Compound 3c Research Articles

A virtual insight into mushroom secondary metabolites: 3D-QSAR, docking, pharmacophore-based analysis and molecular modeling to analyze their anti-breast cancer potential

Breast cancer is a major issue of investigation in drug discovery due to its rising frequency and global dominance. Plants are significant natural sources for the development of novel medications and therapies. Medicinal mushrooms have many biological response modifiers and are used for the treatment of many physical illnesses. In this research, a database of 89 macro-molecules with anti-breast cancer activity, which were previously isolated from the mushrooms in literature, has been selected for the three-dimensional quantitative structure–activity relationships (3D-QSAR) studies. The 3D-QSAR model was necessarily used in Pharmacopoeia virtual evaluation of the database to develop novel MCF-7 inhibitors. With the known potential targets of breast cancer, the docking studies were achieved. Using molecular dynamics simulations, the targets’ stability with the best-chosen natural product molecule was found. Furthermore, the absorption, distribution, metabolism, excretion, and toxicity of three compounds, resulting after the docking study, were predicted. The compound C1 (Pseudonocardian A) showed the features of effective compounds because it has bioavailability from different coral species and is toxicity-free for the prevention of many dermatological illnesses. C1 is chemically active and possesses charge transfer inside the monomer, as seen by the band gaps of highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) electrons. The reactivity descriptors ionization potential, electron affinity, chemical potential (μ), hardness (η), softness (S), electronegativity (χ), and electrophilicity index (ω) have been estimated using the energies of frontier molecular orbitals (HOMO–LUMO). Additionally, molecular electrostatic potential maps were created to show that the C1 is reactive. Communicated by Ramaswamy H. Sarma

Discovery of Novel Pyridazine-Tethered Sulfonamides as Carbonic Anhydrase II Inhibitors for the Management of Glaucoma.

As a progressive neuropathic condition, glaucoma can cause lifelong blindness if left untreated. Novel phenylpyridazine-tethered sulfonamides were designed as selective inhibitors for carbonic anhydrase (CA) isoform II to find effective therapeutic agents for glaucoma. Subsequently, the target inhibitors were synthesized and assessed for their inhibitory action against cytosolic CA I and II. Interestingly, the synthesized molecules poorly inhibited CA I while exhibiting low subnanomolar potency against CA II. Compound 7c disclosed the most potent activity (IC50 = 0.63 nM) with high selectivity against CA II (605-fold than acetazolamide selectivity). Moreover, compound 7c also showed significant in vivo IOP-reducing properties in the in vivo model of glaucoma. Furthermore, the binding of compound 7c to CA II was assessed at the molecular level, exploiting the molecular docking approach.

Discovery of novel selective phosphodiesterase‑1 inhibitors for the treatment of acute myelogenous leukemia

Acute myelogenous leukemia (AML) is the most common form of acute leukemia in adults. PDE1 (Phosphodiesterase 1) is a subfamily of the PDE super-enzyme families that can hydrolyze the second messengers cAMP and cGMP simultaneously. Previous research has shown that suppressing the gene expression of PDE1 can trigger apoptosis of human leukemia cells. However, no selective PDE1 inhibitors have been used to explore whether PDE1 is a potential target for treating AML. Based on our previously reported PDE9/PDE1 dual inhibitor 11a, a series of novel pyrazolopyrimidinone derivatives were designed in this study. The lead compound 6c showed an IC50 of 7.5 nM against PDE1, excellent selectivity over other PDEs and good metabolic stability. In AML cells, compound 6c significantly inhibited the proliferation and induced apoptosis. Further experiments indicated that the apoptosis induced by 6c was through a mitochondria-dependent pathway by decreasing the ratio of Bcl-2/Bax and increasing the cleavage of caspase-3, 7, 9, and PARP. All these results suggested that PDE1 might be a novel target for AML.

