Compounds 4h Research Articles

Design, synthesis of new 4,5-dibenzylidene-9,10-diphenyl-1,2,7,8,9,10 hexahydroacridine-3,6-dione derivatives using extract of Vitexnegundo: Cytotoxic activity & molecular docking study

Among phytochemical and pharmaceutical investigations, the green production of silver nanoparticles has emerged as the crown jewel of this investigation. The production of acridinedione substances is greatly aided by the high catalytic activity of these nanoparticles. Structures and morphologies were determined by using a wide range of analytical techniques, including nuclear magnetic resonance (1H &13C), Fourier transform infrared spectroscopy, mass spectrometry, elemental investigation, scanning electron microscopy, also transmission electron microscopy. Acridinedione compounds' cytotoxicity was measured using the MTT assay with doxorubicin as the reference drug in a number of cancerous and healthy cell lines, comprising Human embryonic kidney cell (HEK293), liver cell (LO2), and lung cell (MRC5). The cytotoxicity compound 1h was shown to be especially active (HepG2, LC50-0.5 µM; MCF-7, LC50-0.64 µM; HeLa, LC50-0.52 µM). By eliciting IC50 values larger than 100 µg/M in normal cell lines (HEK-293), (LO2), and (MRC5), the synthesised compounds proved to be safe. In addition, we present the results from an in-silico analysis of the Methoxsalen protein (1Z11). The binding affinity of compound 1h for the 1Z11 protein is greater than that of other compounds (-11.7 kcal/mol), but it is less than that of Doxorubicin (-10.2 kcal/mol). Hence, the chemical 1h may be used to create powerful cancer drugs.

Synthesis, antiproliferative activity, 3D‐QSAR, and molecular docking studies of novel L‐carvone‐derived pyrimidine‐urea compounds

AbstractTo explore novel natural product‐based nitrogen‐containing heterocyclic compounds with antiproliferative activity, 20 L‐carvone‐derived pyrimidine‐urea compounds 4a–4t were synthesized through the multi‐step reaction of L‐carvone, and structurally characterized by Fourier transform infrared (FT‐IR), hydrogen‐1 nuclear magnetic resonance (1H‐NMR), Carbon‐13 nuclear magnetic resonance (13C‐NMR), and High‐resolution mass spectrometry (HRMS). Besides, the in vitro antiproliferative activity of the target compounds against HepG2, Hela, and MCF‐7 cells was evaluated by methyl thiazolyl tetrazolium (MTT) assay. According to the results, the target compounds showed certain inhibitory activities against the tested cancer cell lines, and five compounds (4b, 4h, 4k, 4l, and 4t) exhibited better inhibition activities against Hela cells than the positive control (5‐FU). Among them, compound 4b held significant antiproliferative activities against Hela and HepG2 cells, and thus deserved further study as a leading compound of new anticancer drugs. In addition, an effective and reasonable three‐dimensional quantitative structure‐activity relationships (3D‐QSAR) model was built by the Comparative molecular field analysis (CoMFA) method to analyze the relationship between the structures of the target compounds and their antiproliferative activities (expressed as pIC50) against Hela cells, and proven to have good predictive ability. Molecular docking was carried out to study the possible binding modes of compound 4b and Survivin, and it was found that compound 4b could be well embedded into the active site, along with the formation of several hydrogen bonds and hydrophobic interactions.

Synthesis, in vitro potency of inhibition, enzyme kinetics and in silico studies of quinoline-based α-glucosidase inhibitors

