Synthesis, characterization, and biological evaluation of certain 1,3-thiazolone derivatives bearing pyrazoline moiety as potential anti-breast cancer agents

A series of 5-arylidene-2-(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)-1,3-thiazol-4(5H)-ones were synthesized and screened for their in vitro antitumor activity against human breast adenocarcinoma cell line (MCF-7). Five of the test compounds exhibited good antitumor activity superior to the reference drug, doxorubicin, with IC₅₀ range 1.4–2.3 μM. Among the test compounds, 2-[3,5-bis(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-1-yl]-5-(2-methoxybenzylidene)-1,3-thiazol-4(5H)-one (3i) was found to show the most potent anticancer activity.     

Synthesis and biological activity of carbocyclic lexitropsins with a bioreductive fragment

Carbocyclic oligopeptides containing of two, three or four aromatic rings with N,N-dimethylpropyl-1,3-diamine group as C-terminus fragment of compounds and 5-[bis(2-chloroethyl)amino]-2,4-dinitrobenzamide as N-terminal were synthesized. These lexitropsins present antitumour activity on the neoplastic cells hepatoblastoma HEP G2. These experiments were evaluated in hypoxic and oxygen conditions. Significant differences of activity in oxygen and hypoxic conditions were shown only in compound N-(3-dimethylaminopropyl)-N′-({3-[5-bis(2-chlorethyl)amino]-2,4-dinitrobenzamide})-phenyl]urea dihydrochloride 1 (IC₅₀=8545 nM in oxygen vs. IC₅₀=710 nM in hypoxia). The rest of compounds (2–6) do not indicate differences of activity in oxygen and hypoxia.     

Design,synthesis, and biological evaluation of novel 3‐(thiophen‐2‐ylthio)pyridine derivatives as potential multitarget anticancer agents

A series of novel 3‐(thiophen‐2‐ylthio)pyridine derivatives as insulin‐like growth factor 1 receptor (IGF‐1R) inhibitors was designed and synthesized. IGF‐1R kinase inhibitory activities and cytotoxicities against HepG2 and WSU‐DLCL2 cell lines were tested. For all of these compounds, potent cancer cell proliferation inhibitory activities were observed, but not through the inhibition of IGR‐1R. Selected compounds were further screened against various kinases. Typical compound 22 (50% inhibitory concentration [IC₅₀] values, HepG2: 2.98 ± 1.11 μM and WSU‐DLCL2: 4.34 ± 0.84 μM) exhibited good inhibitory activities against fibroblast growth factor receptor‐2 (FGFR2), FGFR3, epidermal growth factor receptor, Janus kinase, and RON (receptor originated from Nantes), with IC₅₀ values ranging from 2.14 to 12.20 μM. Additionally, the cell‐cycle analysis showed that compound 22 could arrest HepG2 cells in the G1/G0 phase. Taken together, all the experiments confirmed that the compounds in this series were multitarget anticancer agents worth further optimizing.     

Structural Optimization of Indole Derivatives Acting at Colchicine Binding Site as Potential Anticancer Agents

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Synthesis and biologic evaluation of new 3-phenoxyazetidin-2-one derivatives as selective cyclooxygenase-2 inhibitors

A new series of 3-phenoxyazetidin-2-ones (β-lactams) were designed and synthesized for the evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 inhibition studies showed that all compounds were selective inhibitors of the COX-2 isozyme with IC₅₀ values in the 0.054–0.095 μM range, and COX-2 selectivity indexes in the 228.47–355.6 range. Among the synthesized compounds, 1-(4-methoxyphenyl)-4-(4-(methylsulfonyl)phenyl)-3-phenoxyazetidin-2-one (4j) possessing methoxy group at the para position of N-1 phenyl ring exhibited the highest COX-2 inhibitory selectivity and potency even more potent than the reference drug celecoxib. Molecular modeling studies indicated that the methylsulfonyl pharmacophore group can be inserted into the secondary pocket of COX-2 active site.     