Efficacy of the Ionic Liquid 1,4-Bis(carboxymethyl)piperazine-1,4-diium Chloride as a Catalyst for Xanthenes/Acridines Synthesis: Spectral Characterization, X-ray Structure, and Nematicidal Activity

In this research paper, a straightforward and efficient approach for synthesizing the 1,4-bis(carboxymethyl)piperazine-1,4-diium chloride [BCMPZ][2Cl] ionic liquid salt (IL) catalyst is introduced. The morphology, thermal stability, and functionality of the synthesized [BCMPZ][2Cl] IL were characterized using spectroscopic, electron microscopy, and thermal analysis. A density functional theory (DFT) study, including infrared spectroscopy (IR), powder X-ray diffraction (PXRD), Thermogravimetric analysis (TGA), and scanning electron microscopy with energy-dispersive X-ray spectroscopy (SEM with EDX), were employed. The well-characterized ionic liquid (IL) assisted as a catalyst in the synthesis reaction involving aldehydes, dimidone, and arylamine to yield 1,8-dioxo-octahydroxanthene and 1,8-dioxo-9-aryl-10-aryl-decahydroacridine derivatives (3a-i and 4a-b) with high yields, getting up to 97%. The structure of the synthesized molecules was confirmed through various physicochemical techniques, including 1H and 13C NMR, IR, elemental analysis, and MS. X-ray single crystal diffraction techniques were also used to elucidate the geometry of one of the synthesized molecules (3f). The heterogeneous catalyst (IL) used in the synthesis of the molecules was successfully recycled and reused without additional treatment of purification. The synthesized xanthines were found to inhibit nematode activity, thus they may act as potential nematicides for crop protection. The present study also identified five different compounds that were effective against Meloidogyne incognita. Compound 3a reduced nematode egg hatching by 65% at a concentration of 2000 ppm, which was the highest efficacy in tested compounds. Compound 3c had a mortality rate of 80% against nematodes. Overall, the developed method has many advantages, including fast reaction time, economic efficiency, and minimal catalyst loading, making it a promising method for future research in the field of heterocycle synthesis and crop protection.

New modified thieno[2,3-d]pyrimidine derivatives as VEGFR-2 inhibitors: Design, synthesis, in vitro anti-cancer evaluation and divers in silico studies

Angiogenesis is a critical regulatory mechanism for tumor development and metastasis. Tumor growth is closely related to the production of the vascular endothelial growth factor (VEGF), which is mediated by the cell-surface kinase VEGFR-2. Accordingly, blocking of VEGFR-2 is an important approach to find new treatments for malignancies. The aim of this research is the synthesis of new thieno[2,3-d]pyrimidine derivatives that could be potential anticancer leads inhibiting VEGFR-2. The prepared thieno[2,3-d]pyrimidine derivatives were tested in vitro for their inhibitory effects against the kinase activity of VEGFR-2. In addition, the synthesized compounds were assessed for their anti-proliferative activities against MCF-7 and HepG2 cell lines. Compound 4c displayed the strongest anti-VEGFR-2 potentiality with an IC50 value of 0.15 µM and exhibited good anti-proliferative effects against HepG2 and MCF-7 cells with IC50 of 17.14 and 11.56 µM, respectively. Compound 4c induced cell cycle arrest at the S phase and boosted early and late apoptosis in MCF-7 cells. Additionally, compound 4c increased BAX (4.5-fold), decreased Bcl-2 (3.5-fold), and demonstrated a notable increase in caspase-8 (2.9-fold) and caspase-9 (3.3-fold) levels. Furthermore, compound 4c significantly reduced TNF-α (3.6-fold) and IL-6 (3.2-fold) levels in MCF-7 cells. Molecular docking studies indicated good binding affinities as well as energies of the thieno[2,3-d]pyrimidine derivatives against the VEGFR-2. Molecular dynamics (MD) simulations were utilized to study the structural, energetic, and conformational changes of the VEGFR-2–4c complex, and the results indicated its stability. The MM-GBSA study of the VEGFR-2–4c complex showed a stable thermodynamic behavior with a binding free energy of -44 kcal/mol. The PLIP analysis identified the 3D interactions and binding conformation through the VEGFR-2–4c complex. Moreover, the DFT studies have been performed to study, Mullikan atomic charge distribution, FMO, ESP, the total density of state, and the QTAIM maps of compound 4c to theoretically verify its reactivity. Finally, computational ADMET and toxicity studies were conducted to assess the drug development potential of the thieno[2,3-d]pyrimidine derivatives.