Diabetes mellitus is a multifactorial global health disorder that is rising at an alarming rate. One effective therapeutic approach for controlling hyperglycemia associated with type-2 diabetes is to target α-glucosidase, which catalyzes starch hydrolysis in the intestine. In an attempt to find potential α-glucosidase inhibitors, a series of twenty new quinoline linked benzothiazole hybrids (8a–t) were synthesized in good yields from suitable reaction procedures and their chemical structures were analyzed by 1HNMR, 13CNMR, IR, and ESI–MS analysis. The synthesized derivatives further screened for their activity against α-glucosidase. Among them, compounds 8b, 8h, 8n and 8o exhibited remarkable α-glucosidase inhibitory activity with IC50 values ranging from 38.2 ± 0.3 to 79.9 ± 1.2 µM compared with standard drug acarbose (IC50 = 750.0 ± 2.0 µM). Enzyme kinetic studies of the most active compound (8h) indicated a non-competitive inhibition with Ki value of 38.2 µM. Moreover, the homology modeling, molecular docking and molecular dynamics simulation studies were conducted to reveal key interactions between the most active compound 8h and the targeted enzyme. These results are complementary to the experimental observations. In order to predict the druggability of the novel derivatives, the pharmacokinetic properties were also applied. These findings could be useful for the design and development of new α-glucosidase inhibitors.

Synthesis, biological activities, and evaluation molecular docking-dynamics studies of new phenylisoxazole quinoxalin-2-amine hybrids as potential α-amylase and α-glucosidase inhibitors.

New phenylisoxazole quinoxalin-2-amine hybrids 5a-i were successfully synthesised with yields of 53-85% and characterised with various spectroscopy methods. The synthesised hybrids underwent in vitro α-amylase and α-glucosidase inhibitory assays, with acarbose as the positive control. Through the biological study, compound 5h exhibits the highest α-amylase inhibitory activity with IC50 = 16.4 ± 0.1 μM while compounds 5a-c, 5e and 5h exhibit great potential as α-glucosidase inhibitors, with 5c being the most potent (IC50 = 15.2 ± 0.3 μM). Among the compounds, 5h exhibits potential as a dual inhibitor for both α-amylase (IC50 = 16.4 ± 0.1 μM) and α-glucosidase (IC50 = 31.6 ± 0.4 μM) enzymes. Through the molecular docking studies, the inhibition potential of the selected compounds is supported. Compound 5h showed important interactions with α-amylase enzyme active sites and exhibited the highest binding energy of -8.9 ± 0.10 kcal mol-1, while compound 5c exhibited the highest binding energy of -9.0 ± 0.20 kcal mol-1 by forming important interactions with the α-glucosidase enzyme active sites. The molecular dynamics study showed that the selected compounds exhibited relative stability when binding with α-amylase and α-glucosidase enzymes. Additionally, compound 5h demonstrated a similar pattern of motion and mechanism of action as the commercially available miglitol.

Synthesis and biological evaluation of novel D-ring fused steroidal N(2)-substituted-1,2,3-triazoles.

In this study, a series of 13 new D-ring fused steroidal N(2)-substituted-1,2,3-triazoles were synthesized, characterized and evaluated for their biological activities. The relative binding affinities of the synthesized compounds for the ligand-binding domains of estrogen receptors α and β, androgen receptor and glucocorticoid receptor demonstrated that androstane derivatives 3a and 3h and estratriene derivative 4e showed highly specific and strong binding affinity for estrogen receptor β, while 3b, 3e, 4a and 4b displayed high binding affinity for the glucocorticoid receptor. The synthesized compounds were tested for their ability to inhibit aldo-keto reductases 1C3 and 1C4 in vitro by monitoring NADPH consumption using fluorescence spectroscopy. The most potent aldo-keto reductase 1C3 inhibitors were compounds 3h (71.17%) and 3f (69.9%). Moreover, a molecular docking study was carried out for compounds 3f and 3h against aldo-keto reductase 1C3 and results showed that compounds 3h and 3f could bind in the same site and orientation as EM1404. However, polar atoms in the triazole group enable additional hydrogen bonding deeper in SP1 with Tyr319, Tyr216 and the NADP+ cofactor, which are not visible in the AKR1C3-EM1404 crystal structure. The synthesized compounds were screened for their anticancer activity against four cancer cell lines. Compound 3f demonstrated moderate toxic effects across various cancer types, while displaying lower toxicity towards the healthy cell line. In summary, our findings indicate that N(2)-substituted-1,2,3-triazoles are high-affinity ligands for estrogen receptor β and glucocorticoid receptor, inhibitors of aldo-keto reductase 1C3 enzyme, and exhibit antiproliferative effects against cancer cells, suggesting that they could serve as scaffolds for anticancer drug development.

