Intracellular time course, pharmacokinetics, and biodistribution of isoniazid and rifabutin following pulmonary delivery of inhalable microparticles to mice

Intracellular concentrations of isoniazid and rifabutin resulting from administration of inhalable microparticles of these drugs to phorbol-differentiated THP-1 cells and the pharmacokinetics and biodistribution of these drugs upon inhalation of microparticles or intravenous administration of free drugs to mice were investigated. In cultured cells, both microparticles and dissolved drugs established peak concentrations of isoniazid (~1.4 and 1.1 μg/10⁶ cells) and rifabutin (~2 μg/ml and ~1.4 μg/10⁶ cells) within 10 min. Microparticles maintained the intracellular concentration of isoniazid for 24 h and rifabutin for 96 h, whereas dissolved drugs did not. The following pharmacokinetic parameters were calculated using WinNonlin from samples obtained after inhalation using an in-house apparatus (figures in parentheses refer to parameters obtained after intravenous administration of an equivalent amount, i.e., 100 μg of either drug, to parallel groups): isoniazid, serum half-life (t_1/2) = 18.63 ± 5.89 h (3.91 ± 1.06 h), maximum concentration in serum (C_max) = 2.37 ± 0.23 μg·ml⁻¹ (3.24 ± 0.57 μg·ml⁻¹), area under the concentration-time curve from 0 to 24 h (AUC_0-24) = 55.34 ± 13.72 μg/ml⁻¹ h⁻¹ (16.64 ± 1.80 μg/ml⁻¹ h⁻¹), and clearance (CL) = 63.90 ± 13.32 ml·h⁻¹ (4.43 ± 1.85 ml·h⁻¹); rifabutin, t_1/2 = 119.49 ± 29.62 h (20.18 ± 4.02 h), C_max = 1.59 ± 0.01 μg·ml⁻¹ (3.47 ± 0.33 μg·ml⁻¹), AUC_0-96 = 109.35 ± 14.78 μg/ml⁻¹ h⁻¹ (90.82 ± 7.46 μg/ml⁻¹ h⁻¹), and CL = 11.68 ± 7.00 ml·h⁻¹ (1.03 ± 0.11 ml·h⁻¹). Drug targeting to the lungs in general and alveolar macrophages in particular was observed. It was concluded that inhaled microparticles can reduce dose frequency and improve the pharmacologic index of the drug combination.     

Synthesis,solid state self-assembly driven by antiparallel π⋯π stacking and {⋯H–C–C–F}2 dimer synthons,and in vitro acetyl cholinesterase inhibition activity of phenoxy pendant isatins

A series of novel phenoxy pendant isatins PI1–12 have been synthesized in excellent yields by a simple nucleophilic substitution reaction involving isatins and 1-(2-bromoethoxy)-4-substituted benzenes, and characterized by their FT-IR, ¹H NMR, ¹³C NMR and GC-MS data, and in the case of PI4 by its single crystal X-ray analysis. The solid-state structure of PI4 showed an intriguing and unique 1D-supramolecular chain-based self-assembled structure, the driving force of which is mainly the strong antiparallel π⋯π stacking and {⋯H–C–C–F}₂ dimer synthons. This compound not only highlights the potential of the isatin moiety in forming strong antiparallel π⋯π stacking interactions but also provides a platform to have considerable insight into the nature, strength and directionality of much debated π–π and C–H⋯F–C interactions. The in vitro biological studies revealed that three phenoxy pendant isatins PI1, PI2 and PI4 are highly potent inhibitors of acetylcholinesterase enzyme with IC₅₀ values of 0.52 ± 0.073 μg ml⁻¹, 0.72 ± 0.012 μg ml⁻¹ and 0.68 ± 0.011 μg ml⁻¹, respectively, showing comparable activity to the standard drug, donepezil (IC₅₀ = 0.73 ± 0.015 μg ml⁻¹). A simple and efficient synthesis of phenoxy pendant isatins PI1–12 from inexpensive and commercially available starting materials, and their high potential of acetyl cholinesterase inhibition provide an attractive opportunity to find more effective medication for Alzheimer''s disease (AD).

