Synthesis,characterization, anticancer evaluation and mechanisms of cytotoxic activity of novel 3-hydroxy-3-pyrrolin-2-ones bearing thenoyl fragment: DNA,BSA interactions and molecular docking study

In order to make a progress in discovering a new agents for chemotherapy with improved properties and bearing in mind the fact that substituted 3-hydroxy-3-pyrrolin-2-ones belong to a class of biologically active compounds, series of novel 1,5-diaryl-4-(2-thienylcarbonyl)-3-hydroxy-3-pyrrolin-2-ones were synthesized and characterized by spectral (UV–Vis, IR, NMR, ESI-MS), X-ray and elemental analysis. All compounds were examined for their cytotoxic effect on human cancer cell lines HeLa and MDA-MB 231 and normal fibroblasts (MRC-5). Four compounds, 3-hydroxy-1-(p-tolyl)-4-(2-thienylcarbonyl)-5-(4-chlorophenyl)-2,5-dihydro-1H-pyrrol-2-one (D10), 3-hydroxy-1-(3-nitrophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D13), 3-hydroxy-1-(4-nitrophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D14), and 3-hydroxy-1-(4-chlorophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D15), that showed the highest cytotoxicity against malignant cells and the best selectivity towards normal cells were selected for further experiments. Results obtained by investigating mechanisms of cytotoxic activity suggest that selected 3-hydroxy-3-pyrrolin-2-one derivatives in HeLa cells induce apoptosis that is associated with S phase arrest (D13, D15, and D10) or unrelated to cell cycle distribution (D14). Additionally, to better understand their suitability for potential use as anticancer medicaments we studied the interactions between biomacromolecules (DNA or BSA) and D13 and D15. The results indicated that D13 and D15 have great affinity to displace EB from the EB-DNA complex through intercalation [K_sv = (3.7 ± 0.1) and (3.4 ± 0.1) × 10³ M⁻¹, respectively], an intercalative mode also confirmed through viscosity measurements. K_a values, obtained as result of fluorescence titration of BSA with D13 and D15 [K_a = (4.2 ± 0.2) and (2.6 ± 0.2) × 10⁵ M, respectively], support the fact that a significant amount of the tested compounds could be transported and distributed through the cells. In addition, by DNA and BSA molecular docking study for D13, D14 and D15 is determined and predicted the binding mode and the interaction region.     

Synthesis of Gibbilimbols A-D,Cytotoxic and Antibacterial Alkenylphenols Isolated from Piper gibbilimbum

Gibbilimbols A [(E)-4-(4-decenyl)phenol, 1], B [(E)-4-(3-decenyl)phenol, 2], C [(E)-4-(4-octenyl)phenol, 3] and D [(E)-4-(3-octenyl)phenol, 4] were synthesized by coupling the phenolic parts with the alkyne parts and then reducing the triple bond of the resulting alkynylphenols. These alkenylphenols (1?4) are the cytotoxic and antibacterial constituents of the leaves of a medicinal plant (Piper gibbilimbum) that is used as a traditional medicine in Papua New Guinea.     

RETRACTED ARTICLE: Further in vitro biological activity evaluation of amino-, thio- and ester-derivatives of avarol

The acetylcholinesterase inhibitory and/or antitumour activities of amino-, thio- and ester-derivatives of avarol selected were evaluated for the first time at in vitro conditions. Avarol-3′,4′-dithioglycol (1) and avarol-4′-(3)mercaptopropionic acid (3) were shown to be the best inhibitors of the enzyme tested (0.50?µg and IC50 0.05?mM and 0.50?µg and IC50 0.12?mM, respectively), while 4′-tryptamine-avarone (9) and avarol-3′-(3)mercaptopropionic acid (2) exhibited the highest cytotoxicity against the human breast T-47D cancer cell line (IC50 0.66?µg/mL and 1.25?µg/mL, respectively). According to experimental data obtained, the sesquiterpenoid hydroquinone structure of bioactive avarol derivatives may inspire development of new pharmacologically useful substances to be used in the treatment of Alzheimer's disease and/or human breast tumour.     

