To design, synthesize, and biologically evaluate a novel series of 1-(4-chlorophenyl)-2-(4-methylpyrazol-1-yl)ethenone oxime derivatives (5–15) as targeted anticancer agents, focusing on their selectivity for glioma, mechanistic action, and blood–brain barrier (BBB) permeability. The oxime derivatives were synthesized and characterized using 1H-NMR, 13C-NMR, and mass spectrometry. In vitro cytotoxicity was assessed against C6 (glioma), MCF-7 (breast cancer), and SH-SY5Y (human neuroblastoma) cell lines. Flow cytometry evaluated apoptosis and cell cycle arrest for the lead compound. Molecular docking simulations were performed against CDK6 (PDB: 5L2I) and P-glycoprotein/ABCB1 (PDB: 7A6E). All derivatives exhibited selective potency against C6 glioma cells. Compound 14 demonstrated the highest antiproliferative activity (IC₅₀: 31.23 µM) against tumor lines while sparing SH-SY5Y cells. Flow cytometry confirmed that compound 14 triggers apoptosis and induces cell cycle arrest in C6 cells. Molecular docking predicted the most favorable docking scores for compound 14 against both CDK6 and P-glycoprotein. Structure–activity relationships (SAR) analysis validates the 4-methylpyrazole core as a viable scaffold for targeted glioma therapy. These results suggest that further functionalization of the O-alkyl oxime moiety merits further investigation as a starting point for potentially brain-penetrant scaffolds, although in vivo and target-level validation are required.

In this study, we synthesized novel 2-aryl-6-carboxamide-substituted benzoxazole derivatives and evaluated their anticancer potential against breast cancer cell lines, with a focus on mTOR inhibitory activity. The compounds were synthesized via a three-step method and characterized by NMR analysis. In silico studiesincluding molecular docking, molecular dynamics simulations, and ADMET predictionswere conducted to predict interactions with the target protein and support the observed biological activity. IC50 values were determined in MCF-7 and MDA-MB-231 cells, with MCF-7 cells exhibiting greater sensitivity to the compound. The most active compounds, COH-17 and COH-19, demonstrated cytotoxicity as indicated by LDH release assays. Apoptotic effects were investigated at both molecular and cellular levels: Western blot analysis assessed key apoptotic proteins (Bcl-2, Bax, caspase-3, and p53), while RT-qPCR quantified the expression of BRCA1, BRCA2, PTEN, TP53, BCL-2, BAX, Caspase-3, PI3K, AKT, and BRAD1 genes. Morphological changes associated with apoptosis were confirmed by DAPI staining and fluorescence microscopy, and early and late apoptosis were quantified using Annexin V-FITC/PI flow cytometry. Cell cycle analysis revealed phase-specific arrest, further supporting the antiproliferative activity of the compound. Overall, COH-17 and COH-19 demonstrated potent anticancer effects through mTOR inhibition, induction of apoptosis, and cell cycle arrest, highlighting their potential as targeted therapeutic agents for breast cancer.

AIMS:Antibiotic-resistant bacteria, particularly methicillin-resistant Staphylococcus aureus (MRSA), have renewed interest in antivirulence strategies. This study aimed to design, synthesize, and evaluate asymmetric di‑heterocyclic benzazole derivatives as antibiofilm agents targeting wall teichoic acid (WTA) biosynthesis. MATERIALS AND METHODS:Twenty‑one novel bis‑heterocyclic benzazole derivatives bearing an ethyl‑thio linker were synthesized and characterized. Antibacterial activity was determined by broth microdilution. Antibiofilm activity (inhibition and eradication) was assessed at sub‑minimal inhibitory concentrations (sub‑MICs) using crystal violet. Molecular docking and 200 ns molecular dynamics (MD) simulations were performed against key WTA enzymes (TarGH, TarS, TarM, TarL, and TarJ). RESULTS:Compounds 18, 21, 23, and 24 showed potent antibacterial activity against methicillin‑susceptible S. aureus (MSSA) and MRSA, with MIC values as low as 15.62 µg/mL. All selected compounds significantly inhibited biofilm at sub‑MIC levels. Compound 24 was most effective, with an MBIC50 of 3.90 µg/mL against MSSA and eradicated pre‑formed biofilms at 7.81 µg/mL. Docking and MD simulations revealed stable interactions of compounds 23 and 24 with TarGH and TarS, suggesting a WTA‑targeting mechanism. CONCLUSIONS:Di‑heterocyclic benzazole derivatives, especially compound 24, are promising scaffolds for antibiofilm agents against S. aureus. Our findings support further mechanistic and preclinical evaluation as potential antivirulence therapeutics.