The phenoxy pendant isatins were observed to be highly potent inhibitors of acetylcholinesterase. In addition, the solid-state structure of a phenoxy pendant isatin showed an intriguing 1D-supramolecular self-assembled structure.     

Unravelling the antifungal and antiprotozoal activities and LC-MS/MS quantification of steroidal saponins isolated from Panicum turgidum

Bioassay-guided investigation of Panicum turgidum extract resulted in the identification of seven steroidal saponins (Turgidosterones 1–7). They were evaluated for their in vitro antifungal, antileishmanial, and antitrypanosomal activities. Turgidosterone 6 was the most active antifungal against Candida albicans and Candida neoformans (IC₅₀ values of 2.84 and 1.08 μg mL⁻¹, respectively). Turgidosterones 4–7 displayed antileishmanial activity against Leishmania donovani promastigotes with IC₅₀ values ranging from 4.95 to 8.03 μg mL⁻¹ and against Leishmania donovani amastigote/THP with IC₅₀ values range of 4.50–9.29 μg mL⁻¹. Activity against Trypanosoma brucei was also observed for Turgidosterones 4–7 with an IC₅₀ values range of 1.26–3.77 μg mL⁻¹. Turgidosterones 1–3 did not display any activity against the tested pathogens. The study of structure–activity relationships of the isolated saponins indicated that the antifungal, antileishmanial, and antitrypanosomal activities are markedly affected by the presence of spirostane-type saponins and the elongation of the sugar residue at C-3. To quantitatively determine the most abundant active ingredient in Panicum turgidum extract, a single run, sensitive, and highly selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been applied under positive and negative modes. The obtained results showed that compound 5 was the most abundant (95.93 ± 1.10 mg per gram of dry Panicum turgidum extract), followed by 6 (52.51 ± 1.05 mg gm⁻¹), 4 (32.71 ± 0.48 mg gm⁻¹), and 7 (13.19 ± 0.50 mg gm⁻¹). Docking of these saponins against the Candida albicans oxidoreductases and Leishmania infantum trypanothione reductase active sites revealed their potential to effectively bind with a number of key residues in both receptor targets.

Bioassay-guided investigation of Panicum turgidum extract resulted in the identification of seven steroidal saponins (Turgidosterones 1–7).     

NS3 helicase inhibitory potential of the marine sponge Spongia irregularis

In the current study, an investigation of the activity of the total extract of the marine sponge Spongia irregularis and its different fractions against the hepatitis C virus (HCV) was pursued. The results revealed that the ethyl acetate fraction exhibited the highest anti-HCV activity, with an IC₅₀ value of 12.6 ± 0.05 μg ml⁻¹. Chromatographic resolution of the ethyl acetate fraction resulted in the isolation of four known compounds, 1,3,7-trimethylguanine (1), 3,5-dihydroxyfuran-2(5H)-one (2), thymidine (3), and 1H-indazole (4). By using LC-HR-ESI-MS metabolic profiling, compounds 5–14 were also identified in the same fraction. Molecular docking calculations revealed the high binding affinity of compound 14 against the allosteric pocket of HCV NS3-NS4A and the active site of HCV NS3 helicase (−10.1 and −7.4 kcal mol⁻¹, respectively). Molecular dynamics simulations, followed by molecular mechanics-generalized Born surface area energy calculations, demonstrated the structural and energetic stability of compound 14 in complex with HCV targets.

Our study discusses the anti-HCV activity of Spongia irregularis. The results revealed that the ethyl acetate fraction exhibited the highest anti-HCV activity and Nakijiquinone F is the most likely anti-HCV candidate among the screened compounds.     