Further in vitro biological activity evaluation of amino-, thio- and ester-derivatives of avarol

Abstract

The acetylcholinesterase inhibitory and/or antitumour activities of amino-, thio- and ester-derivatives of avarol selected were evaluated for the first time at in vitro conditions. Avarol-3′,4′-dithioglycol (1) and avarol-4′-(3)mercaptopropionic acid (3) were shown to be the best inhibitors of the enzyme tested (0.50?µg and IC₅₀ 0.05?mM and 0.50?µg and IC₅₀ 0.12?mM, respectively), while 4′-tryptamine-avarone (9) and avarol-3′-(3)mercaptopropionic acid (2) exhibited the highest cytotoxicity against the human breast T-47D cancer cell line (IC₅₀ 0.66?µg/mL and 1.25?µg/mL, respectively). According to experimental data obtained, the sesquiterpenoid hydroquinone structure of bioactive avarol derivatives may inspire development of new pharmacologically useful substances to be used in the treatment of Alzheimer's disease and/or human breast tumour.     

Rourinoside and rouremin, antimalarial constituents from Rourea minor

Bioassay-directed fractionation of the antimalarial active CHCl(3) extract of the dried stems of Rourea minor (Gaertn.) Aubl. (Connaraceae) liana led to isolation of two glycosides, rourinoside (1) and rouremin (2), as well as five known compounds, 1-(26-hydroxyhexacosanoyl)-glycerol (3), 1-O-beta-D-glucopyranosyl-(2S,3R,4E-8Z)-2-N-(2'-hydroxypalmitoyl)-octadecasphinga-4,8-dienine, 9S,12S,13S-trihydroxy-10E-octadecenoic acid, dihydrovomifoliol-9-beta-D-glucopyranoside, and beta-sitosterol glucoside. Compounds 1-3 showed weak in vitro activities against Plasmodium falciparum. Their structures and stereochemistry were elucidated by spectroscopic methods and selected enzyme hydrolysis.     

Synthesis,antimicrobial activity and cytotoxicity of some new carbazole derivatives

In this work, some N-(9-Ethyl-9H-carbazole-3-yl)-2-(phenoxy)acetamide derivatives were synthesised and evaluated for their antimicrobial activity and cytotoxicity. The structural elucidation of the compounds was performed by IR, ¹H-NMR, ¹³C-NMR and FAB⁺-MS spectral data and elemental analyses. The title compounds were obtained by reacting 2-chloro-N-(9-ethyl-9H-carbazole-3-yl)acetamide with some substituted phenols. The synthesised compounds were investigated for their antibacterial and antifungal activities against Micrococcus luteus, Bacillus subtilis, Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Listeria monocytogenes and Candida albicans. The compounds N-(9-Ethyl-9H-carbazole-3-yl)-2-(4-ethylphenoxy)acetamide (2c) and N-(9-Ethyl-9H-carbazole-3-yl)-2-(quinolin-8-yloxy)acetamide (2n) showed notable antimicrobial activity. The compounds were also studied for their cytotoxic effects using MTT assay, and it was seen that 2n had the lowest cytotoxic activity against NIH/3T3 cells.     

Design,Synthesis, and Insecticidal Activities of Novel meta-Diamide Compounds Containing Ethyl Acetate and Their Derivatives

In this study, a series of meta-diamide compounds containing ethyl acetate group and their derivatives were designed and synthesized. Their insecticidal activities against Plutella xylostella, Spodoptera frugiperda and Alfalfa sprouts were evaluated. Preliminary bioassays showed that some of the title compounds exhibited excellent insecticidal activities. Especially compound ethyl N-(3-((2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(4-cyanobenzoyl)glycinate and ethyl N-(3-((2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(6-fluoronicotinoyl)glycinate showed 100 % mortality at 0.1 mg/L against Plutella xylostella and Spodoptera frugiperda, same to broflanilide. Their LC₅₀ against Plutella xylostella is 0.286 mg/L and 0.0218 mg/L, respectively. Moreover, compound ethyl N-(3-((2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)carbamoyl)-2-fluorophenyl)-N-(6-fluoronicotinoyl)glycinate displayed faster control efficacy than broflanilide at 0.1 mg/L. The results indicated that meta-diamide compounds containing ethyl acetate group could be developed as novel and promising insecticides.     

Synthesis and anti-cancer activity evaluation of new aurone derivatives

Abstract

In this study, we have synthesized 2-[3- or 4-(2-aryl-2-oxoethoxy)arylidene]benzofuran-3-one derivatives (D1–D38) and evaluated their anti-cancer activities. The final compounds were obtained in multistep synthesis reactions using benzofuranon-3-one derivatives (A1–A4, B) as starting materials which were gained in various synthetic ways. Aurone derivatives (C1–C10) were acquired with the condensation reaction of these starting materials and 3-/4-hydroxybenzaldehyde which were then reacted with α-bromoacetophenones to get final compounds. The anti-cancer activity of the selected compounds was performed by National Cancer Institute (NCI), USA against 60 human tumor cell lines derived from nine neoplastic diseases. Compounds exhibited anti-cancer activity in varying ratios.     