Design of balanced dual-target inhibitors of EGFR and microtubule

Motivated by the clinical success of combining tyrosine kinase inhibitors with microtubule-targeted drugs in antitumor treatment, this paper presents a novel combi-targeting design for dual-target inhibitors, featuring arylformylurea-coupled quinazoline backbones. A series of target compounds (10a-10r) were designed, synthesized, and characterized. Biological assessments demonstrated that 10c notably potentiated ten tumor cell lines in vitro, with IC50 values ranging from 1.04 µM to 7.66 µM. Importantly, 10c (IC50 = 10.66 nM) exhibited superior inhibitory activity against EGFR kinases compared to the reference drug Gefitinib (25.42 nM) and reduced phosphorylated levels of EGFR, AKT, and ERK. Moreover, 10c significantly impeded tubulin polymerization, disrupted the intracellular microtubule network in A549 cells, induced apoptosis, led to S-phase cell cycle arrest, and hindered cell migration. In anticancer evaluation tests using A549 cancer-bearing nude mice models, 10c showed a therapeutic effect similar to Gefitinib, but required only half the dosage (15 mg/kg). These findings indicate that compound 10c is a promising dual-target candidate for anticancer therapy.

Novel isatin-triazole based thiosemicarbazones as potential anticancer agents: synthesis, DFT and molecular docking studies.

Thiosemicarbazones of isatin have been found to exhibit versatile bioactivities. In this study, two distinct types of isatin-triazole hybrids 3a and 3b were accessed via copper-catalyzed azide-alkyne cycloaddition reaction (CuAAC), together with their mono and bis-thiosemicarbazone derivatives 4a-h and 5a-h. In addition to the characterization by physical, spectral and analytical data, a DFT study was carried out to obtain the optimized geometries of all thiosemicarbazones. The global reactivity values showed that among the synthesized derivatives, 4c, 4g and 5c having nitro substituents are the most soft compounds, with compound 5c having the highest electronegativity and electrophilicity index values among the synthesized series, thus possessing strong binding ability with biomolecules. Molecular docking studies were performed to explore the inhibitory ability of the selected compounds against the active sites of the anticancer protein of phosphoinositide 3-kinase (PI3K). Among the synthesized derivatives, 4-nitro substituted bisthiosemicarbazone 5c showed the highest binding energy of -10.3 kcal mol-1. These findings demonstrated that compound 5c could be used as a favored anticancer scaffold via the mechanism of inhibition against the PI3K signaling pathways.

New 3-Hydroxypyridine-4-one Analogues: Their Synthesis, Antimicrobial Evaluation, Molecular Docking, and In Silico ADME Prediction.

Drug resistance to existing antimicrobial drugs has become a serious threat to human health, which highlights the need to develop new antimicrobial agents. In this study, a new set of 3-hydroxypyridine-4-one derivatives (6a-j) was synthesized, and the antimicrobial effects of these derivatives were evaluated against a variety of microorganisms using the microdilution method. The antimicrobial evaluation indicated that compound 6c, with an electron-donating group -OCH3 at the meta position of the phenyl ring, was the most active compound against S. aureus and E. coli species with an MIC value of 32 μg/mL. Compound 6c was more potent than ampicillin as a reference drug. The in vitro antifungal results showed that the studied derivatives had moderate effects (MIC = 128-512 μg/mL) against C. albicans and A. niger species. The molecular modeling studies revealed the possible mechanism and suitable interactions of these derivatives with the target protein. The obtained biological results offer valuable insights into the design of more effective antimicrobial agents.

Novel Mitochondrial and DNA Damaging Fluorescent Calix[4]arenes Bearing Isatin Groups as Aromatase Inhibitors: Design, Synthesis and Anticancer Activity