In this study, the structural, spectroscopic, and biological properties of a benzazole-2-carboxamide derivatives, N-(1H-benzo[d]imidazole-2-yl)-4-chlorobenzamide, were comprehensively investigated through both experimental and theoretical approaches. First, the crystal structure of the compound was revealed with the help of single-crystal X-ray diffraction (XRD). Subsequently, density functional theory (DFT) calculations were performed using Gaussian 09 W to optimize the molecular geometry, simulate vibrational spectra, predict nuclear magnetic resonance (NMR) parameters, analyze frontier molecular orbitals HOMO (Highest Occupied Molecular Orbital) - LUMO (Lowest Unoccupied Molecular Orbital), and generate molecular electrostatic potential (MEP) surface maps. To enhance the accuracy of vibrational assignments, potential energy distribution (PED) analysis was conducted via the VEDA4 software. Furthermore, theoretical infrared (IR) and NMR data were compared with experimental results, with results from FT-IR, 1H-NMR, and 13CNMR spectra demonstrating strong agreement and validating the computational models. In addition to spectroscopic characterization, the antiproliferative activity of the synthesized compound against human breast cancer cell line MCF7 and a normal mouse fibroblast cell line (L929) was evaluated. Among the tested compounds, those exhibiting the highest inhibitory activity against MCF7 cells were selected for further analysis. In order to explain the underlying molecular interactions, molecular placement studies were carried out with the help of the Schrodinger Maestro software program, which targets the basic protein binding sites to predict binding affinity and interaction patterns. Collectively, this integrated study provides valuable insights into the structural, spectroscopic, and biological behavior of benzazole-based derivatives, highlighting the synergy between experimental techniques and computational modeling in modern drug discovery research.

This study presents the design, synthesis, and biological evaluation of a series of novel pyrrole-tethered bisbenzoxazole (PTB) derivatives as potential apoptosis-inducing agents targeting the MCF-7 human breast cancer cell line. The anticancer activity of these compounds was evaluated in vitro using the MTT assay, with tamoxifen serving as the reference therapeutic agent. Compounds B8, B14, and B18 demonstrated remarkable cytotoxicity against MCF-7 cells, exhibiting approximately 8-fold lower IC50 values compared to tamoxifen, while showing minimal effects on healthy fibroblasts. Further investigations revealed that these compounds effectively induced early-stage apoptosis and selectively arrested the cell cycle at the G1 phase in cancer cells. Gene expression analysis confirmed selective activation of the caspase-9-mediated apoptotic pathway in MCF-7 cells, providing insights into their underlying molecular mechanisms. These findings highlight the promising potential of PTB derivatives as potent anticancer agents, laying the groundwork for the development of targeted therapies for breast cancer that leverage apoptosis induction for improved therapeutic outcomes.

The increasing incidence of diseases and the constraints of current treatments require expedited drug development. Drug repositioning presents an effective approach for discovering new therapeutic applications for drugs already in clinical use. This study examines the efficacy of metronidazole and secnidazole, which are presently utilized as antiprotozoal agents, in the treatment of Alzheimer's disease via ester modifications. The secondary alcohol group in nitroimidazole structures underwent esterification with acetyl, pivaloyl, cyclopropyl, and cyclohexyl carbonyl chlorides. The compounds exhibited significant inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with Ki values between 52.40 +/- 6.99 nM and 240.80 +/- 45.56 nM for AChE and 77.82 +/- 18.01 nM and 323.70 +/- 56.21 nM for BChE. Molecular docking studies demonstrated significant interactions of the most active compounds (MNZ 8 and MNZ 4) with essential residues, including Trp84 and Phe330 in AChE, as well as Trp82 and active-site water molecules in BChE. These findings corroborate their inhibitory potential, notwithstanding initial positional alterations observed during simulations. The synthesized compounds' absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties were also assessed in silico. All compounds demonstrated drug-like properties and did not exhibit undesirable toxic effects. The findings indicate that repositioned derivatives of metronidazole and secnidazole may serve as promising lead compounds for the development of cholinesterase inhibitors aimed at treating Alzheimer's disease.