Unsymmetrical 1,3-disubstituted urea derivatives as α-chymotrypsin inhibitors

The objective of this study was to synthesize potent and/or novel inhibitors for α-chymotrypsin activity. Eighteen derivatives of N-methylphenyl-N′-(alkyl/aryl) urea (1–18) were synthesized, and their inhibitory effects on α-chymotrypsin enzyme were evaluated. Two compounds exhibited potent inhibitory activities. The most potent, N-(2-methylphenyl)-2-oxo-1-pyrrolidinecarboxamide (15) having a methyl group at ortho position was the most active inhibitor with an IC₅₀ value of 8.10 ± 0.14 μM, which was comparable to standard chymostatin (IC₅₀ = 8.24 ± 0.11 μM). A slightly less potent, N-(2-acetylphenyl)-N′-(3-methylphenyl) urea (10), exhibited an IC₅₀ of 13.6 ± 0.23 μM. Compounds 3, 4, 7, 11, and 13 exhibited moderate activities. The results demonstrated that α-chymotrypsin inhibition is related to the position of the methyl group and the presence of substituent at the nitrogen of the urea bridge. The inhibitory trend suggests that α-chymotrypsin inhibitory activity declines with ortho > meta > para substitution order. In conclusion, our data suggest that the compound 15 may serve as a lead compound for further designing of other potent or novel α-chymotrypsin inhibitors.     

Synthesis and evaluation of new potent inhibitors of CK1 and CDK5, two kinases involved in Alzheimer’s disease

Cyclin-dependent kinase 5 (CDK5) and Casein kinase 1 (CK1) are both involved in the hyperphosphorylation of the Tau protein and in the amyloid-β production, the two major hallmarks of Alzheimer’s disease. In the present paper, we describe the synthesis and biological evaluation of new series of 2,6,9-trisubstituted purines derived from DRF53, a dual specificity inhibitor of the kinase activity of CDK5 (IC₅₀ = 80 nM) and CK1 (IC₅₀ = 10 nM), and are able to prevent in a dose-dependent manner the CK1-dependent production of amyloid-β in a cell model. Several molecules (e.g., 6e, 6g, 7c) displayed potent kinase inhibitory activities against CDK5 and CK1 (IC₅₀ values ranging from 20 to 50 nM) among which a selective inhibitor of CK1 has been identified (5a, IC₅₀ = 60 nM). In addition, some compounds exhibit sub-micromolar activities against DYRK1A (dual specificity, tyrosine phosphorylation regulated kinase 1A), a kinase involved in Down syndrome and Alzheimer’s disease (6g, IC₅₀ = 510 nM).     

Synthesis,biological evaluation,and molecular modeling of (<Emphasis Type="Italic">E</Emphasis>)-2-aryl-5-styryl-1,3,4-oxadiazole derivatives as acetylcholine esterase inhibitors

A library of 2,5-disubstituted 1,3,4-oxadiazole derivatives of (E)-2-aryl-5-(3,4,5-trimethoxystyryl)-1,3,4-oxadiazoles 4(a–o) and (E)-2-aryl-5-(2-benzo[d][1,3]dioxol-5-yl)vinyl)-1,3,4-oxadiazoles 5(a–q) were synthesized and evaluated for their in vitro acetylcholinesterase (AChE) inhibitory activity. All the synthesized compounds exhibited moderate to good inhibitory activity toward the AChE enzyme. Among the oxadiazole derivatives examined, compounds 4a, 4g, 5c, and 5m (IC₅₀ values of 24.89, 13.72, 37.65, and 19.63 μM, respectively) were found to be promising inhibitors of AChE. Molecular protein–ligand docking studies were examined for these compounds using GOLD docking software and their binding conformations were determined and the simultaneous interactions mode was also established for the potent derivatives.     