Breast cancer causes a high rate of mortality all over the world. Therefore, the present study focuses on the anticancer activity of new lower rim-functionalized calix[4]arenes integrated with isatin and the p-position of calixarenes with 1,4-dimethylpyridinium iodine against various human cancer cells such as MCF-7 and MDA-MB-231 breast cancer cell lines, as well as the PNT1A healthy epithelial cell line. It was observed that compound 6c had the lowest values in MCF-7 (8.83 µM) and MDA-MB-231 (3.32 µM). Cell imaging and apoptotic activity studies were performed using confocal microscopy and flow cytometry, respectively. The confocal imaging studies with 6c showed that the compound easily entered the cell, and it was observed that 6c accumulated in the mitochondria.The Comet assay test was used to detect DNA damage of compounds in cells. It was found that treated cells had abnormal tail nuclei and damaged DNA structures compared with untreated cells. In vitro human aromatase enzyme inhibition profiles showed that compound 6c had a remarkable inhibitory effect on aromatase. Compound 6c displayed a significant inhibition capacity on aromatase enzyme with the IC50 value of 0.104 ± 0.004 µM. Thus, not only the anticancer activity of the new fluorescent derivatives, which are the subject of this study, but the aromatase inhibitory profiles have also been proven.

Discovery of a new pyrido[2,3-d]pyridazine-2,8-dione derivative as a potential anti-inflammatory agent through COX-1/COX-2 dual inhibition.

In this paper, we present the design and synthesis of a novel series of pyrido[2,3-d]pyridazine-2,8-dione derivatives via the annulation of the 2-pyridone pattern. The synthesized derivatives were evaluated for in vivo anti-inflammatory activity using an ear edema model. Compound 7c, which showed a greater inhibition of ear edema (82%), was further tested for its in vitro COX-1/COX-2 inhibitory activity. Compound 7c showed similar inhibitory activities against COX-1 and COX-2 isoenzymes. The structural features that ensure the dual inhibition of COX-1 and COX-2 were elucidated using molecular docking studies. Overall, the ring closing of 2-pyridone pattern I transformed this highly selective COX-2 inhibitor into a dual COX inhibitor (7c), which could serve as a model for determining selectivity for COX-2.

Crystal structures of sixteen phosphane chalcogenide complexes of gold(I) chloride, bromide and iodide.

The structures of 16 phosphane chalcogenide complexes of gold(I) halides, with the general formula R 1 3- nR 2 nPEAuX (R 1 = t-butyl; R 2 = isopropyl; n = 0 to 3; E = S or Se; X = Cl, Br or I), are presented. The eight possible chlorido derivatives are: 1a, n = 3, E = S; 2a, n = 2, E = S; 3a, n = 1, E = S; 4a, n = 0, E = S; 5a, n = 3, E = Se; 6a, n = 2, E = Se; 7a, n = 1, E = Se; and 8a, n = 0, E = Se, and the corresponding bromido derivatives are 1b-8b in the same order. However, 2a and 2b were badly disordered and 8a was not obtained. The iodido derivatives are 2c, 6c and 7c (numbered as for the series a and b). All structures are solvent-free and all have Z' = 1 except for 6b and 6c (Z' = 2). All mol-ecules show the expected linear geometry at gold and approximately tetra-hedral angles P-E-Au. The presence of bulky ligands forces some short intra-molecular contacts, in particular H⋯Au and H⋯E. The Au-E bond lengths have a slight but consistent tendency to be longer when trans to a softer X ligand, and vice versa. The five compounds 1a, 5a, 6a, 1b and 5b form an isotypic set, despite the different alkyl groups in 6a. Compounds 3a/3b, 4b/8b and 6b/6c form isotypic pairs. The crystal packing can be analysed in terms of various types of secondary inter-actions, of which the most frequent are 'weak' hydrogen bonds from methine hydrogen atoms to the halogenido ligands. For the structure type 1a, H⋯X and H⋯E contacts combine to form a layer structure. For 3a/3b, the packing is almost featureless, but can be described in terms of a double-layer structure involving borderline H⋯Cl/Br and H⋯S contacts. In 4a and 4b/8b, which lack methine groups, Cmeth-yl-H⋯X contacts combine to form layer structures. In 7a/7b, short C-H⋯X inter-actions form chains of mol-ecules that are further linked by association of short Au⋯Se contacts to form a layer structure. The packing of compound 6b/6c can conveniently be analysed for each independent mol-ecule separately, because they occupy different regions of the cell. Mol-ecule 1 forms chains in which the mol-ecules are linked by a Cmethine⋯Au contact. The mol-ecules 2 associate via a short Se⋯Se contact and a short H⋯X contact to form a layer structure. The packing of compound 2c can be described in terms of two short Cmethine-H⋯I contacts, which combine to form a corrugated ribbon structure. Compound 7c is the only compound in this paper to feature Au⋯Au contacts, which lead to twofold-symmetric dimers. Apart from this, the packing is almost featureless, consisting of layers with only translation symmetry except for two very borderline Au⋯H contacts.