HCV NS3/4A protease is a crucial target for antiviral therapy, but resistance remains a significant challenge. Understanding substrate recognition is key to developing effective inhibitors. The aim of this study was to investigate four new compounds (10-12 and 13) that mimic natural substrate binding. Compound activities were determined with enzymatic assays and anti-proliferative activities were evaluated. Compound 12 exhibited the highest potency with an IC50 of 17.78 mu M and a Ki value of 16.39 mu M. All compounds demonstrated moderate to high anti-proliferative activity against HFF-1 and HepG2 cells, with 12 and 11 showing the most potent effects. In silico studies revealed that compounds 11 and 12 formed stable complexes with the HCV NS3/4A protease, establishing significant interactions with key residues of the catalytic triad. Their docking scores and molecular dynamics simulations were comparable to those of the reference molecule, simeprevir. These findings suggest that compounds 10-12 and 13 hold promise as potential therapeutic agents against HCV, warranting further investigation.

This study presents the synthesis and bioactivity screening of a series of substituted bisbenzimidazoles (3a-l), assessed for their inhibitory effects on alpha-glycosidase, alpha-amylase, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), as well as their antibacterial activities and metal chelation properties. Compound 3e exhibited the most significant inhibitory activity against intestinal alpha-glycosidase and alpha-amylase, showing IC50 values of 15.51 mu M and 18.18 mu M, respectively. All bisbenzimidazole derivatives demonstrated significant inhibitory activities, with Ki values between 0.99 and 2.98 nM for AChE and 0.40 to 2.18 nM for BChE. Antimicrobial analyses revealed significant antibacterial efficacy in compounds 3c and 3f, with IC50 values ranging from 10.75 to 12.83 mu g/mu L. This article presents a thorough evaluation of the pharmacological activities associated with bisbenzimidazole compounds 3a-l. To validate experimental results, selected compounds exhibiting notable enzyme inhibitory potential were subjected to molecular docking studies, which demonstrated their binding interactions within the active sites of target enzymes. Molecular dynamics simulation studies were carried out for 100 ns to determine the stability of the compounds in target proteins. During the simulation, it was observed that 3 h, 3 g, 3l, and 3e were stable in 4EY7, 4BDS, 3TOP, and 2QV4, respectively. Compounds 3 h, 3 g, 3e, and 3l have been identified as promising candidates for the inhibition of AChE, BChE, alpha-glycosidase, and alpha-amylase, respectively.

The emergence of antibiotic-resistant pathogens has reduced the efficacy of current antimicrobial therapies, emphasizing the need for new therapeutic agents. This study presents the design, synthesis, and evaluation of bisbenzimidazole-chalcone hybrid compounds as potential antimicrobial agents. These compounds were tested for their antimicrobial activity against eleven common pathogens, as well as their ability to inhibit biofilm formation and eradicate preformed biofilms in Escherichia coli. Compounds EA1, EA3, EA4, and EA5 demonstrated antibacterial activity against E. coli comparable to ampicillin (31.25 mu g/mL) and outperformed the other tested compounds. Notably, EA4 and EA5 inhibited biofilm formation at sub-MIC concentrations and effectively eradicated preformed biofilms, as confirmed by the crystal violet assay. The synergistic effects of the most active compounds in combination with ampicillin were assessed using checkerboard synergy testing, with all combinations showing 'indifference' effects. Further analysis of the most potent compounds against E. coli ATCC 25,922 included the inhibition of DNA gyrase using E. coli DNA gyrase and a plasmid-based relaxed DNA kit. Molecular docking and molecular dynamics simulations were conducted to elucidate the binding modes and stability of these compounds within E. coli DNA gyrase enzymes. EA4 exhibited significant affinity for DNA gyrase B subunit (docking score: -4.026 kcal/mol, average RMSD value: 4.4 & Aring;), while EA5 displayed dual affinity for both DNA gyrase B subunit and DNA gyrase A subunit (docking scores: -6.944 and -3.432 kcal/mol, respectively), maintaining stable interactions in the active sites during simulations (average RMSD values of 3.2 & Aring; and 3.1 & Aring;). These results highlight the potential of bisbenzimidazole-chalcone hybrids as promising antibacterial agents, particularly in their dualtargeting capabilities against biofilm formation and DNA gyrase inhibition.