A comparative assessment of in vitro cytotoxic activity and phytochemical profiling of Andrographis nallamalayana J.L.Ellis and Andrographis paniculata (Burm. f.) Nees using UPLC-QTOF-MS/MS approach

Andrographis paniculata (Burm. f.) Nees and Andrographis nallamalayana J.L.Ellis have traditionally been used to treat various ailments such as mouth ulcers, intermittent fever, inflammation, snake bite. This study compares the comparative in vitro cytotoxic activity, and phytochemical profiling of methanol extract of A. nallamalayana (ANM) and A. paniculata (APM). UPLC-ESI-QTOF-MS/MS analysis has been performed. The cytotoxic activity of crude methanol extracts were evaluated against three different cancer cell lines (HCT 116, HepG2, and A549 cell line). Both plants'' extract exhibited significant cytotoxic activity against tested cell lines in a dose-dependent manner. IC₅₀ of ANM and APM in HCT 116 cell was 11.71 ± 2.48 μg ml⁻¹ and 45.32 ± 0.86 μg ml⁻¹ and in HepG2 cell line was 15.65 ± 2.25 μg ml⁻¹ and 60.32 ± 1.05 μg ml⁻¹ respectively. Cytotoxicity of these two extracts was comparatively similar in A549 cells. ANM induced cytotoxicity involved programmed cell death, externalisation of phosphatidylserine, ROS generation, up-regulation and down-regulation of major apoptotic markers. HRMS analysis of ANM and APM resulted in the identification of 59 and 42 compounds, respectively. Further, using the MS/MS fragmentation approach, 20 compounds, of which 18 compounds were identified for the first time from ANM, which belongs to phenolic acids, flavonoids, and their glycosides. Three known compounds, echioidinin, skullcapflavone I and 5,2′,6′-trihydroxy-7-methoxyflavone 2′-O-β-d-glucopyranoside, were isolated from A. nallamalayana and their crystal structures were reported for the first time. Subsequently, seven major compounds were identified in A. nallamalayana by direct comparison (retention time and UV-spectra) with authentic commercial standards and isolated compounds using HPLC-UV analysis. The cytotoxicity of phytochemicals from both the plants using in silico tools also justify their in vitro cytotoxic activity. It is the first report on the comparative characterisation of phytochemicals present in the methanolic extract of both the species of Andrographis, along with the cytotoxic activity of A. nallamalayana.

A comparative study of two Andrographis species have been done, and it was found that Andrographis nallamalayana J.L.Ellis is phytochemically and biologically different from Andrographis paniculata (Burm. f.) Nees.     

β-Blockers bearing hydroxyethylamine and hydroxyethylene as potential SARS-CoV-2 Mpro inhibitors: rational based design,in silico,in vitro,and SAR studies for lead optimization

The global COVID-19 pandemic became more threatening especially after the introduction of the second and third waves with the current large expectations for a fourth one as well. This urged scientists to rapidly develop a new effective therapy to combat SARS-CoV-2. Based on the structures of β-adrenergic blockers having the same hydroxyethylamine and hydroxyethylene moieties present in the HIV-1 protease inhibitors which were found previously to inhibit the replication of SARS-CoV, we suggested that they may decrease the SARS-CoV-2 entry into the host cell through their ability to decrease the activity of RAAS and ACE2 as well. Herein, molecular docking of twenty FDA-approved β-blockers was performed targeting SARS-CoV-2 Mpro. Results showed promising inhibitory activities especially for Carvedilol (CAR) and Nebivolol (NEB) members. Moreover, these two drugs together with Bisoprolol (BIS) as an example from the lower active ones were subjected to molecular dynamics simulations at 100 ns. Great stability across the whole 100 ns timeframe was observed for the top docked ligands, CAR and NEB, over BIS. Conformational analysis of the examined drugs and hydrogen bond investigation with the pocket''s crucial residues confirm the great affinity and confinement of CAR and NEB within the Mpro binding site. Moreover, the binding-free energy analysis and residue-wise contribution analysis highlight the nature of ligand–protein interaction and provide guidance for lead development and optimization. Furthermore, the examined three drugs were tested for their in vitro inhibitory activities towards SARS-CoV-2. It is worth mentioning that NEB achieved the most potential anti-SARS-CoV-2 activity with an IC₅₀ value of 0.030 μg ml⁻¹. Besides, CAR was found to have a promising inhibitory activity with an IC₅₀ of 0.350 μg ml⁻¹. Also, the IC₅₀ value of BIS was found to be as low as 15.917 μg ml⁻¹. Finally, the SARS-CoV-2 Mpro assay was performed to evaluate and confirm the inhibitory effects of the tested compounds (BIS, CAR, and NEB) towards the SARS-CoV-2 Mpro enzyme. The obtained results showed very promising SARS-CoV-2 Mpro inhibitory activities of BIS, CAR, and NEB (IC₅₀ = 118.50, 204.60, and 60.20 μg ml⁻¹, respectively) compared to lopinavir (IC₅₀ = 73.68 μg ml⁻¹) as a reference standard.