Novel sulphonamide-azaheterocycle conjugates and their anti-cancer, anti-inflammatory, anti-diabetic, anti-angiogenesis activity and molecular docking studies

The present study reports the synthesis of sulphonamide-azaheterocycle conjugates (3 a-j) and evaluates its in vitro anticancer activity against breast cancer cell line (MCF-7) and liver cancer cell line (HepG2). The compound 3g was found to be the most active compound with IC50 values of 40.54 ± 0.25 μg/ml against MCF 7 cell line and 55.38 ± 0.18 μg/mL against HepG2 cell line. The compound 3h was found to be most active with IC50 value of 36.70 ± 0.90 μg/mL against MCF 7 cell line and 54.75 ± 0.68 μg/mL against HepG2 cell line as compared to the standard drug 5-fluorouracil (26.08 ± 0.82 μg/mL and 45.50 ± 2.35 μg/mL). The compounds 3 a-j showed characteristic changes, particularly in the nucleus, which were observed through nuclear staining with the fluorescent dye DAPI. The compound 3h has shown strong anti-inflammatory activity with IC50 values of 31.17 ± 0.23 μg/mL. Furthermore, the anti-diabetic activity of 3g and 3h exhibited significant activity with IC50 values 34.51 ± 1.31 and 33.87 ± 1.54 μg/mL as compared to the standard drug acarbose. Compounds 3a, 3b, 3d, 3f, 3g and 3h displayed a strong antiangiogenic effect, with an antiangiogenic score of 1.34, 1.28, 1.32, 1.41, 1.41 and 1.45. Moreover, in silico bioactivity prediction studies demonstrated significant interactions between the compounds and putative drug targets. Results of DFT analysis highlighted that 3h possesses a favorable electronic structure with the possibility of having promising potential in biological applications. The analysis of binding affinities in docking studies highlighted that 3h exhibited the most favorable binding among all sulphonamide-azaheterocycle conjugates (3 a-j) tested against both the HER2 (PDB: 3PP0) and EGFR (PDB: 4HJO).

Synthesis of a new series of 4-pyrazolylquinolinones with apoptotic antiproliferative effects as dual EGFR/BRAFV600E inhibitors.

The current study focuses on developing a single molecule that acts as an antiproliferative agent with dual or multi-targeted action, reducing drug resistance and adverse effects. A new series of 4-pyrazolylquinolin-2-ones (5a-j) with apoptotic antiproliferative effects as dual EGFR/BRAFV600E inhibitors were designed and synthesized. Compounds 5a-j were investigated for their cell viability effect against a normal cell line (MCF-10A). Results showed that none of the compounds were cytotoxic, and all 5a-j demonstrated more than 90% cell viability at 50 μM concentration. Using erlotinib as a reference, the MTT assay investigated the antiproliferative impact of targets 5a-j against four human cancer cell lines. Compounds 5e, 5f, 5h, 5i, and 5j were the most potent antiproliferative agents with GI50 values of 42, 26, 29, 34, and 37 nM, making compounds 5f and 5h more potent than erlotinib (GI50 = 33 nM). Moreover, compounds 5e, 5f, 5h, 5i, and 5j were further investigated as dual EGFR/BRAFV600E inhibitors, and results revealed that compounds 5f, 5h, and 5i are potent antiproliferative agents that act as dual EGFR/BRAFV600E inhibitors. Cell cycle analysis and apoptosis detection revealed that compound 5h displaying cell cycle arrest at the G1 transition could induce apoptosis with a high necrosis percentage. Docking studies revealed that compound 5f exhibited a strong affinity for EGFR and BRAFV600E, with high docking scores of -8.55 kcal mol-1 and -8.22 kcal mol-1, respectively. Furthermore, the ADME analysis of compounds 5a-j highlighted the diversity in their pharmacokinetic properties, emphasizing the importance of experimental validation.