Synthesis and in vitro cytotoxicity study of 3-(1H-indol-3-yl)-1,3-diphenylpropan-1-ones

A series of 3-(1H-indol-3-yl)-1,3-diphenylpropan-1-ones 3a–l were synthesized in good to excellent yield by Michael addition of indole 1 with α,β-unsaturated ketones 2a–l in presence of indium(III) sulphate (20 mol%). The structure of the title compounds were established by ¹H NMR, ¹³C NMR, mass and elemental analysis. All the synthesized compounds were evaluated for in vitro cytotoxicity against five different cancer cell lines such as ACHN (human kidney adenocarcinoma), Panc1 (pancreatic), Calu1 (lung), H460 (non small cell lung), HCT116 (human colon cancer cell) and MCF10A (normal breast epithelium) using propidium iodide staining assay protocol. The result showed that the compounds 3e and 3l have excellent cytotoxic activity with the IC₅₀ value ranging from 1.4–2.7 to 2.4–3.4 μM, respectively, in comparison with the other compounds, Flavopiridol and Gemcitabine were employed as a positive control. The findings conferred 3-(1H-indol-3-yl)-1,3-diphenylpropan-1-ones seem to be promising candidates for the development of new anticancer drugs.     

Cytotoxicity and QSAR study of (thio)ureas derived from phenylalkylamines and pyridylalkylamines

Simplified 1,3-disubstituted urea derivatives (11–24) of phenylethylamines, homoveratylamines, 2-pyridylethylamines, 2-picolylamines as well as xylylenediamines were synthesized and investigated for their cytotoxic activities. The results revealed that most analogs displayed cytotoxicity against HepG2 and MOLT-3 cell lines. The bis-thiourea derivatives 23 and 24 exhibited higher inhibitory potency against HepG2 cell than the reference drug, etoposide. 1,1′-(1,3-phenylenebis(methylene))bis(3-(4-chlorophenyl)thiourea) 24 was shown to be the most potent cytotoxic compound against MOLT-3 cell line with an IC₅₀ value of 1.62 μM. QSAR studies suggested that compounds with high ionization potential displayed high cytotoxicity against HuCCA-1 cell line. Furthermore, derivatives with dimethoxyphenyl group had high radial distribution function with a correspondingly high cytotoxicity against A549 cell line. Moreover, analogs 23 and 24 had low values of E _HOMO (energy of the highest occupied molecular orbital energy) as well as high cytotoxicity against HepG2 cell line. This study affords an easily accessible approach for the synthesis of promising anticancer agents. The developed QSAR models provided pertinent information into the physicochemical properties governing the investigated biologic properties.     

Recyclable CuO nanoparticles-catalyzed synthesis of novel-2,5-disubstituted 1,3,4-oxadiazoles as antiproliferative,antibacterial, and antifungal agents

A series of new 2,5-disubstituted 1,3,4-oxadiazoles have been conveniently synthesized through an oxidative C–O coupling by direct C–H bond activation of N-aroyl-N-arylidinehydrazines using a catalytic quantity of CuO nanoparticles. Twenty compounds have been synthesized in good to excellent yields (75–90 %). All the synthesized compounds were evaluated for their in vitro antiproliferative, antibacterial, and antifungal activity. Compounds 8d and 10d are more promising antiproliferative agents with IC₅₀ value of 3.66 and 3.89 µM in MCF-7 cell line, and compounds 8a and 10a were showed more potent antifungal activity than standard drug.     

Synthesis and CNS Activity of N,N-Disubstituted 1-(Aminomethyl)-5-alkyl-3-(aryloxyacetylhydrazono)indolin-2-ones

Isatin and 5-methylisatin were condensed with various aryloxyacetylhydrazides to furnish the 3-(aryloxyacetylhydrazono)-5-alkylindolin-2-ones 1–4 . When 1–4 were subjected to Mannich reaction, the N,N-disubstituted 1-(aminomethyl)-5-alkyl-3-(aryloxyacetylhydrazono)indolin-2-ones 5–8 were obtained. The compounds were CNS active and relatively non-toxic (albino mice).     