Type V MAPK inhibitors are distinguished by their capacity to target both the ATP binding site and a specific allosteric site on the enzyme. The present work utilized in silico analysis with Maestro 13.8.135 (Schrodinger) software in conjunction with experimental investigations to enhance the antiproliferative efficacy and forecast the likely mechanism of action of benzothiazole derivatives. Approximately 28 compounds were developed, produced, and assessed for their antiproliferative properties against two breast cancer cell lines: ER+ (MCF7) and ER- (MDA-MB-231), in addition to one normal mouse fibroblast cell line (L929). Their antiproliferative activities were evaluated via the MTT test, with doxorubicin and cisplatin serving as reference drugs for comparison. Consequently, the compounds with the greatest activity against the MCF7 cell line were chosen, and their inhibitory effects on the p38α MAPK enzyme were examined. The molecular docking studies of compounds 15 and 19 demonstrated significant binding affinities for p38α MAPK. Molecular dynamics simulations conducted over 100 ns revealed that compounds 15 and 19 exhibit stability inside both the ATP-binding domain and the lipid domain of p38α MAPK. The research focused on creating effective Type V MAPK inhibitors demonstrate that compounds 15 and 19 possess considerable ability to inhibit p38α MAPK, hence establishing them as promising anticancer agents.

Invasive fungal infections (IFIs) pose significant challenges in clinical settings, particularly due to their high morbidity and mortality rates. The rising incidence of these infections, coupled with increasing antifungal resistance, underscores the urgent need for novel therapeutic strategies. Current antifungal drugs target the fungal cell membrane, cell wall, or intracellular components, but resistance mechanisms such as altered drug-target interactions, enhanced efflux, and adaptive cellular responses have diminished their efficacy. Recent research has highlighted the potential of dual inhibitors that simultaneously target multiple pathways or enzymes involved in fungal growth and survival. Combining pharmacophores, such as lanosterol 14α-demethylase (CYP51), heat shock protein 90 (HSP90), histone deacetylase (HDAC), and squalene epoxidase (SE) inhibitors, has led to the development of compounds with enhanced antifungal activity and reduced resistance. This dual-target approach, along with novel chemical scaffolds, not only represents a promising strategy for combating antifungal resistance but is also being utilized in the development of anticancer agents. This review explores the development of new antifungal agents that employ mono-, dual-, or multi-target strategies to combat IFIs. We discuss emerging antifungal targets, resistance mechanisms, and innovative therapeutic approaches that offer hope in managing these challenging infections.

Cancer continues to be a major worldwide health concern, with angiogenesis playing a pivotal role in its progression and metastasis. The capacity of tumors to induce angiogenesis is crucial for their proliferation and metastasis, rendering it a significant target for treatment strategies. This study involved the synthesis of sulfonamide-chalcone hybrid compounds and the evaluation of their anti-angiogenic activity by the assessment of their effects on vascular endothelial growth factor receptors (VEGFR1/VEGFR2) in human umbilical vein endothelial cells (HUVECs). Among the synthesized compounds, 28 and 31 exhibited the most promising inhibitory effects similar to sorafenib as positive control, with IC50 values superior to 10 μM. They dramatically diminished endothelial cell proliferation and tube formation without exhibiting significant cytotoxicity against healthy human cells. Molecular docking simulations validated their binding affinity to VEGFR1/VEGFR2 receptors, elucidating their molecular mechanisms. Moreover, compounds 28 and 31 exhibited significant anti-angiogenic activity in both 2D and 3D angiogenesis assays, indicating their potential as novel anti-cancer agents. These findings underscore the therapeutic potential of these compounds in blocking angiogenesis and necessitate additional in vivo research to confirm their clinical relevance.

Clinical use of mTOR inhibitors in cancer treatment is well established due to the critical role of mTOR signaling in tumor progression. In this study, we report the structure‐based design and biological evaluation of a series of benzoxazole derivatives as potential mTOR inhibitors. Cytotoxicity studies using MTT assays showed that compounds B4, B11, B12, and B20 exhibited significant antiproliferative effects against breast cancer cell lines with IC₅₀ values between 4.96 and 9.82 µM. Colorimetric enzymatic assays further revealed that among these, only B12 and B20 effectively inhibited mTOR phosphorylation at Ser2448 in MCF‐7 cells. Additionally, both compounds modulated the expression of key apoptotic proteins, including Bax, caspase‐3, p53, and Bcl2. Molecular docking studies against the 4JT5 protein demonstrated binding affinities with docking scores ranging from −7.084 to −7.426 kcal/mol, comparable to the reference compound P2X (−7.309 kcal/mol). Molecular dynamics simulations over 150 ns confirmed the stability of B12 and B20 in the active site, with an average RMSD of 2.8 Å and 3.0 Å, respectively. The absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of the synthesized compounds were evaluated in silico. Among them, B4, B11, B12, and B20 exhibited drug‐like characteristics and showed no undesirable toxic effects. These findings highlight the potential of B12 and B20 as lead compounds for the development of novel mTOR inhibitors in breast cancer therapy.