Design, synthesis, inhibitory activity, and molecular simulations study for d-glucose-conjugated thioureas containing pyrimidine ring as multitarget inhibitors against α-amylase, α-glucosidase, DDP-4, and PTP1B in Type 2 diabetes mellitus.

A series of tetra-O-acetyl-α-d-glucopyranosyl thioureas 8a-l of substituted 2-aminopyrimidines 4a-l have been designed and synthesized. The latter were prepared from corresponding chalcones 3a-l of p-bromoacetophenone and appropriate substituted benzaldehydes by their reaction with guanidine. The target thiourea compounds 8a-l exhibited significant inhibitory activity in vitro against enzymes that were related to type 2 diabetes mellitus, including α-amylase, α-glucosidase, DPP-4, and PTP1B. Amongst these thioureas, compound 8k with an ortho-methoxy group was the most potential enzyme inhibitor against α-amylase with an IC50 value of 9.72 ± 0.34 μM. Its meta-isomer 8j was the strongest inhibitor against α-glucosidase with IC50 = 9.73 ± 0.72 μM. In the inhibition against DPP-4, compound 8f with a para-bromo substituent exhibited the strongest activity with an IC50 value of 2.53 ± 0.03 nM. In the inhibition against PTP1B, compound 8h with a para-isopropyl substituent had the strongest inhibitory activity with an IC50 value of 2.74 ± 0.03 μM. The enzyme kinetics of the most active compounds, including 8j, 8f and 8h against α-glucosidase, DPP-4, and PTP1B, respectively, were studied. The obtained results showed that 8j was a competitive α-glucosidase inhibitor with an inhibitory constant K I value of 9.31 μM. Compound 8f was a non-competitive inhibitor for DDP-4 with an inhibitory constant K I value of 12.57 μM. Compound 8h was also a non-competitive inhibitor for DDP-4 with an inhibitory constant K I value of 12.41 μM. The cytotoxicity of the most active compounds, including 8f and 8k (against α-amylase), 8i and 8j (against α-glucosidase), 8a, 8f, and 8g (against DPP-4), and 8d, 8f, and 8h (against PTP1B) was screened. The obtained cytotoxicity showed that all tested inhibitors were noncytotoxic to human normal cell line 3T3. Induced fit docking simulations of all synthesized compounds 8a-l were performed on four enzymes 4W93 (for α-amylase), 3TOP (for α-glucosidase), 3W2T (for DPP-4), and 1NNY (for PTP1B). Key interactions of each of these ligands with residues in the active pocket of each studied enzyme have been shown.

Synthesis, characterization and biological research of novel 2-(quinoline-4-carbonyl)hydrazide-acrylamide hybrids as potential anticancer agents on MCF-7 breast carcinoma cells by targeting EGFR-TK.

Novel derivatives of the 2-(quinoline-4-carbonyl)hydrazide scaffold carrying the acrylamide moiety were synthesized and tested for their cytotoxic efficacy against the breast carcinoma MCF-7 cell line. The most active members 6a, 6b and 6h revealed significant antiproliferative action with an IC50 value of 3.39, 5.94 and 2.71 μM, respectively, which were more potent than the reference drug Dox (IC50 = 6.18 μM). Aiming to enlighten the antiproliferative activity, compounds 6a and 6h were examined for their inhibitory potential against EGFR kinase. The results demonstrated that compound 6h displayed potent inhibitory activity, as concluded from the IC50 value (IC50 = 0.22 μM) compared to the standard drug Lapatinib (IC50 value of 0.18 μM). Compound 6h was found to induce significant cellular cycle arrest at the G1 phase and provoke apoptosis. Besides, compound 6h triggered apoptosis via upregulating p53 and initiator caspase 9 by 7.4- and 8.7-fold, respectively, compared to DMSO controls.

