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.     

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.     

Synthesis and biological evaluation of some thiazole derivatives as new cholinesterase inhibitors

In the present study, some thiazole derivatives were synthesized via the ring closure reaction of 1-[2-(2-oxobenzo[d]thiazol-3(2H)-yl)acetyl]thiosemicarbazide with various phenacyl bromides. The chemical structures of the compounds were elucidated by ¹H NMR, ¹³C NMR and mass spectral data and elemental analyses. Each derivative was evaluated for its ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) using a modification of Ellman’s spectrophotometric method. The compounds were also investigated for their cytotoxic properties using MTT assay. The most potent AChE inhibitor was found as compound 4e (IC₅₀?=?25.5?±?2.12 µg/mL) followed by compounds 4i (IC₅₀?=?38.50?±?2.12 µg/mL), 4c (IC₅₀?=?58.42?±?3.14 µg/mL) and 4g (IC₅₀?=?68?±?2.12 µg/mL) when compared with eserine (IC₅₀?=?0.025?±?0.01 µg/mL). Effective compounds on AChE exhibited weak inhibition on BuChE (IC₅₀ > 80 µg/mL). MTT assay indicated that the cytotoxic dose (IC₅₀?=?71.67?±?7.63 µg/mL) of compound 4e was higher than its effective dose.     

Urease inhibitors from Hypericum oblongifolium WALL.

The bioassay-guided fractionation of H. oblongifolium has led to the isolation of potent urease inhibitors 1–3. The structures were elucidated by NMR and mass spectroscopic techniques. Compound 2 showed a potent enzyme inhibition activity (IC₅₀ 20.96?±?0.93), which is comparatively higher than that for the standard thiourea (IC₅₀ 21.01?±?0.51 μM). Compounds 1 and 3 also showed a significant activity, with IC₅₀ 37.95?±?1.93 and 138.43?±?1.23 μM, respectively. The sub crude fractions (F1, F2, F3, and F4) were tested in vitro for their urease inhibition activity. Fractions F2 and F4 showed significant activity with IC₅₀ 140.37?±?1.93 and 167.43?±?3.03 μM, respectively.     

Synthesis of new isoxazoline derivatives from harmine and evaluation of their anti-Alzheimer,anti-cancer and anti-inflammatory activities

Abstract

In our study, a series of new harmine derivatives has been prepared by cycloaddition reaction using various arylnitrile oxides and evaluated in vitro against acetylcholinesterase and 5-lipoxygenase enzymes, MCF7 and HCT116 cancer cell lines. Some of these molecules have been shown to be potent inhibitors of acetylcholinesterase and MCF7 cell line. The greatest activity against acetylcholinesterase (IC₅₀?=?10.4?µM) was obtained for harmine 1 and cytotoxic activities (IC₅₀?=?0.2?µM) for compound 3a. Two derivatives 3e and 3f with the thiophene and furan systems, respectively, showed good activity against 5- lipoxygenase enzyme (IC₅₀?=?29.2 and 55.5?µM, respectively).     

Synthesis,inhibition of NO production and antiproliferative activities of some indole derivatives

The synthesis and the biological evaluation of pyrano[3,2-e]indoles and their reaction intermediates are described. The compounds prepared were evaluated for their inhibition of NO production, antioxidant activity and also for their ability to inhibit in vitro the growth of four human tumor cell lines: large lung carcinoma (COR-L23), alveolar basal epithelial carcinoma (A549), amelanotic melanoma (C32) and melanoma (A375). The two reaction intermediates, 5a and 5b, showed the highest inhibition of NO production in murine monocytic macrophage (IC₅₀?=?1.1?μM and IC₅₀?=?2.3 μM respectively). Compound 5a was the most active against melanotic melanoma (IC₅₀?=?11.8?μM) while the other compounds exhibited weak cytotoxicity with IC₅₀ values >50?μM on all cell lines.     

