Elucidation of the Structures of Metabolites of Picroside II in Rat Bile by LC�CESI�CIT�CMS

Picroside II is one of the main active constituents of Picrorhiza kurroa, which has hepatoprotective, anticholestatic, antioxidant, and immune-modulating activity. To gain an understanding of the biotransformation of picroside II in vivo, liquid chromatography?Celectrospray ionization ion-trap mass spectrometry (LC?CESI?CIT?CMS) was used to investigate the metabolism of picroside II in rats after intravenous administration of a single dose. This method could simultaneously determine picroside II and its metabolites in rat bile. The bile samples were purified by use of a C₁₈ solid-phase extraction (SPE) cartridge and were separated on a Hypersil ODS2 C₁₈ analytical column. Two phase II metabolites of picroside II in rat bile were characterized, and elucidation of their structures was performed by comparing changes in molecular masses (??M), retention times, and MS² spectral patterns of metabolites with those of the parent drug. Two metabolites identified for the first time in this research were glucuronide and sulfate conjugates.     

Pictalignans D-F,three new neolignan derivatives from Selaginella picta

Abstract

Three new neolignan derivatives (1–3), together with three known isolariciresinol derivatives (4–6) were isolated from Selaginella picta. Their structures were elucidated by spectroscopic methods (1D/2D NMR, HRESIMS and CD). All isolated compounds were assayed on the neuroprotective activity against the injury of HT-22 cells induced by L-Glutamate in vitro. All compounds displayed potent protective effect on HT-22 cells.     

Design,synthesis and biological evaluation of some 2-(6-nitrobenzo[d]thiazol-2-ylthio)-N-benzyl-N-(6-nitrobenzo[d]thiazol-2-yl)acetamide derivatives as selective DprE1 inhibitors

Abstract

Tuberculosis (TB) is an infectious disease and caused by various strains of mycobacteria. In the present study, pharmacophore model was developed using single ligand by ligand-based drug discovery approach. The key features responsible for DprE1 inhibitory activity were taken into consideration for developing pharmacophore. After the virtual screening, top 1000 hits were further subjected to docking study using GLIDE module, Schrödinger. Docking studies have shown promising interaction with amino residues with better glide score. Ligand-based drug design approach yielded a series of 15, 2-(6-nitrobenzo[d]thiazol-2-ylthio)-N-benzyl-N-(6-nitrobenzo[d]thiazol-2-yl)acetamide derivatives. All synthesized derivatives were characterized using NMR, mass, CHN analysis. The synthesized compounds were screened for In vitro antitubercular activity against Mycobacterium tuberculosis (H₃₇Rv). Four compounds, 5g (MIC-1.01?μM); 5i (MIC-0.91?μM); 5k (MIC-0.82?μM); and 5o (MIC-1.04?μM) has shown promising activity compared to MIC of standard isoniazid (INH) and DprE1 enzyme inhibition was compared to BTZ043. Two halogen-substituted compounds have exhibited drastic enzyme inhibition.     

Synthesis of nitrogen-containing monoterpenoids with antibacterial activity

Abstract

Incorporation of the Beckmann rearrangement into the presented research resulted in the formation of nitrogen-containing terpenoid derivatives originating from naturally occurring compounds. Both starting monoterpenes and obtained derivatives were subjected to estimation of their antibacterial potential. In the presented study, Staphylococcus aureus was the most sensitive to examined compounds. The Minimal Inhibitory Concentration (MIC) experiments performed on S. aureus demonstrated that the (?)-menthone oxime (?)-8 and (+)-pulegone oxime (+)-13 had the best antibacterial activity among the tested derivatives and starting compounds. Their MIC₉₀ value was 100?µg/mL. The obtained derivatives were also evaluated for their inhibitory activity against bacterial urease. Among the tested compounds, three active inhibitors were found – oxime 14 and lactams (?)-15 and 16 limited the activity of Sporosarcina pasteurii urease with K_i values of 174.3?µM, 43.0?µM and 4.6?µM, respectively. To our knowledge, derivative 16 is the most active antiureolytic lactam described to date.     