Calcitriol derivatives with two different side chains at C-20 III. An epimeric pair of the gemini family with unprecedented antiproliferative effects on tumor cells and renin mRNA expression inhibition

The searches for drugs that exhibit antineoplastic activity and regulate blood pressure are among the most prevalent and compelling research activities today. Amazingly, there is ample precedence for the antiproliferative action of vitamin-D-related compounds and their role as endocrine suppressors of renin biosynthesis. We have recently synthesized a number of novel calcitriol analogs of the gemini family and originally selected for further studies an epimeric pair related to 19-nor-calcitriol whose 21-methyl group was replaced by a 5,5,5-trifluoro-4-hydroxy-4-(trifluoromethyl)-2-pentynyl group. While maintaining the acceptable calcemic responses, the IC50 concentrations of interferon-γ release were reduced and the antiproliferative activity and inhibition of renin mRNA expression enhanced. Replacing the geminal methyl groups on the calcitriol-related side chain of these gemini compounds with trideuteriomethyl moieties further boosted the potency in the colon cancer model in mice some 10-fold, reduced NMU-induced breast cancer carcinogenesis in rats and decreased the IC₅₀ values for renin mRNA inhibition into the pM range.     

Synthesis,characterization, and antimicrobial evaluation of some new hydrazinecarbothioamide, 1,2,4-triazole and 1,3,4-thiadiazole derivatives

In this work, we reported the synthesis and evaluation of antibacterial and antifungal activities of three new compound series obtained from 6-(phenyl/4-chlorophenyl)imidazo[2,1-b]thiazole-3-acetic acid hydrazide: 2-{[6-(phenyl/4-chlorophenyl)imidazo[2,1-b]thiazol-3-yl]acetyl}-N-alkyl/arylhydrazinecarbothioamides (2a–d), 4-alkyl/aryl-2,4-dihydro-5-{[6-(phenyl/4-chlorophenyl)imidazo[2,1-b]thiazol-3-yl]methyl}-3H-1,2,4-triazole-3-thiones (3a–n), and 2-alkyl/arylamino-5-{[6-(phenyl/4-chlorophenyl)imidazo[2,1-b]thiazol-3-yl]methyl}-1,3,4-thiadiazoles (4a–g). The newly synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR (APT), mass and elemental analysis. Their antibacterial and antifungal activities were evaluated against Staphylococcus aureus ATCC 29213, Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922, Candida albicans ATCC 10231, C. parapsilosis ATCC 22019, C. krusei ATCC 6258, Trichophyton mentagrophytes var. erinacei NCPF 375, Microsporum gypseum NCPF 580, and T. tonsurans NCPF 245. 3c, 3f, 3m, 3n, and 4e showed the highest antibacterial activity. Particularly 3c, 3f, 3g, 3k, 3n, 4a, 4e, and 4g showed the highest antifungal activity against tested fungi.     

Synthesis,Crystal Structure,Biological Evaluation and in Silico Studies on Novel (E)-1-(Substituted Benzylidene)-4-(3-isopropylphenyl)thiosemicarbazone Derivatives

A series of (E)-1-(substituted benzylidene)-4-(3-isopropylphenyl)thiosemicarbazone derivatives were synthesized and characterized by FT-IR spectrum, elemental analysis, NMR spectrum, HR-MS spectrum, and X-ray single crystal diffraction technology. The crystal structures and packing of (E)-1-(4-fluorobenzylidene)-4-(3-isopropylphenyl)thiosemicarbazone and (E)-1-(3-fluorobenzylidene)-4-(3-isopropylphenyl)thiosemicarbazone were maintained through the intramolecular hydrogen bond (N3-H6⋅⋅⋅N1) and intermolecular hydrogen bonds (N2-H4⋅⋅⋅S1, C14-H14⋅⋅⋅F1 and C7-H7⋅⋅⋅S1). The results obtained by employing the DPPH free radicals scavenging assay indicated that (E)-1-(4-methoxylbenzylidene)-4-(3-isopropylphenyl)thiosemicarbazone had a more significant antioxidant activity compared with other compounds. The results measured by adopting the disc diffusion method elucidated that (E)-1-(4-trifluoromethylbenzylidene)-4-(3-isopropylphenyl)thiosemicarbazone possessed a more prominent antifungal activity than other compounds. Molecular docking showed that (E)-1-(4-chlorobenzylidene)-4-(3-isopropylphenyl)thiosemicarbazone had the highest affinity with receptor protein (1NMT). Moreover, the drug-likeness characteristic, physicochemical properties, pharmacokinetic profiles, and bioactivity scores of all the compounds were predicted through in silico studies. The results illustrated that (E)-1-(4-fluorobenzylidene)-4-(3-isopropylphenyl)thiosemicarbazone had the drug-likeness characteristic and all the compounds were considered as moderately biological active molecules.     