Alzheimer's disease (AD), the most prevalent form of dementia, leads to progressive cognitive decline due to pathological hallmarks including amyloid plaques, neurofibrillary tangles, synaptic loss, neuroinflammation, and neuronal cell death, highlighting the urgent need for multitarget therapeutic strategies. The p38α mitogen-activated protein kinase (p38α MAPK) pathway is a key regulator of neuroinflammation and has been implicated in AD pathogenesis. Additionally, dysregulation of p38α MAPK is associated with tumorigenesis, making it a promising target for both neurodegenerative and proliferative diseases. In this article, a series of benzoxazole derivatives is designed and synthesized to evaluate their dual inhibitory potential against p38α MAPK and acetylcholinesterase (AChE), aiming for a multifaceted therapeutic approach to AD. A total of 31 compounds are synthesized and assessed for their antiproliferative activity, p38α MAPK inhibition, and AChE inhibitory effects. In vitro assays demonstrate that several compounds exhibit potent dual inhibition of p38α MAPK and AChE, while molecular docking studies provide insights into their binding interactions within the active sites. These findings suggest that benzoxazole-based scaffolds offer a promising framework for the development of dual-acting inhibitors targeting both neuroinflammation and tumorigenesis. Further in vivo and mechanistic studies are warranted to explore their therapeutic potential.

Cumulative escalation in antibiotic-resistant pathogens necessitates the quest for novel antimicrobial agents, as current options continue to diminish bacterial resistance. Herein, we report the synthesis of di-heterocyclic benzazole structures (12-19) and their in vitro evaluation for some biological activities. Compounds 16 and 17 demonstrated potent antibacterial activity (MIC = 7.81 μg/mL) against Staphylococcus aureus, along with significant anti-biofilm activity. Noteworthy is the capability of Compound 17 to inhibit biofilm formation by at least 50% at sub-MIC (3.90 μg/mL) concentration. Furthermore, both compounds exhibited the potential to inhibit preformed biofilm by at least 50% at the MIC concentration (7.81 μg/mL). Additionally, Compounds 16 and 17 were examined for cytotoxic effects in HFF-1 cells, using the MTT method, and screened for binding interactions within the active site of S. aureus DNA gyrase using in silico molecular docking technique, employing AutoDock 4.2.6 and Schrödinger Glidse programs. Overall, our findings highlight Compounds 16 and 17 as promising scaffolds warranting further optimization for the development of effective antibacterial and anti-biofilm agents.

Multidrug-resistant Mycobacterium tuberculosis strains' increasing emergence and rapid spread necessitate the urgent development of innovative antimycobacterial agents. In pursuit of novel agents, a series of N-(benzazole-2-ylmethyl)-2-substituted phenylacetamide or N-(benzazole-2-ylmethyl)-2-(thiophen-2-yl)acetamide compounds (6-11) were synthesized. Their efficacy against multidrug-resistant Mycobacterium tuberculosis was assessed. Compounds exhibited potent antimycobacterial activity with minimum inhibitory concentrations (MIC) ranging from 1.05 to 4.10 µM and demonstrated low cytotoxicity towards fibroblast cell line (L929). ADMET predictions suggested that these synthesized compounds possess drug-like properties. Our findings offer a promising starting point for designing more selective and potent antimycobacterial agents.

Because of the growing bacterial resistance to antibiotics, the discovery of new antibiotics is critical. The search for new antimicrobial drugs that are effective in treating new and existing microbial diseases is arduous and timeconsuming. Deep learning (DL) can help find potential candidates resulting in a more efficient, and cost-effective, and it is more useful on large datasets than other algorithms.Our research team focused on developing an effective DL workflow for discovering new antimicrobial agents. Our group has previously synthesized and tested bisbenzazole structures with various linkers for a variety of pharmacological activities. Antimicrobial activities of bisbenzazole compounds have been also reported in the literature. Deep Neural Networks (DNN) were used to predict the activity of all bisbenzazole compounds synthesized by our group against Staphylococcus aureus and Candida albicans. DNN successfully predicted compounds 16, 17, and 30 out of six molecules (11, 16, 17, 29, 30, and 33) with activity results of 31.25 mu g /mL or better results based on in vitro studies. Compounds 13 and 15 out of four molecules (13, 15, 29, and 30) for C. albicans were successfully predicted. Molecular modeling studies were also carried out, and the compounds' docking scores agreed with the DNN models and in vitro antimicrobial activity results. Finally, this workflow, which includes deep learning, molecular docking, and in vitro studies, is a dependable and efficient way of discovering new antimicrobial agents for S. aureus and C. albicans.