Discovery of dibenzylbutane lignan LCA derivatives as potent anti-inflammatory agents.

Inflammation is the body's response to defence against infection or injury, and is associated with the progression of many diseases, such as inflammatory bowel disease (IBD) and rheumatoid arthritis (RA). LCA, a dibenzylbutane lignan extracted from the roots of traditional medicinal plant Litsea cubeba (Lour.) Pers., has demonstrated promising anti-inflammatory activity. In this study, a series of novel LCA derivatives were designed, synthesized, and evaluated for anti-inflammatory activity. Lipopolysaccharide (LPS)-induced RAW 264.7 cell model experiments showed that compound 10h (at 20 μM of concentration) had the strongest inhibitory effect on NO release, and inhibited the secretion and gene expression levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in vitro. In addition, western blot, immunofluorescence, and molecular docking showed that the anti-inflammatory mechanism of compound 10h may be related to the nuclear factor (NF)-κB signalling pathway. In vivo studies based on a carrageenan-induced mouse paw edema model have shown significant anti-inflammatory activity of compound 10h at 20 mg kg-1. Preliminary in vitro and in vivo studies indicate that compound 10h has the potential to be developed as a novel anti-inflammatory agent.

Identification of chalcone analogues as anti-inflammatory agents through the regulation of NF-κB and JNK activation.

To develop new anti-inflammatory agents with improved pharmaceutical profiles, a series of chalcone analogues were designed and synthesized. In vitro anti-inflammatory activity of these compounds was evaluated by screening their inhibitory effects on NO production in RAW264.7 cell lines. The most promising compounds 3h and 3l were selected for further investigation by assessment of their dose-dependent inhibitory activity against cytokines such as TNF-α, IL-1β, and IL-6 and PGE2 release. The further study also indicated that 3h and 3l could significantly suppress the expression of iNOS and COX-2 through the NF-κB/JNK signaling pathway. Furthermore, compounds 3h and 3l could also remarkably inhibit the mRNA expression of inflammation-related genes. Meanwhile, 3h could also down-regulate ROS production. Docking simulation was conducted to position compounds 3h and 3l into the iNOS binding site to predict the probable binding mode. In conclusion, this series of chalcone analogues with reasonable drug-likeness obtained via in silico rapid prediction can be used as promising lead candidates.

Novel PPAR-γ agonists as potential neuroprotective agents against Alzheimer's disease: rational design, synthesis, in silico evaluation, PPAR-γ binding assay and transactivation and expression studies.

Alzheimer's disease (AD) is a neurological disorder. It is caused by accumulation of amyloid beta (Aβ) plaques and tau tangles, which gradually leads to cognitive decline and memory loss. Peroxisome proliferator-activated receptor gamma (PPAR-γ), a nuclear receptor, plays a significant role in regulating genes responsible for metabolism and inflammation. Studies have shown that PPAR-γ activation has neuroprotective effects, can potentially reduce inflammation and oxidative stress, and stimulates mitochondrial biogenesis. Current study presents the design, synthesis and in vitro evaluation of PPAR-γ agonists for AD that are tailored to optimize binding with the PPAR-γ receptor. The compounds 4a, 4h and 4j exhibited notable binding affinities towards PPAR-γ LBD, with IC50 values of 8.607, 9.242, and 5.974 μM, respectively, in TR-FRET binding assay. These compounds were cell proliferative and non-cytotoxic in a neuroblastoma cell line (SH-SY5Y). They also demonstrated dose-dependent PPAR-γ activation in transactivation assay. Their neuroprotective effect was studied based on their anti-inflammatory and anti-oxidant potential by reducing the levels of proinflammatory markers (TNF-α, IL-6 and IL-1β) and ROS in Aβ-induced SH-SY5Y neuroblastoma cells using a flow cytometry method. The synthesized compounds also showed interactions in molecular docking study with the PPAR-γ receptor and demonstrated good stability in MD simulation. Our results highlight that through activation of PPAR-γ, the compounds 4a, 4h and 4j offer neuroprotective effects by reducing neuroinflammation and oxidative stress, and hence, they may be considered lead molecules for treating AD.