Synthesis and antitumor activity of novel 2, 3-didithiocarbamate substituted naphthoquinones as inhibitors of pyruvate kinase M2 isoform

The M2 isoform of pyruvate kinase (PKM2) is a potential antitumor therapeutic target. In this study, we designed and synthesised a series of 2, 3-didithiocarbamate substituted naphthoquinones as PKM2 inhibitors based on the lead compound 3k that we previously reported. Among them, compound 3f (IC₅₀?=?1.05?±?0.17 µM) and 3h (IC₅₀?=?0.96?±?0.18 µM) exhibited potent inhibition of PKM2, and their inhibitory activities are superior to compound 3k (IC₅₀?=?2.95?±?0.53 µM) and the known PKM2 inhibitor shikonin (IC₅₀?=?8.82?±?2.62 µM). In addition, we evaluated in vitro antiproliferative effects of target compounds using MTS assay. Most target compounds exhibited dose-dependent cytotoxicity with IC₅₀ values in nanomolar concentrations against HCT116, MCF7, Hela, H1299 and B16 cells. These small molecule PKM2 inhibitors not only provide candidate compounds for cancer therapy, but also offer a tool to probe the biological effects of PKM2 inhibition on cancer cells.     

Antioxidative iridoid glycosides from the sky flower (Duranta repens Linn)

Phytochemical investigations were performed on the EtOAc-soluble fraction of the whole plant of the sky flower (Duranta repens) which led to the isolation of the iridoid glycosides 1–6. Their structures were elucidated by both 1D and 2D NMR spectroscopic analysis. All the compounds showed potent antioxidative scavenging activity in four different tests, with half maximal inhibitory concentration (IC₅₀) values in the range 0.481–0.719?mM against DPPH radicals, 4.07–17.21 µM for the hydroxyl radical (^?OH) inhibitory activity test, 43.3–97.37 µM in the total reactive oxygen species (ROS) inhibitory activity test, and 3.39–18.94 µM in the peroxynitrite (ONOO^?) scavenging activity test. Duranterectoside A (1) displayed the strongest scavenging potential with IC₅₀ values of (0.481?±?0.06?mM, 4.07?±?0.03, 43.30?±?0.05, 3.39?±?0.02?µM) for the DPPH radicals, ^?OH inhibitory activity test, total ROS inhibitory activity test and the ONOO^? scavenging activity test, respectively.     

Design,synthesis and biological evaluation of novel 1H-1,2,4-triazole,benzothiazole and indazole-based derivatives as potent FGFR1 inhibitors viafragment-based virtual screening

Abstract

Fibroblast growth-factor receptor (FGFR) is a potential target for cancer therapy. We designed three novel series of FGFR1 inhibitors bearing indazole, benzothiazole, and 1H-1,2,4-triazole scaffold via fragment-based virtual screening. All the newly synthesised compounds were evaluated in vitro for their inhibitory activities against FGFR1. Compound 9d bearing an indazole scaffold was first identified as a hit compound, with excellent kinase inhibitory activity (IC₅₀ = 15.0?nM) and modest anti-proliferative activity (IC₅₀ = 785.8?nM). Through two rounds of optimisation, the indazole derivative 9?u stood out as the most potent FGFR1 inhibitors with the best enzyme inhibitory activity (IC₅₀ = 3.3?nM) and cellular activity (IC₅₀ = 468.2?nM). Moreover, 9?u also exhibited good kinase selectivity. In addition, molecular docking study was performed to investigate the binding mode between target compounds and FGFR1.     

Pyrrolo[3,2-c]pyridine derivatives with potential inhibitory effect against FMS kinase: in vitro biological studies

A series of eighteen pyrrolo[3,2-c]pyridine derivatives were tested for inhibitory effect against FMS kinase. Compounds 1e and 1r were the most potent among all the other tested analogues (IC₅₀?=?60?nM and 30?nM, respectively). They were 1.6 and 3.2 times, respectively, more potent than our lead compound, KIST101029 (IC₅₀?=?96?nM). Compound 1r was tested over a panel of 40 kinases including FMS, and exerted selectivity against FMS kinase. It was further tested against bone marrow-derived macrophages (BMDM) and its IC₅₀ was 84?nM (2.32-fold more potent than KIST101029 (IC₅₀?=?195?nM)). Compound 1r was also tested for antiproliferative activity against a panel of six ovarian, two prostate, and five breast cancer cell lines, and its IC₅₀ values ranged from 0.15–1.78?µM. It possesses also the merit of selectivity towards cancer cells than normal fibroblasts.     