New bioactive compounds from aquatic endophyte Chaetomium globosum

Two new oxidation products-related aureonitol and cytochalasan were isolated from Chaetomium globosum fermented in Chinese yam (Dioscorea opposita) and determined as 10,11-dihydroxyl- aureonitol (1) and yamchaetoglobosin A (2). Compound 2 indicated significant inhibitory effect on nitric oxide production in LPS-activated macrophages, anti-acetylcholinesterase activity with the inhibition ratios of 92.5, 38.2% at 50 μM, and cytotoxicity to HL-60, A-549, SMMC-7721, MCF-7 and SW480 with the range of inhibition ratio at 51–96% for a concentration of 40 μM. Compounds 1, 2 showed weak anticoagulant activity with PT at 16.8 s. Few work was reported on the anti-acetylcholinesterase, and anticoagulant activities of aureonitol, and cytochalasan derivatives. The preliminary structure–activity relationship stated that the oxidation ring-opening in yamchaetoglobosin A can retain the inhibitory effect against NO production and tumor cell.     

Diorganotin(IV) carboxylates of 3-methylphenyl ethanoic acid: Synthesis,crystal structure,antibacterial, anticancer and molecular docking studies

Abstract

Di-n-butyl- (1) and diethyltin(IV) (2) derivatives of 3-methylphenylethanoic acid were synthesized and characterized by elemental analysis, atomic absorption, IR, ¹H and 13C NMR spectroscopy and mass spectrometry. The spectroscopic data and single crystal X-ray diffraction studies for complex 2 have confirmed a bidentate coordination mode of the carboxylate ligand and the presence of hexacoordinated tin atoms in the complexes. The complexes were screened for their in vitro antibacterial activity against selected gram positive and gram negative bacterial strains. The anticancer potential was assessed against prostate cancer cell lines. Both complexes have shown higher activities than the ligand acid. Complex 1 with an IC₅₀ value of 4.97?±?0.27?μg/mL was found to be better anti prostate cancer agent than complex 2 (IC₅₀ = 11.26?±?2.18?μg/mL). Molecular docking study has suggested antibacterial action of the complexes in terms of their ability to develop hydrogen bonding and hydrophobic interactions with vital residues of the target proteins like tyrosyl-tRNA synthase from Staphylococcus aureus (gram-positive bacteria) and undecaprenyl diphosphate synthase from Escherichia coli (gram-negative bacteria).     

Chemical constituents from Sambucus williamsii Hance fruits and hepatoprotective effects in mouse hepatocytes

Chemical investigation of Chinese folk medicine Sambucus williamsii Hance has resulted in the isolation and characterisation of seventeen compounds from the n-BuOH extract of its fruits, including two new phenylethanoid glycosides and fifteen known compounds. Structures of new compounds were elucidated primarily on the basis of their extensive spectroscopic data including 2D NMR. In addition, the n-BuOH extract from the fruits of S. williamsii was found to show a protective effect on D-galactosamine (D-GalN)-induced cytotoxicity in primary cultured mouse hepatocytes. So the hepatoprotective effects of principal constituents from it were tested by MTT assays. The results showed that Compounds 13, 16 and 17 displayed hepatoprotective effects.     

Anti-inflammatory activity of saponins from roots of Impatiens parviflora DC.