Synthesis,molecular structure and urease inhibitory activity of novel bis-Schiff bases of benzyl phenyl ketone: A combined theoretical and experimental approach

BackgroundUrease belongs to the family of amid hydrolases with two nickel atoms in their core structure. On the basis of literature survey, this research work is mainly focused on the study of bis-Schiff base derivatives of benzyl phenyl ketone nucleus.ObjectiveSynthesis of benzyl phenyl ketone based bis-Schiff bases in search of potent urease inhibitors.MethodIn the current work, bis-Schiff bases were synthesized through two steps reaction by reacting benzyl phenyl ketone with excess of hydrazine hydrate in ethanol solvent in the first step to get the desired hydrazone. In last, different substituted aromatic aldehydes were refluxed in catalytic amount of acetic acid with the desired hydrazone to obtain bis-Schiff base derivatives in tremendous yields. Using various spectroscopic techniques including FTIR, HR-ESI-MS, and ¹H NMR spectroscopy were used to clarify the structures of the created bis-Schiff base derivatives.ResultsThe prepared compounds were finally screened for their in-vitro urease inhibition activity. All the synthesized derivatives (3–9) showed excellent to less inhibitory activity when compared with standard thiourea (IC₅₀ = 21.15 ± 0.32 µM). Compounds 3 (IC₅₀ = 22.21 ± 0.42 µM), 4 (IC₅₀ = 26.11 ± 0.22 µM) and 6 (IC₅₀ = 28.11 ± 0.22 µM) were found the most active urease inhibitors near to standard thiourea among the synthesized series. Similarly, compound 5 having IC₅₀ value of 34.32 ± 0.65 µM showed significant inhibitory activity against urease enzyme. Furthermore, three compounds 7, 8, and 9 exhibited less activity with IC₅₀ values of 45.91 ± 0.14, 47.91 ± 0.14, and 48.33 ± 0.72 µM respectively. DFT used to calculate frontier molecular orbitals including; HOMO and LUMO to indicate the charge transfer from molecule to biological transfer, and MEP map to indicate the chemically reactive zone suitable for drug action. The electron localization function (ELF), non-bonding orbitals, AIM charges are also calculated. The docking study contributed to the analysis of urease protein binding.     

Design, synthesis and biological evaluation of some novel 3-cinnamoyl-4-hydroxy-2H-chromen-2-ones as antimalarial agents

A novel series of 3-cinnamoyl-4-hydroxy-2H-chromen-2-ones were designed, synthesized and screened for antiplasmodial activity. Eleven compounds of the series exhibited micromolar potency against chloroquine sensitive and chloroquine resistant strains. The most potent compound 4-hydroxy-3-(3-(4-nitrophenyl)acryloyl)-2H-chromen-2-one showed inhibitory potency (IC₅₀) of 3.1 and 4?μg/ml against chloroquine sensitive and chloroquine resistant strains, respectively. A structure activity relationship study was performed by correlating the effect of substituents with the antimalarial activity of the title compounds. The novel 3-cinnamoyl-4-hydroxy-2H-chromen-2-ones reported here should be good lead for further development of antimalarial agents that can overcome resistance.     

Design, synthesis, antitumor evaluations and molecular modeling studies of novel 3,5-substituted indolin-2-one derivatives

AIM: To design and synthesize a novel class of antitumor agents, featuring the 3, 5-substituted indolin-2-one framework. METHODS: Based on enzyme binding features of (Z)-SU5402, introducing a beta-pyrrole group at the 3-position of the indolin- 2-one core, a series of novel 3,5-substituted indolin-2-ones were designed and synthesized. Four human carcinoma cell lines of A-431, A-549, MDA-MB-468, and Autosomal Dominant Polycystic Kidney disease were chosen for the cell proliferation assay. RESULTS: Twenty new compounds (1a-t) with E configuration have been designed, synthesized and bioassayed. Their structural features were determined by nuclear magnetic resonance (NMR) spectra, low- and high-resolution mass spectra, and confirmed by X-ray crystallography. Although the enzyme assay showed a weak inhibition effect against the epidermal growth factor receptor, vascular endothelial growth factor receptor, fibroblast growth factor receptor and platelet-derived growth factor receptor tyrosine kinases, the cell-based antitumor activity was promising. Compounds 1 g and 1 h showed higher inhibitory activity toward the A-549 and MDA-MB-468 cell lines with IC(50 ) of 0.065-9.4 micromol/L. CONCLUSION: This study provides a new template for further development of potent antitumor drugs.     

