and characterized by single-crystal X-ray diffraction. Their molecular and crystal packing features were explored using a combination of experimental and computational techniques, including Hirshfeld surface analysis, CLP-PIXEL energy calculations, molecular electrostatic potential surfaces, deformation electron density maps, and Bader's quantum theory of atoms in molecules (QTAIM). Both compounds exhibit robust N-H & sdot;& sdot;& sdot;O hydrogen bonding motifs, complemented by various noncovalent interactions such as C-H & sdot;& sdot;& sdot;it, chalcogen bonding (S & sdot;& sdot;& sdot;S), and tetrel bonding (C & sdot;& sdot;& sdot;N). Notably, compound 2 displays it-it stacking and CN & sdot;& sdot;& sdot;it interactions that are absent in compound 1. The energetic contributions of individual dimers were evaluated to understand their roles in crystal stabilization. Hirshfeld surface analysis identified key intermolecular contacts contributing to the stability of the crystal structures. Additionally, molecular docking analysis of compounds 1 and 2 was performed against two bacterial drug targets namely, dihydrofolate reductase (DHFR) from Staphylococcus aureus and ampC beta-lactamase from Escherichia coli. Both compounds were found to bind at the active sites of these targets and revealed key interacting residues. Further validation by molecular dynamics simulations (MD) confirmed the stability of the protein-ligand complexes. MM-GBSA binding free energy calculations using molecular dynamics data suggested that the compounds exhibit stronger binding affinities than the reference inhibitors (trimethoprim and 4MB). Overall, our study supports the potential of the pyrimidine-5-carbonitrile scaffold as a promising core for the development of antibacterial agents, particularly targeting these two key enzymes.

[This corrects the article DOI: 10.3389/fchem.2025.1638489.].