Novel azole-sulfonamide conjugates as potential antimicrobial candidates: synthesis and biological assessment.

Background: Azole and sulfonamide molecular frameworks are endowed with potent antimicrobial activity. Materials & methods: A series of azole-sulfonamide conjugates were synthesized using click reaction of N-propargylated imidazole with azide of sulfonamide and its antimicrobial efficacy was evaluated. Results: The compounds 7c, 7i and 7r displayed promising antibacterial activities, better than the standards sulfonamide and norfloxacin. Allmolecules exhibited promising antifungal activity, more potent than fluconazole. Docking studies of the active conjugates signified the importance of hydrophobic interactions in hosting the molecules in theactive site of dihydrofolate reductase. Conclusion: Azole-sulfonamide conjugates are more active than single sulfonamide moieties and 7c, 7i and 7r may prove valuable leads for further optimization as novel antimicrobial agents.

Quinoline-based Schiff bases as possible antidiabetic agents: ligand-based pharmacophore modeling, 3D QSAR, docking, and molecular dynamics simulations study.

α-Glucosidase enzyme inhibition is a legitimate approach to combat type 2 diabetes mellitus as it manages to control postprandial hyperglycemia. In this pursuit, a literature search identified quinoline-based molecules as potential α-glucosidase inhibitors. Thus our intended approach is to identify pharmacophoric features responsible for the α-glucosidase inhibition. This was achieved by performing, ligand-based pharmacophore modeling, 3D QSAR model development, pharmacophore-based screening of a rationally designed quinoline-based benzohydrazide Schiff base library, identifying, synthesizing and characterizing molecules (6a-6j) by IR, (1H and 13C) NMR, and mass studies. Further, these molecules were evaluated for α-glucosidase and α-amylase inhibitory potential. Compound 6c was found to inhibit α-glucosidase enzyme with an IC50 value of 12.95 ± 2.35 μM. Similarly, compound 6b was found to have an IC50 value of 19.37 ± 0.96 μM as compared to acarbose (IC50: 32.63 ± 1.07 μM); the inhibitory kinetics of compounds 6b and 6c revealed a competitive type of inhibition; the inhibitory effect can be attributed to its mapped pharmacophoric feature and model validation with a survival score of 5.0697 and vector score of 0.9552. The QSAR model showed a strong correlation with an R 2 value of 0.96. All the compounds (6a-6j) showed no toxicity in L929 cell lines by the MTT assay method. Further, the binding orientation and stability of the molecules were assessed using molecular docking studies and MD trajectory analysis. The energy profile of the molecules with protein as a complex and molecules alone was evaluated using MM/GBSA and DFT calculations, respectively; finally, the pharmacokinetic profile was computed using ADMET analysis.

Synthesis of novel fatty acid 3,4-dihydropyrimidin-2-(1H)-one and antitumoral activity against breast and gastric cancer cells.

Monastrol is the best-known small compound from the dihydropyrimidinones/thiones (DHPMs) heterocycle family, a cell-permeable molecule recognized as an inhibitor of mitotic kinesin Eg5, that is over-expressed in tumor cells and is a very promising target for the development of new drugs for cancer. The lipophilic properties of the DHPMs have been demonstrated to be of pivotal importance in the design of new molecules. This work describes the synthesis and antitumoral activity of novel C5-substituted fatty-DHPMs against breast and gastric cancer cell lines. The compounds were synthesized via Biginelli multicomponent reaction from oleyl β-ketoester in good yields (40-72%) using a simple approach catalyzed by nontoxic and free-metal sulfamic acid. Among the compounds tested, the compound 10c, derived from 3-hydroxybenzaldehyde and urea, exhibited 77% cellular viability to normal cells (C2C12) and was selected to be evaluated against tumoral breast (MCF-7) and gastric (AGS) cell lines. The results obtained afforded an IC50 of breast cancer cells of 2.3 μM, qualifying the molecule as the most potent, and making it a promising compound for future experiments in vivo.