Synthesis,antielastase, antioxidant and radical scavenging activities of 4-(aza substituted) methylene substituted dihydroxy coumarines

A series of some 4-(aza substituted) methylene substituted dihydroxy coumarines were evaluated for their antioxidant and antielastase activities. Different in vitro methodologies such as total reducing power, 1,1-diphenyl-2-picryl-hydrazil (DPPH·) free radical scavenging, ABTS radical scavenging activity were used as antioxidant activity. All the tested compounds exhibited potent free radical scavenging ability and antielastase activites.     

Ethenesulfonyl fluoride derivatives as telomerase inhibitors: structure-based design,SAR, and anticancer evaluation in vitro

Based on our previous docking model, in order to carry out more rational drug design, totally 82 vinyl sulfonyl fluorides, including some 2-(hetero)arylethenesulfonyl fluorides and 1,3-dienylsulfonyl fluorides derivatives as potential human telomerase inhibitors were designed and synthesised. The in vitro anticancer activity assay showed that compound 57 (1E,3E)-4-(4-((E)-2-(fluorosulfonyl)vinyl)phenyl)buta-1,3-diene-1-sulfonyl fluoride exhibited high activity against A375 and MDA-MB-231 cell lines with IC₅₀ 1.58 and 3.22?µM, but it manifested obvious un-toxic effect against GES-1 and L-02 with IC₅₀ with IC₅₀ values less than 2.00?mM. By the modified TRAP assay, some compounds including 57 exhibited potent inhibitory activities against telomerase with IC₅₀ values of 0.71–0.97?µM.     

Inhibition of COX-1 activity and COX-2 expression by 3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans propenoic acid and its semi-synthetic derivatives

Oxyprenylated naturally occurring cinnamic acids displayed efficient and promising biological activities. Aim of this study was to characterize the effects of 3-(4'-geranyl-3'-methoxy)phenyl-2-trans propenoic acid and its selected semi-synthetic analogues, on COX-2 expression and activity, and on COX-1 activity, in purified systems or in whole cell systems. The anti-inflammatory activity of title compounds (1) was tested as inhibition of COX-2 on isolated monocytes stimulated with LPS (10 μg/ml). COX-2 expression was completely suppressed when monocytes were incubated with 100 μM of 3-(4'-geranyl-3'-methoxy)phenyl-2-trans propenoic acid (1) or 3-(4'-isopentenyloxy)phenyl-2-trans propenoic acid (4). Moreover compounds (1) and (4) inhibit dose-dependently LPS-induced COX-2 expression.     

Design,synthesis, and biological evaluation of novel aminopyrimidinylisoindolines as AXL kinase inhibitors

A novel series of aminopyrimidinylisoindoline derivatives 1a-w having an aminopyrimidine scaffold as a hinge region binding motif were designed and synthesized. Among them, six compounds showed potent inhibitory activities against AXL kinase with IC₅₀ values of submicromolar range. Especially, compound 1u possessing (4-acetylpiperazin-1-yl)phenyl moiety exhibited extremely excellent efficacy (IC₅₀?=?<0.00050?μM). Their in vitro antiproliferative activities were tested over five cancer cell lines. Most compounds showed good antiproliferative activities against HeLa cell line. The kinase panel profiling of 50 different kinases and the selected inhibitory activities for the representative compound 1u were carried out. The compound 1u exhibited excellent inhibitory activities (IC₅₀?=?<0.00050, 0.025, and 0.050?μM for AXL, MER, and TYRO3, respectively) against TAM family, together with potent antiproliferative activity against MV4-11 cell line (GI₅₀?=?0.10?μM) related to acute myeloid leukemia (AML).     