SYNTHESIS AND CHARACTERIZATION OF NEW NILUTAMIDE NO2 GROUP MODIFIED 1,2,3-TRIAZOLES AS In vitro ANTICANCER AGENTS

Nilutamide (1) of the NO2 group can be converted to NH2 by addition of triethyl silane and Wilkinson’s catalyst to give amino compound (2) via reduction. It is further treated with t_BuONO by TMSN3 in RB flask containing CH3CN to give 3-(4-(4-azido-3-(trifluoromethyl) phenyl)-5-5-dimmethylimidazolidine-2,4-dione (3). Azide furthermore reacted with different terminal alkynes in the presence of Sharpless catalyst to form 5,5-dimethyl-3-(4-(4-phenyl-1H1,2,3-triazol-1-yl)-3-trifluoromethyl imidazolidine-2,4-diones(4a-4j) with favorable yields depicted (scheme-I) in this manuscript. All the compounds were screened for in vitro anti-cancer activity, among them compound 4h containing the 4-CN group showed highest anticancer activity PC3=-1.94±1.16µM and DU-145=1.54±0.32 and MCF7=1.43±0.92 µM. Compound 4d NO2 group resulting compound 4d exhibited PC3 3.38±2.07 and DU-145 =3.58±1.57 µM. Compound 4C containing Ome group PC3=2.10±1.38, DU-145=1.57±0.32 and MCF-7=2.08±1.64 µM as IC50 in µM, Etoposide is used as a reference.

Synthesis and antifungal evaluation of new azole derivatives containing 1,2,3-triazole.

Invasive fungal infections caused by C. albicans are becoming increasingly serious and there is an urgent need for exploring new antifungal drugs. In the present work, a series of new azole derivatives containing a 1,2,3-triazole moiety have been prepared, and in vitro antifungal activity have been evaluated. The results revealed that most compounds showed excellent antifungal activity against C. albicans SC5314 and drug-resistant SC5314-FR. In particular, compounds 4h, 4j, 4l, 4s and 4w exhibited better antifungal activity than FLC. The preliminary mechanism study indicated that 4s could damage the integrity of the cell structure, increase the permeability of the cell membrane, and cause the leakage of cell contents of C. albicans. The molecular docking study indicated that 4s showed an obvious binding site with the target CYP51 (PDB ID: 5TL8). Therefore, 4s could be considered as a new antifungal agent targeting CYP51 for further study.

Synthesis and antiproliferative activity of 2-oxo-3-phenylquinoxaline derivatives and related compounds against colon cancer.

We have designed 17 new 2-oxo-3-phenylquinoxalines via the chemoselective Michael reaction of 3-phenylquinoxalin-2(1H)-one with acrylic acid derivatives. The ester, ethyl 3-(2-oxo-3-phenylquinoxalin-1(2H)-yl)propanoate, was reacted with hydroxylamine and hydrazine to produce N-hydroxy-3-(2-oxo-3-phenylquinoxalin-1(2H)-yl)propanamide and hydrazide, respectively. Further modifications were made through reactions with isothiocyanates and azide coupling with amines, yielding thiosemicarbazides and N-alkyl derivatives. Molecular docking studies identified compound 7j as the most potent binder, fitting well into the active site, with the phenyl ring occupying the S1 pocket and the amino acid chain positioned in the S2 pocket. The synthesized compounds (2a, 4, 7a, 7g, 7d, 7h, 7e, 7b, 7c, 7f, and 7j) were evaluated for their anti-cancer activity on colorectal cancer (HCT-116) cells. Compounds 2a and 7j showed significant reductions in cell viability, with IC50 values of 28.85 ± 3.26 μg mL-1 and 26.75 ± 3.50 μg mL-1, respectively. Image analysis of HCT-116 cells treated with 60 μg mL-1 of compound 7j for 48 hours revealed notable morphological changes in both nuclei and cells. The number of cells reduced from 447 in the control to 238 in the treated group, with a corresponding reduction in the area covered by cells from 41.9% to 17.6%. Nuclear disintegration and chromatin fragmentation were observed, confirming apoptosis. These results highlight the potent cytotoxic effect of compound 7j.