Design and synthesis of novel oridonin analogues as potent anticancer agents

To identify anticancer agents with higher potency and lower toxicity, a series of oridonin derivatives with substituted benzene moieties at the C17 position were designed, synthesised, and evaluated for their antiproliferative properties. Most of the derivatives exhibited antiproliferative effects against AGS, MGC803, Bel7402, HCT116, A549, and HeLa cells. Compound 2p (IC_50?=?1.05?µM) exhibited the most potent antiproliferative activity against HCT116 cells; it was more potent than oridonin (IC₅₀?=?6.84?µM) and 5-fluorouracil (5-FU) (IC_50?=?24.80?µM). The IC₅₀ value of 2p in L02 cells was 6.5-fold higher than that in HCT116 cells. Overall, it exhibited better selective antiproliferative activity and specificity than oridonin and 5-FU. Furthermore, compound 2p arrested HCT116 cells at the G2 phase of the cell cycle and increased the percentage of apoptotic cells to a greater extent than oridonin.     

(3,4-Dihydroxyphenyl)(2,3,4-trihydroxyphenyl)methanone and its derivatives as carbonic anhydrase isoenzymes inhibitors

In this study, we have synthesised (3,4-dihydroxyphenyl)(2,3,4-trihydroxyphenyl)methanone and a series of its derivatives (5, 13–16) and tested the ability of these compounds to inhibit two metalloenzyme human carbonic anhydrase (hCA, EC 4.2.1.1) isozymes, hCA I and hCA II. The synthesised compounds showed inhibitory effect on hCA I and hCA II isozymes. The results showed that synthesised compounds (5, 13–16) demonstrated the best inhibition activity against hCA I (IC₅₀: 3.22–54.28 μM) and hCA II (IC₅₀: 18.52–142.01 μM). The compound 14 showed the highest inhibiton effect against hCA I (IC₅₀: 3.22 μM; K_i: 1.19?±?1.4 μM). On the other hand, the compound 13 showed the highest inhibiton effect against hCA II (IC₅₀: 18.52 μM; K_i: 3.25?±?1.13 μM).     

Synthesis,biological evaluation,and molecular modelling of new naphthalene-chalcone derivatives as potential anticancer agents on MCF-7 breast cancer cells by targeting tubulin colchicine binding site

Abstract

A series of naphthalene-chalcone derivatives (3a–3t) were prepared and evaluated as tubulin polymerisation inhibitor for the treatment of breast cancer. All compounds were evaluated for their antiproliferative activity against MCF-7 cell line. The most of compounds displayed potent antiproliferative activity. Among them, compound 3a displayed the most potent antiproliferative activity with an IC₅₀ value of 1.42?±?0.15?µM, as compared to cisplatin (IC₅₀?=?15.24?±?1.27?µM). Additionally, the promising compound 3a demonstrated relatively lower cytotoxicity on normal cell line (HEK293) compared to tumour cell line. Furthermore, compound 3a was found to induce significant cell cycle arrest at the G₂/M phase and cell apoptosis. Compound 3a displayed potent tubulin polymerisation inhibitory activity with an IC₅₀ value of 8.4?µM, which was slightly more active than the reference compound colchicine (IC₅₀?=?10.6?µM). Molecular docking analysis suggested that 3a interact and bind at the colchicine binding site of the tubulin.     

Synthesis and biological evaluation of 2-styrylquinolines as antitumour agents and EGFR kinase inhibitors: molecular docking study