Synthesis,anti-inflammatory,analgesic and antioxidant activities of some tetrasubstituted thiophenes

Sets of tetrasubstituted thiophene esters 4a-4g, 5a-5f and 6a-6e were synthesized by reaction of 1-(α-Carbomethoxy-β-aminothiocrotonoyl)-aryl/aroyl amines (3) with 3-(bromoacetyl)coumarin, 1,4-dibromodiacetyl and chloroacetone respectively. The compound 3 were synthesized by nucleophilic addition of aryl/aroylisothiocyanate and enamine (2). The synthesized targeted compounds (4a-4g, 5a-5f and 6a-6e) were evaluated for their in vivo anti-inflammatory activity in carrageenin-induced rat hind paw oedema model at three graded doses employed at 10, 20 and 40 mg/kg body weight using mefanamic acid, ibuprofen and in vivo analgesic activity in acetic acid induced writhing response model at 10 mg/kg dose using ibuprofen as standard drug. The compounds 4a-4f, 5c, 5f, 6c and 6e were evaluated for their in vitro antioxidant nitric oxide radical scavenging assay at the concentrations of 5, 10, 15, 20, 25, 30 and 35 μg/mL using ascorbic acid as standard drug. Among all the targeted compounds 4c showed maximum anti-inflammatory activity of 71% protection at 10 mg/kg and 77% protection at 20 mg/kg to inflamed paw and analgesic activity of 56% inhibition and also maximum in vitro nitric oxide radical scavenging activity having IC₅₀ value 31.59 μg/mL.     

Design,synthesis, 3D pharmacophore,QSAR, and docking studies of carboxylic acid derivatives as Histone Deacetylase inhibitors and cytotoxic agents

In this study, five series of (E)-6-(4-substituted phenyl)-4-oxohex-5-enoic acids IIb–f (E), (E)-3-(4-(substituted)-phenyl)acrylic acids IIIa–g (E), 4-(4-(substituted)phenylamino)-4-oxobutanoic acids VIa,b,e, 5-(4-(substituted)phenylamino)-5-oxopentanoic acids VIIa,f and 2-[(4-(substituted)phenyl) carbamoyl]benzoic acids VIIIa,e were designed and synthesized. Selected compounds were screened in vitro for their cytotoxic effect on 60 human NCI tumor cell lines. Compound IIf (E) displayed significant inhibitory activity against NCI Non-Small Cell Lung A549/ATCC Cancer cell line (68% inhibition) and NCI-H460 Cancer cell line (66% inhibition). Moreover, the final compounds were evaluated in vitro for their cytotoxic activity on HepG2 Cancer cell line in which histone deacetylase (HDAC) is overexpressed. Compounds IIc (E), IIf (E), IIIb (E), and IIIg (E) exhibited the highest cytotoxic activity against HepG2 human cancer cell lines with IC₅₀ ranging from 2.27 to 10.71 μM. In addition, selected compounds were tested on histone deacetylase isoforms (HDAC1–11). Molecular docking simulation was also carried out for HDLP enzyme to investigate their HDAC binding affinity. In addition, generation of 3D-pharmacophore model and quantitative structure activity relationship (QSAR) models were combined to explore the structural requirements controlling the observed cytotoxic properties.     

Synthesis,antimicrobial and antiviral activity of substituted benzimidazoles

In the present study we have synthesized (4-nitrophenyl)-[2-(substituted phenyl)-benzoimidazol-1-yl]-methanones, (2-bromophenyl)-[2-(substituted phenyl)-benzoimidazol-1-yl]-methanone analogues (1–14) and evaluated them for their antimicrobial and antiviral potential. The results of antimicrobial screening indicated that none of the synthesized compounds were effective against the tested bacterial strains. Compounds 3, 11, 13 and compounds 5, 11, 12 were found to be active against Aspergillus niger and Candida albicans respectively, and may be further developed as antifungal agents. Furthermore, evaluation against a panel of different viruses pointed out the selective activity of compounds 5 and 6 against vaccinia virus and Coxsackie virus B4.     

Structure and cytotoxic activity of enzymatic hydrolysis products of secoiridoid glucosides, isoligustroside and isooleuropein

Hydrolysis of isoligustroside (1) and isooleuropein (2), secoiridoid glucosides, in the presence of β-glucosidase provided 2-(4-hydroxyphenyl)methyl (2R,3S,4S)-3-formyl-3,4-dihydro-4-(2-methoxy-2-oxoethyl)-2-methyl-2H-pyran-5-carboxylate (3) and 2-(3,4-dihydroxyphenyl)methyl (2R,3S,4S)-3-formyl-3,4-dihydro-4-(2-methoxy-2-oxoethyl)-2-methyl-2H-pyran-5-carboxylate (4), respectively. The structures of 3 and 4 were elucidated on the basis of extensive spectral analyses, including 2D-NMR experiments. Compounds 3 and 4 were found to be new rearrangement products of the aglycones of 1 and 2. The cytotoxic activities of 3 and 4 were evaluated using a disease-oriented panel of 39 human cancer cell lines and showed moderate cytotoxic activity for 4, while 3 exhibited weaker activity compared to that of 4.