Design and synthesis of new 1,2,4-oxadiazole/quinazoline-4-one hybrids with antiproliferative activity as multitargeted inhibitors.

The combination of BRAF and tyrosine kinase (TK) inhibitors has been demonstrated to be highly effective in inhibiting tumor development and is an approach for overcoming resistance in clinical trials. Accordingly, a novel series of 1,2,4-oxadiazole/quinazoline-4-one hybrids was developed as antiproliferative multitargeted inhibitors. The structures of the newly synthesized compounds 9a-o were validated using IR, NMR, MS, and elemental techniques. 9a-o were tested as antiproliferative agents. The results showed that the majority of the tested compounds showed significant antiproliferative action with 9b, 9c, 9h, 9k, and 9l being the most potent. Compounds 9b, 9c, 9h, 9k, and 9l were tested as EGFR and BRAFV600E inhibitors. These in vitro tests revealed that compounds 9b, 9c, and 9h are strong antiproliferative agents that may act as dual EGFR/BRAFV600E inhibitors. 9b, 9c, and 9h were further investigated for their inhibitory effect on mutant EGFR (EGFRT790M), and the results showed that the tested compounds had considerable inhibitory action. Cell cycle study and apoptosis detection demonstrated that compound 9b exhibits cell cycle arrest at the G2/M transition. Molecular docking simulations reveal the binding mechanism of the most active antiproliferative agents.

A novel green and efficient heterogeneous acid catalyst for the one-pot synthesis of benzopyrazine-aminoimidazole hybrids with antiproliferative potential.

A novel, green, efficient, and stable magnetically heterogeneous nanocatalyst was developed by immobilizing butanesulfonic acid (BuSO3H) onto the surface of MFe2O4 magnetic nanoparticles (MNPs). The resulting core-shell structure of the MFe2O4@PDA@BuSO3H nanocatalyst was thoroughly characterized using various analytical techniques, including Fourier-Transform Infrared Spectroscopy (FT-IR), X-ray Diffraction (XRD), Energy-Dispersive X-ray Spectroscopy (EDS), Field Emission Scanning Electron Microscopy (FESEM), Transmission Electron Microscopy (TEM), Vibrating Sample Magnetometry (VSM), and Brunauer-Emmett-Teller (BET) analysis. A nanocatalyst was used to synthesize 2-benzopyrazine-aminoimidazole hybrid derivatives through a domino multicomponent Knoevenagel-condensation-cyclization reaction (5a-p) in an environmentally friendly manner. The resulting compounds were then tested for their anticancer activity against three types of human cancer cells (MCF-7, A549, and U87) using the MTT assay. The experiment showed that the nanocatalyst had excellent catalytic activity, and the synthesized compounds exhibited promising antiproliferative activity. Notably, compounds 5g and 5h, containing a 2-naphthyl ring, showed the highest antiproliferative effects against MCF-7 cells, with IC50 values of 0.03 and 0.32 μM, respectively. Additionally, the activity of compounds 5g and 5h in tubulin polymerization, apoptosis induction, and cell cycle arrest in MCF-7 cells were investigated. The results demonstrated that these compounds effectively induced apoptosis and cell cycle arrest. The binding of representative compounds to the colchicine binding site of tubulin was confirmed through molecular modeling studies.

Synthesis and biological research of new imidazolone-sulphonamide-pyrimidine hybrids as potential EGFR-TK inhibitors and apoptosis-inducing agents.