Abstract

Two triterpene saponins (IPS-1, IPS-2) for the first time were isolated from the roots of Impatiens parviflora DC. (Balsaminaceae). Their anti-inflammatory activity was evaluated by means of two in vitro models: anti-hyaluronidase and anti-denaturation assays. Both saponins were shown to be potent hyaluronidase inhibitors that affect the enzyme in a dose-dependent manner. The anti-hyaluronidase effect of IPS-2 (IC₅₀?=?286.7?µg/mL) was higher than that of the reference drug: escin (IC₅₀?=?303.93?µg/mL). Both saponins protected bovine serum albumin from heat-induced denaturation in a dose-dependent manner. IPS-1 demonstrated higher anti-denaturation effect (IC₅₀?=?86.7?µg/ml) than IPS-2 (IC₅₀?=?109.76?µg/mL) or the standard drug: acetylsalicylic acid (IC₅₀?=?262.22?µg/mL). In conclusion, potent activity of IPS-1, IPS-2 in both in vitro assays shows that saponins from I. parviflora have anti-inflammatory activity. The obtained results allow to suggest that such compounds may be beneficial in inflammatory conditions, especially associated with excessive degradation of hyaluronic acid.     

1,2-Benzisoxazole-3-acetamide derivatives as dual agents for DPP-IV inhibition and anticancer activity

Abstract

Herein, we have designed various benzisoxazole acetamide derivatives with and without glycine spacer as DPP-IV inhibitors. Compounds 9a–d and 11a–e were synthesized and screened for their in vitro DPP-IV inhibition. Compounds 11a and 11c showed moderate activity for DPP-IV inhibition, whereas other remained inactive at 25–200?µM concentrations. DPP-IV inhibition can be a good strategy for modulating diabetes and cancer; hence, we have screened compounds 9a–d and 11a–e for their anticancer activity using MTT assay against A549 and MCF7 cell lines. Compounds 9a–d without glycine spacer have shown good anticancer activity compared to compounds 11a–e with glycine spacer. Compound 9b has shown moderate activity with IC₅₀ values 4.72?±?0.72 and 4.39?±?0.809?µM against A549 and MCF7 cell lines, respectively. Interestingly, compound 9c with cyano group has shown very good anticancer activity with IC₅₀ 2.36?±?0.34?µM against MCF7 cell line as compared to fluorouracil with IC₅₀ 45.04?±?1.02?µM.     

Synthesis,crystal structure,and bioactivity of two triphenylantimony derivatives with benzohydroxamic acid and N-phenylbenzohydroxamic acid

Reaction of triphenylantimony dichloride with benzohydroxamic acid or N-phenylbenzohydroxamic acid in 1?:?1 stoichiometry yielded two new triphenylantimony derivatives formulated as [Ph₃SbL₁L₂] (L₁?=?benzohydroxamato, L₂?=?methoxide, 1; L₁?=?N-phenylbenzohydroxamato, L₂?=?Cl, 2), which have been characterized by FT-IR, NMR spectroscopy, elemental analysis, and melting point. Single-crystal X-ray diffraction analyses for 1 and 2 reveal that the antimony is six-coordinate adopting distorted octahedral geometry with one phenyl and methoxide or chloride in axial positions. In the supramolecular structure, a double-chain is shown for 2 constructed by C–H?···?X (X?=?O, C or π) weak interactions, while 1 exhibits a 1-D-chain structure connected by O–H?···?O and N–H?···?N hydrogen bonds. In vitro antitumor study reveals that 1 and 2 display activities against two human tumor cell lines – A549 and HCT-8. To explore the antitumor activity mechanism, DNA binding properties of 1 and 2 with calf thymus DNA (ct-DNA) have been investigated by fluorescence spectra, indicating that 1 and 2 bind to ct-DNA via intercalation, which could induce the death of cancer cells.     

Acridone alkaloids from the rhizomes of Luvunga scandens (Roxb.) Buch. Ham.