Hydroxyethylamine and hydroxyethylene moieties of β-blockers exert potential SARS-CoV-2 inhibitory effects: rational-based design and in silico, in vitro, and SAR Studies.     

Novel N-arylamide derivatives of (S)-perillic acid ((S)-PA): in vitro and in vivo cytotoxicity and antitumor evaluation

Hepatocellular carcinoma (HC) and glioblastoma (GBA) are the most commonly aggressive malignant liver and brain tumors. Based on an established method for the synthesis of amide, two novel analogues (4 and 5) of (S)-perillic acid were synthesized and their structures were affirmed using nuclear magnetic resonance spectroscopic analysis. An MTT cytotoxic assay showed that our derivatives (4 and 5) demonstrated a substantial anti-proliferative effect against HC (HepG2) and GBA (U251) cell lines. Particularly, compound 5 showed growth inhibitory (IC₅₀) effects on U251 (IC₅₀ = 3.10 ± 0.12 μg mL⁻¹) and HepG2 cells (IC₅₀ = 1.49 ± 0.43 μg mL⁻¹), which fall within the acceptable standard recommended by the National institute of cancer (Bethesda, MD, USA) for the selection of anticancer drug candidates. Consequently, we assessed the in vivo antitumor and organ/tissue toxicity of 4, 5 and 5-fluorouracil (5-FU) in hepatoma H22-inoculated mice. The results obtained indicated remarkable tumor growth inhibition with no substantial toxicological effects on the mice and the organs/tissues in the treated groups compared well with the control.

(S)-Perillic acid derivatives bearing N-aryl moiety with enhanced cytotoxic and antitumor effect against hepatocellular carcinoma and glioblastoma.     

Newly synthesised oxime and lactone derivatives from Dipterocarpus alatus dipterocarpol as anti-diabetic inhibitors: experimental bioassay-based evidence and theoretical computation-based prediction

Dipterocarpus alatus-derived products are expected to exhibit anti-diabetes properties. Natural dipterocarpol (1) was isolated from Dipterocarpus alatus collected in Quang Nam province, Vietnam; afterwards, 20 derivatives including 13 oxime esters (2 and 3a–3m) and 7 lactones (4, 5, 6a–6e) were semi-synthesised. Their inhibitory effects towards diabetes-related proteins were investigated experimentally (α-glucosidase) and computationally (3W37, 3AJ7, and PTP1B). Except for compound 2, the other 19 compounds (3a–3m, 4, 5, and 6a–6d) are reported for the first time, which were modified at positions C-3, C-24 and C-25 of the dipterocarpol via imidation, esterification, oxidative cleavage and lactonisation reactions. A framework based on docking-QSARIS combination was proposed to predict the inhibitory behaviour of the ligand-protein complexes. Enzyme assays revealed the most effective α-glucosidase inhibitors, which follow the order 5 (IC₅₀ of 2.73 ± 0.05 μM) > 6c (IC₅₀ of 4.62 ± 0.12 μM) > 6e (IC₅₀ of 7.31 ± 0.11 μM), and the computation-based analysis confirmed this, i.e., 5 (mass: 416.2 amu; polarisability: 52.4 ų; DS: −14.9 kcal mol⁻¹) > 6c (mass: 490.1 amu; polarisability: 48.8 ų; DS: −13.7 kcal mol⁻¹) > 6e (mass: 549.2 amu; polarisability: 51.6 ų; DS: −15.2 kcal mol⁻¹). Further theoretical justifications predicted 5 and 6c as versatile anti-diabetic inhibitors. The experimental results encourage next stages for the development of anti-diabetic drugs and the computational strategy invites more relevant work for validation.

Dipterocarpus alatus-derived products are expected to exhibit anti-diabetes properties.     