A new series of 4,6-disubstituted 2-(4-(dimethylamino)styryl)quinoline 4a,b–9a,b was synthesized by the reaction of 2-(4-(dimethylamino)styryl)-6-substituted quinoline-4-carboxylic acids 3a,b with thiosemicarbazide, p-hydroxybenzaldehyde, ethylcyanoacetate, and 2,4-pentandione. In addition, the antitumour activity of all synthesized compounds 3a,b–9a,b was studied via MTT assay against two cancer cell lines (HepG2 and HCT116). Furthermore, epidermal growth factor receptor (EGFR) inhibition, using the most potent antitumour compounds, 3a, 3b, 4a, 4b, and 8a, was evaluated. The interpretation of the results showed clearly that the derivatives 3a, 4a, and 4b exhibited the highest antitumour activities against the tested cell lines HepG2 and HCT116 with IC₅₀ range of 7.7–14.2?µg/ml, in comparison with the reference drugs 5-fluorouracil (IC₅₀?=?7.9 and 5.3?µg/ml, respectively) and afatinib (IC₅₀?=?5.4 and 11.4?µg/ml, respectively). In vitro EGFR screening showed that compounds 3a, 3b, 4a, 4b, and 8a exhibited moderate inhibition towards EGFR with IC₅₀ values at micromolar levels (IC₅₀ range of 16.01–1.11?µM) compared with the reference drugs sorafenib (IC₅₀ =?1.14?µM) and erlotinib (IC₅₀ =?0.1?µM). Molecular docking was performed to study the mode of interaction of compounds 3a and 4b with EGFR kinase.     

Constituents with tyrosinase inhibitory activities from branches of Ficus erecta var. sieboldii King

Phytochemical investigation of the branches of Ficus erecta var. sieboldii King resulted in the isolation of eight constituents: p-hydroxybenzoic acid (1), methyl p-hydroxybenzoate (2), vanillic acid (3), methyl vanillate (4), syringic acid (5), β-sitosterol (6), α-amyrin acetate (7), and ethyl linoleate (8). Their chemical structures were identified via spectroscopic means as well as by comparing their data with literature values. Studies on tyrosinase inhibition activities were conducted for the isolated compounds. Among them, p-hydroxybenzoic acid (1) and methyl p-hydroxybenzoate (2) were identified as active tyrosinase inhibitors with IC₅₀ values of 0.98?±?0.042 and 0.66?±?0.025?mM, respectively, showing comparable activities to that of arbutin (IC₅₀?=?0.32?±?0.015?mM), a standard control. Inhibition kinetics, as analyzed by Lineweaver-Burk plots, indicated that compounds 1 and 2 were competitive inhibitors of diphenolase of mushroom tyrosinase. Notably, isolated compounds 1–8 were reported for the first time as constituents of F. erecta.     

Synthesis of chiral pyrazolo[4,3-e][1,2,4]triazine sulfonamides with tyrosinase and urease inhibitory activity

A new series of sulfonamide derivatives of pyrazolo[4,3-e][1,2,4]triazine with chiral amino group has been synthesized and characterized. The compounds were tested for their tyrosinase and urease inhibitory activity. Evaluation of prepared derivatives demonstrated that compounds (8b) and (8j) are most potent mushroom tyrosinase inhibitors whereas all of the obtained compounds showed higher urease inhibitory activity than the standard thiourea. The compounds (8a), (8f) and (8i) exhibited excellent enzyme inhibitory activity with IC₅₀ 0.037, 0.044 and 0.042?μM, respectively, while IC₅₀ of thiourea is 20.9?μM.     

Inhibition studies of soybean (Glycine max) urease with heavy metals,sodium salts of mineral acids,boric acid,and boronic acids

Various inhibitors were tested for their inhibitory effects on soybean urease. The K_i values for boric acid, 4-bromophenylboronic acid, butylboronic acid, and phenylboronic acid were 0.20?±?0.05?mM, 0.22?±?0.04?mM, 1.50?±?0.10?mM, and 2.00?±?0.11?mM, respectively. The inhibition was competitive type with boric acid and boronic acids. Heavy metal ions including Ag⁺, Hg²⁺, and Cu²⁺ showed strong inhibition on soybean urease, with the silver ion being a potent inhibitor (IC₅₀ = 2.3?×?10^?8 mM). Time-dependent inhibition studies exhibited biphasic kinetics with all heavy metal ions. Furthermore, inhibition studies with sodium salts of mineral acids (NaF, NaCl, NaNO₃, and Na₂SO₄) showed that only F^? inhibited soybean urease significantly (IC₅₀ = 2.9?mM). Competitive type of inhibition was observed for this anion with a K_i value of 1.30?mM.     