Thiazolo-pyridopyrimidines: An in silico evaluation as a lead for CDK4/6 inhibition, synthesis and cytotoxicity screening against breast cancer cell lines.

Pyridopyrimidines belong to a class of compounds characterized by the presence of nitrogen as heteroatoms. These compounds exhibit diverse biological effects, particularly showing promise as anticancer agents, including actions that inhibit CDK4/6. We designed and synthesized a range of substituted thiazolo-pyridopyrimidines (4a-p). Computational ADME/T analysis and molecular docking were performed using the crystal structure of CDK4/6. Subsequently, we synthesized the top-scoring compounds, characterized them using IR, NMR, and Mass spectroscopy, and assessed their impact on MCF-7 and MDAMB-231 cell lines using the SRB assay. To further evaluate stability, molecular dynamics simulations were conducted for the two most promising compounds within the binding site. The docking scores indicated stronger interactions for compounds 4a, 4c, 4d, and 4g. As a result, these specific compounds (4a, 4c, 4d, and 4g) were chosen for synthesis and subsequent screening to assess their cytotoxic effects. Remarkably, compounds 4c and 4a exhibited the most promising activity in terms of their IC50 values across both tested cell lines. Furthermore, molecular dynamics simulation studies uncovered an elevated level of stability within the 4c-6OQO complex. By integrating insights from computational, in vitro, and molecular dynamics simulation findings, compound 4c emerges as a leading candidate for future investigations. The presence of a polar hydroxyl group at the C2 position of the 8-phenyl substitution on the pyridopyrimidine rings appears to contribute to the heightened activity of the compound. Further enhancements to cytotoxic potential could be achieved through structural refinements.

Design, synthesis and computational studies of new azaheterocyclic coumarin derivatives as anti-Mycobacterium tuberculosis agents targeting enoyl acyl carrier protein reductase (InhA).

In this study, we designed and synthesized a series of coumarin derivatives as antitubercular agents targeting the enoyl acyl carrier protein reductase (InhA) enzyme. Among the synthesized compounds, the tetrazole derivative 4c showed the most potent antitubercular effect with a minimum inhibitory concentration value (MIC) of 15 μg mL-1 against Mtb H37Rv and could also inhibit the growth of the mutant strain (ΔkatG). Compound 4c was able to penetrate Mtb-infected human macrophages and suppress the intracellular growth of tubercle bacilli. Moreover, the target derivative 4c showed a potent inhibitory effect against InhA enzyme with an IC50 value of 0.565 μM, which was superior to the reference InhA inhibitor triclosan. Molecular docking of compound 4c within the InhA active site revealed the importance of the 4-phenylcoumarin ring system and tetrazole moiety for activity. Finally, the physicochemical properties and pharmacokinetic parameters of 4c were investigated.

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, enzyme inhibition assay, and molecular modeling study of novel pyrazolines linked to 4-methylsulfonylphenyl scaffold: antitumor activity and cell cycle analysis.

Antitumor activity using 59 cancer cell lines and enzyme inhibitory activity of a newly synthesized pyrazoline-linked 4-methylsulfonylphenyl scaffold (compounds 18a-q) were measured and compared with those of standard drugs. Pyrazolines 18b, 18c, 18f, 18g, 18h, and 18n possessed significant antitumor activity, with a positive cytotoxic effect (PCE) of 22/59, 21/59, 21/59, 48/59, 51/59, and 20/59, respectively. The cancer cell lines HL60, MCF-7, and MDA-MB-231 were used to measure the IC50 values of derivatives 18c, 18g, and 18hvia the MTT assay method, and the results were compared with those of reference drugs. Derivatives 18g and 18h showed potent and broad-spectrum antitumor activities against HL60 (IC50 of 10.43, 8.99 μM, respectively), MCF-7 (IC50 of 11.7 and 12.4 μM, respectively), and MDA-MB-231 (IC50 of 4.07 and 7.18 μM, respectively). Compound 18c exhibited strong antitumor activity against HL60 and MDA-MB-231 cell lines with IC50 values of 8.43 and 12.54 μM, respectively, and moderate antitumor activity against MCF-7 cell lines with an IC50 value of 16.20 μM. Compounds 18c, 18g, and 18h remarkably inhibited VEGFR2 kinase (IC50 = 0.218, 0.168, and 0.135 μM, respectively) compared with the reference drug sorafenib (IC50 = 0.041 μM). Compounds 18g and 18h effectively inhibited HER2 kinase (IC50 = 0.496 and 0.253 μM, respectively) compared with erlotinib (IC50 = 0.085 μM). Compound 18h inhibited EGFR kinase (IC50 = 0.574 μM) with a potency comparable with that of the reference drug erlotinib (IC50 = 0.105 μM). Pyrazolines 18c, 18f, and 18h arrested the S/G2 phase of the cell cycle in HL-60 cells. In addition, derivatives 18c, 18f, and 18h revealed lower Bcl-2 protein expression anti-apoptotic levels and higher Bax, caspase-3, and caspase-9 expression levels. Molecular docking studies of derivative 18h into the binding sites of EGFR, HER2, and VEGFR2 kinases explored the interaction mode of these pyrazoline derivatives and their structural requirements for antitumor activity.