Development of new effective EGFR-targeted antitumor agents is needed because of their clinical significance. A new series of imidazolone-sulphonamide-pyrimidine hybrids was designed and synthesized as modified analogs of some reported EGFR inhibitors. The cytotoxic activity of all the synthesized hybrids was investigated against the breast MCF-7 cancerous cell line using doxorubicin (Dox) as a positive control. 4-(Furan-2-ylmethylene)imidazolone-sulphonamide-pyrimidine 6b had the best potent activity against MCF-7 cells with IC50 result of 1.05 μM, which was better than Dox (IC50 = 1.91 μM). In addition, mechanistic studies revealed the ability of compounds 5g, 5h and 6b to inhibit EGFR kinase. Cell cycle analysis revealed that compound 6b can halt MCF-7 cells at the G1 phase with a concomitant decrease in cellular percentage at the S and G2/M phases. This compound produced a noticeable rise in the proportion of apoptotic cells with regard to the untreated control. Furthermore, the effects of hybrid 6b on the expression levels of pro-apoptotic Bax and pro-survival Bcl2 were assessed. The results showed that this compound upregulated the level of Bax expression as well as declined the expression value of Bcl-2 with regard to the untreated control.

Synthesis, characterization and antimicrobial activity of new thioxo tetrahydropyrimidine derivatives

A sequence of thioxotetrahydropyrimidenes derivatives, N-(4-chloro/methoxyphenyl)-3-formyl-6-methyl-4-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamides (4a-l) were synthesized by the formylation of N-(4-chloro/methoxyphenyl)-6-methyl-4-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamides (3a-l) by dry dimethyl formamide (DMF) and phosphorous oxychloride at room temperature. Formerly, compounds (3a-l) were synthesized by the condensation of N-(4-chloro/methoxyphenyl)-3-oxobutanamide (1), various aromatic aldehydes (2a-f) and thiourea with catalytic amount of concentrated hydrochloric acid under reflux temperature. The structures of the synthesized various thioxotetrahydropyrimidenes have been characterized by using elemental analysis, Infrared, 1H-NMR, 13C-NMR spectroscopy and further supported by Mass spectroscopy. All the products have been screened for their in-vitro biological assay like antibacterial activity towards Gram-positive and Gram-negative bacterial strains and antifungal activity towards Aspergillus niger at a concentration of 40 µg/ml. It was showing that the compounds 4a, 4e, 4g, 4h, 4i and 4l displayed inspirational antibacterial and antifungal activity compared to the used reference standard.

Synthesis, molecular docking analysis and in vitro evaluation of new heterocyclic hybrids of 4-aza-podophyllotoxin as potent cytotoxic agents.

Two different synthetic approaches to novel heterocyclic hybrid compounds of 4-azapodophyllotoxin were investigated. The obtained products were characterized by infrared spectroscopy, nuclear magnetic resonance spectroscopy, and high-resolution mass spectrometry. MTT protocol was then performed to examine the cytotoxic activity of these products against KB, HepG2, A549, MCF7, and Hek-293 cell lines. The cytotoxic assessment indicated that all products displayed moderate to high cytotoxicity against all tested cancer cell lines. The most active compound 13k containing the 2-methoxypyridin-4-yl group exhibited selective cytotoxicity against KB, A549, and HepG2 cell lines with the IC50 values ranging from 0.23 to 0.27 μM, which were between 5- to 10-fold more potent than the positive control ellipticine. Compounds 13a (HetAr = thiophen-3-yl) and 13d (HetAr = 5-bromofuran-2-yl) displayed high cytotoxic selectivity for A549 and HepG2 cancer cell lines when compared to the other cancer cell lines and low toxicity to the normal Hek-293 cell line. Molecular docking study was conducted to evaluate the interaction of new synthesized compounds with the colchicine-binding-site of tubulin. Besides that, physicochemical and pharmacokinetic properties of the most active compounds 13h,k were predicted.