New antihyperglycemic, α-glucosidase inhibitory,and cytotoxic derivatives of benzimidazoles

Glycosidases play an important role in a wide range of physiological and pathological conditions, and have become potential targets for the discovery and development of agents useful for the treatment of diseases such as diabetes, cancer, influenza, and even AIDS. In this study, several benzimidazole derivatives were prepared from o-phenylenediamine and aromatic and heteroaromatic carboxaldehydes in very good yields, using PdCl₂(CH₃CN)₂ as the most efficient catalyst. Synthesized compounds were assayed for their activity on yeast and rat intestinal α-glucosidase inhibition and cytotoxic activity against colon carcinoma cell line HT-29. Compound 3e exhibited 95.6% and 75.3% inhibition of yeast and rat intestinal α-glucosidase enzyme, while showing 74.8% cytotoxic activity against the HT-29 cell line at primary screening concentrations of 2.1?mM for yeast and rat intestinal α-glucosidase enzyme and 0.2?mM for cytotoxic activity against the HT-29 cell line, respectively. Compound 3c displayed 76% and 34.4% inhibition of yeast and rat intestinal α-glucosidase enzyme, and 80.4% cytotoxic activity against the HT-29 cell line at similar primary screening concentrations. The IC₅₀ value for the most potent intestinal α-glucosidase inhibitor compound 3e was found to be 99.4?μM. The IC₅₀ values for the most active cytotoxic compounds 3c and 3e were 82?μM and 98.8?μM, respectively. Both compounds displayed significant antihyperglycemic activity in starch-induced postprandial hyperglycemia in rats. This is the first report assigning yeast and rat intestinal α-glucosidase enzyme inhibition, cytotoxic activity against the HT-29 cell line, and antihyperglycemic activity to benzimidazole compounds 3c and 3e.     

Disaccharide Pyrimidine Nucleosides and Their Derivatives: A Novel Group of Cell-Penetrating Inhibitors of Poly(ADP-Ribose) Polymerase 1

Nearly 30 synthetic nucleosides were tested with human recombinant poly(ADP-ribose) polymerase 1 as potential inhibitors of this enzyme. The most active compounds were some disaccharide analogues of thymidine: 3′-O-β-D-ribofuranosyl-5-iodo-dUrd (2d; IC₅₀ = 45 μM), 3′-O-β-D-ribofuranosyl-2′-deoxythymidine (2e; IC₅₀ = 38 μM), and 3′-O-β-D-ribofuranosyl-2′-deoxythymidine oxidized (4; IC₅₀ = 25 μM). These compounds also reduced H₂O₂-induced synthesis of poly(ADP-ribose) in cultured human ovarian carcinoma (SKOV-3) cells in a dose-dependent manner. Furthermore, compounds 2d or 2e until a concentration of 1 mM did not affect growth of SKOV-3 cells, whereas dialdehyde compound 4, as well as thymidine, exhibited a significant cytotoxicity.     

Design,synthesis of novel pyranotriazolopyrimidines and evaluation of their anti-soybean lipoxygenase,anti-xanthine oxidase,and cytotoxic activities

The synthesis of 14-(aryl)-14H-naphto[2,1-b]pyrano[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine-2-yl) acetamidoximes 2a–e has been accomplished by reaction of 2-acetonitrile derivatives 1a–e with hydroxylamine. Cyclocondensation reaction of precursors 2a–e with some elctrophilic species such as ethylorthoformate, acetic anhydride, and methyl-acetoacetate provided the new oxadiazole derivatives 3a–e, 4a–e, and 5a–e, respectively. On the other hand, the reaction of precursors 2a–e with 2-chloropropanoyl chloride afforded the new acetimidamides 6a–e which evolve under reflux of toluene to the new oxadiazoles 7a–e. The synthetic compounds were screened for their anti-xanthine oxidase, anti-soybean lipoxygenase, and cytotoxic activities. Moderate to weak xanthine oxidase and soybean lipoxygenase inhibitions were obtained but significant cytotoxic activities were noted. The most cytotoxic activities were recorded mainly (i) 5a was the most active (IC_50?=_?4.0?μM) and selective against MCF-7 and (ii) 2a was cytotoxic against the four cell lines with selectivity for MCF-7 and OVCAR-3 (IC_50?=_?17 and 12?μM, respectively) while 2e is highly selective against OVCAR-3 (IC_50?=_?10?μM).