Synthesis and evaluation of tetrahydropyrrolo[1,2-a]quinolin-1(2H)-ones as new tubulin polymerization inhibitors.

Here we explored new 1,5-disubstituted pyrrolidin-2-ones 1, 2 and 5-aryl-3,3a,4,5-tetrahydropyrrolo[1,2-a]quinoline-1(2H)-ones 3 as inhibitors of tubulin polymerization. We evaluated their effects on microtubule dynamics in vitro and on the proliferation of A549 cells, using flow cytometry-based cell cycle analysis. The results were verified with phase-contrast microscopy in three cancer cell lines: A549, HeLa and MCF-7. Guided by molecular modeling of the interactions between tubulin and the most active of the identified compounds, we designed, synthesized, and tested the 3-hydroxyphenyl-substituted compound 3c. This compound was further shown to bind to the colchicine site of tubulin and reduce microtubule growth rates in vitro. Moreover, compound 3c arrested division of the A549 cells in the low micromolar range (IC50 = 5.9 μM) and exhibited cytotoxicity against four different cell lines in the MTT assay for cell proliferation. Our findings demonstrate that 5-aryltetrahydropyrrolo[1,2-a]quinoline-1(2H)-one is a promising scaffold for the development of novel tubulin polymerization inhibitors.

Phenolylazoindole scaffold for facilely synthesized and bis-functional photoswitches combining controllable fluorescence and antifungal properties using theoretical methods.

Functionalization is a major challenge for the application of photoswitches. With the aim to develop novel bis-functional azo photoswitches with stationary photophysical properties, a series of phenolylazoindole derivatives were designed, synthesized, and characterized via NMR spectroscopy studies and high-resolution mass spectrometry (HRMS). Herein, UV/Vis and 1H NMR spectra revealed that the photostationary state (PSS) proportions for PSScis and PSStrans were 76-80% and 68-81%, respectively. Furthermore, the thermal half-lives (t1/2) of compounds A2-A4 and B2 ranged from 0.9 to 5.3 h, affected by the diverse substituents at the R1 and R2 positions. The results indicated that azo photoswitches based on the phenolylazoindole scaffold had stationary photophysical properties and wouldn't be excessively affected by modifying the functional groups. Compounds A4 and B2, which were modified with an aryl group, also exhibited fluorescence emission properties (the quantum yields of A4 and B2 were 2.32% and 13.34%) through the modification of the flexible conjugated structure (benzene) at the R2 position. Significantly, compound C1 was obtained via modification with a pharmacophore in order to acquire antifungal activities against three plant fungi, Rhizoctonia solani (R. solani), Botrytis cinerea (B. cinerea), and Fusarium graminearum (F. graminearum). Strikingly, the inhibitory activity of the cis-isomer of compound C1towards R. solani (53.3%) was significantly better than that of the trans-isomer (34.2%) at 50 μg mL-1. In order to further reveal the antifungal mechanism, molecular docking simulations demonstrated that compound C1 effectively integrates into the cavity of succinate dehydrogenase (SDH); the optically controlled cis-isomer showed a lower binding energy with SDH than that of the trans-isomer. This research confirmed that phenolylazoindole photoswitches can be appropriately applied as molecular regulatory devices and functional photoswitch molecules via bis-functionalization.