The ethyl acetate extract of the rhizomes of Luvunga scandens (Roxb.) Buch. - Ham. ex Wight &; Arn (Rutaceae) delivered one new acridone alkaloid named Luvungaside A (1) together with three known acridone alkaloids, namely 1,3-dihydroxy-2-methoxy-10-methyl-9-acridone (2), arborinine (3) and 1-hydroxy-3-methoxy-10-methyl-9-acridone (4). Compounds were reported for the first time from the species L. scandens applying various chromatography methods. Chemical structures were elucidated by IR, UV, HR-ESI-MS, NMR 1D &; 2D experiments and comparison with the literature. The cytotoxicity and hepatoprotective activity of compounds 1–4 in human hepatoma cell line HepG2 was measured by MTT assay. At 10–100?μM, compounds expressed significant hepatoprotective effect with prevention percentage ranging from 81.1% to 194.3%, compared to the positive control quercetin displaying 49.0%.     

Synthesis and Anticonvulsant Activity of 9-Alkoxy-6,7-dihydro-2H-benzo[c][1,2,4]triazolo[4,3-a]azepin-3[5H]-ones

A series of novel 9-alkoxy-6,7-dihydro-2H-benzo[c][1,2,4]triazolo[4,3-a]azepin-3(5H)-one derivatives was designed and synthesized starting from 2,3,4,5-tetrahydro-7-hydroxy-1H-2-benzazepin-1-one. The structures of these compounds were confirmed by mass, ¹H NMR infrared spectra, and elemental analysis. Their anticonvulsant activity was evaluated by maximal electroshock (MES) test, and their neurotoxic effects were determined by the rotarod neurotoxicity test. The results shown that 3k was the most active compound with median effective dose (ED₅₀) of 27.3 mg/kg, median toxicity dose (TD₅₀) of 118.3 mg/kg, and protective index (PI) of 4.3. Possible structure–activity relationship is discussed.     

Design and synthesis of novel 7-[(N-substituted-thioureidopiperazinyl)-methyl]-camptothecin derivatives as potential cytotoxic agents

Abstract

As part of continuing our research on diverse C-7 derivatives of camptothecin (CPT), 16 CPT derivatives bearing piperazinyl-thiourea chemical scaffold and different substituent groups have been designed, synthesized and evaluated in vitro for cytotoxicity against five tumor cell lines (A-549, MDA-MB-231, MCF-7, KB and KBvin). As a result, all the synthesized compounds showed promising in vitro cytotoxic activity against the five tumor cell lines tested, and were more potent than irinotecan. Importantly, compounds 13?g (IC₅₀ = 0.514?μM) and 13o (IC₅₀ = 0.275?μM) possessed similar or better antiproliferative activity against the multidrug-resistant (MDR) KBvin subline than that of topotecan (IC₅₀ = 0.511?μM) and merit further development as anticancer candidates for clinical trail. With these results in hand, we have a reason to conclude that incorporating piperazinyl-thiourea motifs into position-7 of camptothecin confers well cytotoxic activity against cancer cell lines, probably resulting in new anticancer drugs.     

An ancient remedial repurposing: synthesis of new pinocembrin fatty acid acyl derivatives as potential antimicrobial/anti-inflammatory agents

Five new pinocembrin derivatives (MC1-MC5) were synthesized by Steglich reaction, and investigated for their antimicrobial, antioxidant, and anti-inflammatory activity. MC2 (oleoyl derivative) and MC3 (linoleoyl derivative) have shown the highest inhibitory effects on bacterial proliferation, with MIC values of 32 μg/mL against Staphylococcus aureus. The docosahexaenoyl derivative MC5 displayed the highest anti-inflammatory activity, decreasing NO production in LPS-stimulated macrophages with an IC₅₀ value of 15.51 μg/mL higher than the positive control diclofenac (IC₅₀ of 39.71 μg/mL). All new synthesized compounds showed no anti-proliferative effects on RAW 264.7 cells. Results demonstrated as the introduction of fatty acid substituents improved the biological profile of pinocembrin. Moreover, the chemical nature of substituents significantly affects the bioactivity. These preliminary results outline the importance to investigate the synthesis of pinocembrin fatty acids derivatives as new and safe anti-microbial/anti-inflammatory agents.     