Pathological angiogenesis plays a critical role in tumorigenesis and tumor progression, and anti-angiogenesis therapies have evinced promising antitumor effects in solid tumors. Chalcone skeleton has been regarded as a potential antitumor agent that also targets angiogenesis. In this study, we designed twenty-one non-fluoro-substituted chalcones (13-18, 24-27) and saturated chalcone derivatives (19-23, 28-33) as anti-angiogenic compounds. During the initial stage, these compounds were assessed for their anti-cancer activities against MCF-7 cancer cell lines according to the MTT assay. The compounds revealed satisfactory anti-proliferative capability. An ex vivo fertilized hens' egg-chorioallantoic membrane (HET-CAM) angiogenic study was conducted for the compounds to gauge their mortality and toxicity, which, in turn, revealed a potent anti-angiogenic effect. Eight compounds (16, 17, 21, 24, 26, 27, 29, and 31) significantly reduced densities of capillaries on CAM, whereas compounds 27 and 29 were the most effective anti-angiogenic agents, when compared with Suramin. Moreover, RT-qPCR analysis demonstrated that the anti-angiogenic activity was associated with the fold changes of VEGFR2. Molecular docking studies were conducted for compounds to investigate their mode of interaction within the binding site of VEGFR-2 kinases. This work provided a basis for further design, structural modification, and development of chalcone derivatives as new anti-angiogenic agents.

In this study, we investigate the inhibitory potential of a series of hydrazide derivatives bearing different substituents with the pyridazine structure (5 a-i and 6 a-f) against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using a modified Ellman's method. The inhibitory profiles of the synthesized compounds were assessed by comparing their IC50 and Ki values. Our results demonstrate that all the compounds exhibit significant inhibitory activity against both AChE and BChE when compared to the reference compound, tacrine. Particularly, compound 6 a exhibited the highest activity against Electrophorus electricus AChE (EeAChE) with a Ki value of 3.26 nM, while compound 5 a displayed the most potent inhibition against equine BChE (eqBChE) with a Ki value of 0.94 nM. The compounds did not possess significant cytotoxicity action using the MTT assay on the cancer cell lines. The DPPH assays revealed that all the compounds have moderate antioxidant activities. Furthermore, molecular docking studies provided valuable insights into the interaction mechanisms of these compounds within the active sites of AChE and BChE crystal structures (PDB ID: 4EY7 and 4BDS, respectively). The above results indicated that the pyridazine-based compounds were a promising functional agent for the treatment of Alzheimer's disease. This study reveals the potential of hydrazide derivatives, each with distinct substituents on the pyridazine structure, as potent enzyme inhibitors (AChE and BChE) with antioxidant properties. The provided structural insights, inhibitory profiles, and molecular docking results emphasize their therapeutic potential for neurological disorders. These findings lay the groundwork for subsequent exploration and drug development within the domain of pyridazine compounds. image

Vascular endothelial growth factor receptor 2 (VEGFR-2) stands as a prominent therapeutic target in oncology, playing a critical role in angiogenesis, tumor growth, and metastasis. FDA-approved VEGFR-2 inhibitors are associated with diverse side effects. Thus, finding novel and more effective inhibitors is of utmost importance. In this study, a deep learning (DL) classification model was first developed and then employed to select putative active VEGFR-2 inhibitors from an in-house chemical library including 187 druglike compounds. A pool of 18 promising candidates was shortlisted and screened against VEGFR-2 by using molecular docking. Finally, two compounds, RHE-334 and EA-11, were prioritized as promising VEGFR-2 inhibitors by employing PLATO, our target fishing and bioactivity prediction platform. Based on this rationale, we prepared RHE-334 and EA-11 and successfully tested their anti-proliferative potential against MCF-7 human breast cancer cells with IC50 values of 26.78±4.02 and 38.73±3.84 μM, respectively. Their toxicities were instead challenged against the WI-38. Interestingly, expression studies indicated that, in the presence of RHE-334, VEGFR-2 was equal to 0.52±0.03, thus comparable to imatinib equal to 0.63±0.03. In conclusion, this workflow based on theoretical and experimental approaches demonstrates effective in identifying VEGFR-2 inhibitors and can be easily adapted to other medicinal chemistry goals.