Synthesis, molecular docking studies, and in vitro screening of sulfanilamide-thiourea hybrids as antimicrobial and urease inhibitors

A series of novel hybrid molecules containing sulfanilamide and thiourea templates was designed and synthesized. These compounds were screened for antimicrobial and urease inhibitory activities. Some of the compounds revealed promising antibacterial and antifungal activities. Fascinatingly, the majority of the compounds exhibited potential urease inhibitory activities with IC₅₀ ranging from 0.20 to 7.50 μM. Compound 2b was identified as the most potent urease inhibitor (IC₅₀ 0.20 μM), and was 100-fold more potent than thiourea, the standard inhibitor. Molecular docking studies of compounds were performed on 3D crystal structures of Jack bean and Helicobacter pylori ureases.     

Synthesis,in vitro and in vivo biological evaluation of novel lappaconitine derivatives as potential anti-inflammatory agents

Lappaconitine (LA), a natural compound with a novel C18-diterpenoid alkaloid skeleton, displayed extensive biological profile. Recent research on LA is focused mainly on its anti-tumor and analgesic effects, and therefore we aimed to investigate its anti-inflammatory potential. A series of novel LA derivatives with various substituents on the 20-N position was designed and synthesized. In the initial screening of LA derivatives against NO production, all the target compounds, except compound E2, exhibited excellent inhibitory ability relative to that of LA. Particularly, compound A4 exhibited the most potent inhibition with IC₅₀ of 12.91 μmol/L. The elementary structure–activity relationships (SARs) of NO inhibitory activity indicated that replacement of the benzene ring with an electron donating group could improve the anti-inflammatory efficacy. Furthermore, compound A4 shows an anti-inflammatory mechanism by inhibiting NO, PGE2, and TNF-α generation via the suppression of NF-κB and MAPK signaling pathways. Notably, compound A4 could exert a significant therapeutic effect on LPS-induced acute lung injury (ALI) in vivo. Based on the above research, we further investigated the preliminary pharmacokinetic property of A4 in rats. Therefore, compound A4 could be a promising candidate for the development of anti-inflammatory agents in the future.     

Synthesis and evaluation of thiopyrano[3,4-c]quinoline-9-carboxamide derivatives as inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1)

A series of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors, 5-oxo-2,4,5,6-tetrahydro-1H-thiopyrano[3,4-c]quinoline-9-carboxamide derivatives, were successfully synthesized and their PARP-1 inhibitory activity was evaluated. These compounds were prepared from carboxylic acid 7 and the appropriate amines, and a number of the synthesized compounds were found to have significant PARP-1 activity. Among them, 9m showed potent activity in a PARP-1 enzymatic assay and cell-based assay (IC₅₀?=?0.045?μM, ED₅₀?=?0.54?μM). Molecular modeling studies confirmed the obtained biological results.     

Synthesis,molecular docking studies,and in vitro screening of barbiturates/thiobarbiturates as antibacterial and cholinesterase inhibitors

On the basis of observed biological activity of barbiturates/thiobarbiturates, a set of 13 hydrazinecarboxamide/hydrazinecarbothioamides derivatives were designed and synthesized in good to excellent yield with extensive structural characterization. These compounds were screened for antibacterial and cholinesterase inhibitory activities. Two of the compounds 1 and 2 showed moderate bactericidal activity. Compounds 10 and 4 were found to be the most active acetyl/butyryl cholinesterase inhibitor, respectively (AChEI; 10; IC₅₀ = 40.78 μM and BChEI; 4; IC₅₀ = 3.31 μM). In silico molecular docking studies were carried out to identify active interacting sites of drug and enzyme and to establish structure–activity relationships. When predicted cholinesterase binding energies were compared with the experimentally determined inhibitory concentrations (IC₅₀), most active compounds were also found to be the most favorable for binding. The binding scores of compounds 10 and 4 were ?10.2 and ?9.3 kcal/mol, respectively.