Synthesis and investigation of antibacterial activities and carbonic anhydrase and acetyl cholinesterase inhibition profiles of novel 4,5-dihydropyrazol and pyrazolyl-thiazole derivatives containing methanoisoindol-1,3-dion unit

Novel 4,5-dihydropyrazole derivatives (3a–i), 3-(4-((3aR,4S,7R,7aS)-1,3-dioxo-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindol-2(3H)-yl)phenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-1-carbothio amide, were obtained by the addition of thiosemicarbazide (2) to the chalcones (1a–i). The addition–cyclization of 2,4′-dibromoacetophenone (4) to pyrazole derivatives (3a–i) gave the new pyrazolyl-thiazole derivatives (5a–i), (3aR,4S,7R,7aS)-2-(4-(1-(4-(4-bromophenyl)thiazol-2-yl)-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)phenyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione. Antibacterial and acetylcholinesterase (AChE) enzyme and human carbonic anhydrase (hCA) I, and II isoform inhibitory activities of the compounds 3a–i and 5a–i were investigated. Some of the compounds showed promising antibacterial activity. In addition, the hCA II and I were effectively inhibited by the lately synthesized derivatives, with K_i values in the range of 18.90?±?2.37 ?58.25?±?13.62?nM for hCA II and 5.72?±?0.98 ?37.67?±?5.54?nM for hCA I. Also, the K_i parameters of these compounds for AChE were obtained in the range of 25.47?±?11.11???255.74?±?82.20?nM. Also, acetazolamide, clinical molecule, was used as a CA standard inhibitor that showed K_i value of 70.55?±?12.30?nM against hCA II, and 67.17?±?9.1?nM against hCA I, and tacrine inhibited AChE showed K_i value of 263.67?±?91.95.     

Synthesis and antitumor activity of new silver(I)-N-heterocyclic carbene complexes

Abstract

In this study, two novel benzimidazole-based N-heterocyclic carbene ligands (1a-b) and their silver(I) complexes (2a-b) were synthesized. All new compounds were characterized by FT-IR, LC-MS, ¹H NMR, and ¹³C NMR spectroscopies. The in vitro antitumor activities of NHC ligands (1a-b) and their silver(I) complexes (2a-b) against DU-145 human prostate cancer cells, MDA-MB-231 and MCF-7 human breast cancer cells and L-929 (normal cells adipose from mouse) were also determined using MTT analysis for 24?h, 48?h, and 72?h. The results showed that while NHC ligands did not have in vitro antitumor activity on MCF-7, MDA-MB-231 and DU-145 cells, Ag(I)-NHC complexes have in vitro antitumor activities. The in vitro antitumor activity of 2a was found to be lower than that of 2b. Ag(I)-NHC complexes were observed to have higher IC₅₀ values for non-cancerous cell lines than cancer cells.     

TLC densitometric quantification of picrosides (picroside-I and picroside-II) in Picrorhiza kurroa and its substitute Picrorhiza scrophulariiflora and their antioxidant studies

Picroside‐I and picroside‐II are known bioactive metabolites in Picrorhiza species. In the present study a simple, precise method has been established for the simultaneous determination of picrosides (picroside‐I and picroside‐II) in two different Picrorhiza species, P. kurroa and P. scrophulariiflora. This method was also validated for accuracy, precision, robustness, limit of detection and quantification, repeatability and recovery, according to International Conference of Harmonization guidelines. Separation and quantification was achieved by HPTLC using as the mobile phase chloroform–methanol (88:12, v/v) on precoated silica gel 60F₂₅₄ aluminum plates. Densitometric determination was carried out at wavelength λ_max 254 nm in UV absorbance mode. Comparative study also revealed that picroside‐I and picroside‐II are higher in P. scrophulariiflora than P. kurroa. Picroside‐I content was found to be 1.258 and 1.611%, and picroside‐II was estimated as 0.481 and 0.613% in P. kurroa and P. scrophulariiflora, respectively. Antioxidant potential of these two Picrorhiza species was also studied using DPPH. At a concentration of 0.1 mg/mL the scavenging activities of P. kurroa and P. scrophulariiflora were found to 37.70 and 34.30%, respectively. Copyright © 2011 John Wiley & Sons, Ltd.     

Polyoxometalate cobalt–gatifloxacin complex with DNA binding and antibacterial activity

An unusual inorganic–organic antibacterial complex based on polyoxometalates (POMs) and the cobalt–gatifloxacin (GT), [Co^II(C₁₉FH₂₂N₃O₄)₃][C₁₉FH₂₃N₃O₄][HSiW₁₂O₄₀]·23H₂O (1), has been synthesized. Single-crystal structural analysis shows that 1 represents for the first time an unusual tripodal coordination style with three GT molecules coordinating to cobalt(II) by six carboxylate and hydroxyl oxygens. The biological activity of 1 has been evaluated by investigating its binding ability to calf thymus DNA (CT-DNA). UV spectrum study of 1 has shown that it can bind to CT-DNA by intercalation. The DNA-binding constant K_b was 9.6?×?10⁴?M?L^?1, higher than that of pure GT, 3.8?×?10^4?M?L^?1. Furthermore, the antibacterial activities of 1 were tested against Staphylococcus aureus and Escherichia coli, respectively, and have shown slightly lower antibacterial activity than that of free GT at the same mass concentration. If the GT component in the complexes was controlled at the same molar concentration, 1 generates the biggest antibacterial area during the Kirby–Bauer disc diffusion detection. This result indicates that the integration of heteropolyanions and GT exhibits synergistic effects on the antibacterial activity, which paves a new way to design low-cost antibacterial compound by the introduction of POMs.     

Synthesis,molecular docking,antibacterial, antioxidant,and cytotoxicity activities of novel pyrido-cyclopenta[b]indole analogs

Abstract

A series of new pyrido-cyclopenta[1,2-b]indole derivatives were synthesized via Knoevenagel reaction and followed by reflux with dimethylformamide dimethyl acetal. Their structures were investigated by spectral techniques and elemental analysis. In vitro antibacterial assessment against seven selected microorganisms evidenced that the compounds with halogen substituent have strong inhibitory action than that of the reference drugs. The antioxidant results were apparent that the compounds 5b, 5c, and 6c manifested explicit activity when compared with Butylhydroxyanisole and Vitamin-C. Cytotoxic activity analysis toward HeLa and MCF-7 cell lines was also assessed. Analogs 6c (IC₅₀ values 15.1?μM and 18.6?μM) and 6d (IC₅₀ values 17.4?μM and 20.7?μM) illustrated the interesting cytotoxicity activity. Molecular docking studies against p38 MAP kinase displayed a potential binding affinity with the receptor. Furthermore, in silico pharmacokinetic studies articulated the drug-likeness nature of the target compounds.     

Novel silicon-containing drugs derived from the indomethacin scaffold: Synthesis, characterization and evaluation of biological activity

Synthesis, spectroscopic characterization and in vitro pharmacological and cancer cell growth inhibitory activity studies of new silicon-containing compounds based on the indomethacin scaffold are now reported. Amidation of the indomethacin carboxylate group using amino-functional silanes generated a series of novel lipophilic derivatives of indomethacin. The pharmacological activity of these derivatives tested against human recombinant cyclooxygenase-1 and 2 demonstrated that the silicon-containing derivatives are cyclooxygenase-2 (COX-2) selective. The silicon-containing amides of indomethacin demonstrated in vitro growth inhibitory activity against human MiaPaCa-2 pancreatic carcinoma cells at low μM concentrations. The 3a and 3c derivatives exhibited the most potent in vitro antiproliferative activity, with IC₅₀ <6.0 μM, compared to unmodified indomethacin having an IC₅₀100 μM. We dedicate this paper to Prof. Mitsuo Kira, outstanding organosilicon chemist and valued friend.