Phytochemical composition and the cholinesterase and xanthine oxidase inhibitory properties of seed extracts from the Washingtonia filifera palm fruit

The chemical composition and biological properties of palm Washingtonia filifera (Lindl.) H. Wendl. seeds are seldom studied. Bearing this in mind, the seeds of W. filifera fruits were analysed for their fatty acid and phenolic composition and their antioxidant activity in addition to their cholinesterase and xanthine oxidase inhibitory activities. Seed extracts were revealed as a good source of phenolics with significant antioxidant activity. The phenolic profile mainly consisted of proanthocyanidins or procyanidin dimers B1–B4 among the major compounds. The highest butyrylcholinesterase inhibitory activity was found in the ethanolic extracts of seeds, with IC₅₀ values of 13.73 ± 1.31 μg mL⁻¹. Seed alcoholic extracts also displayed interesting xanthine oxidase inhibitory activity, with IC₅₀ values ranging between 75.2 ± 17.0 μg mL⁻¹ and 95.8 ± 5.9 μg mL⁻¹. Procyanidin B1, a major component in the extracts, could be an important contributor to that activity, as it was found to possess good xanthine oxidase inhibition capacity (IC₅₀ value of 53.51 ± 6.03 μg mL⁻¹). Docking studies were also performed to predict the binding sites of procyanidins B1 and B2 within the xanthine oxidase structure. In all, W. filifera seeds appear as a promising natural source for the extraction of bioactive compounds with antioxidant and butyrylcholinesterase as well as xanthine oxidase inhibitory potential.

The chemical composition and biological properties of palm Washingtonia filifera (Lindl.) H. Wendl. seeds are seldom studied.     

Knecorticosanones C–H from the fruits of Knema globularia (Lam.) warb

Six undescribed polyketides, 1–6, were discovered from the fruits of Knema globularia (Lam.) warb. Two known polyketides and three known lignans were also isolated. Cytotoxicities against HepG2 and KKU-M156 cells of all polyketides were evaluated. Compound 1 displayed the most cytotoxic activity against HepG2 and KKU-M156 cell lines with IC₅₀ values of 1.57 ± 0.37 and 1.78 ± 0.14 μg mL⁻¹, respectively. The structure of all isolates was identified using spectroscopic methods including NMR, IR, MS and ECD.

Compound 1 displayed the most cytotoxic activity against HepG2 and KKU-M156 cell lines with IC₅₀ values of 1.57 ± 0.37 and 1.78 ± 0.14 μg mL⁻¹, respectively.     

Structural transformation of methasterone with Cunninghamella blakesleeana and Macrophomina phaseolina

An anabolic-androgenic synthetic steroidal drug, methasterone (1) was transformed by two fungi, Cunninghamella blakesleeana and Macrophimina phaseclina. A total of six transformed products, 6β,7β,17β-trihydroxy-2α,17α-dimethyl-5α-androstane-3-one (2), 6β,7α,17β-trihydroxy-2α,17α-dimethyl-5α-androstane-3-one (3), 6α,17β-dihydroxy-2α,17α-dimethyl-5α-androstane-3,7-dione (4), 3β,6β,17β-trihydroxy-2α,17α-dimethyl-5α-androstane-7-one (5), 7α,17β-dihydroxy-2α,17α-dimethyl-5α-androstane-3-one (6), and 6β,9α,17β-trihydroxy-2α,17α-dimethyl-5α-androstane-3-one (7) were synthesized. Among those, compounds 2–5, and 7 were identified as new transformed products. MS, NMR, and other spectroscopic techniques were performed for the characterization of all compounds. Substrate 1 (IC₅₀ = 23.9 ± 0.2 μg mL⁻¹) showed a remarkable anti-inflammatory activity against nitric oxide (NO) production, in comparison to standard LNMMA (IC₅₀ = 24.2 ± 0.8 μg mL⁻¹). Whereas, its metabolites 2, and 7 showed moderate inhibition with IC₅₀ values of 38.1 ± 0.5 μg mL⁻¹, and 40.2 ± 3.3 μg mL⁻¹, respectively. Moreover, substrate 1 was found to be cytotoxic for the human normal cell line (BJ) with an IC₅₀ of 8.01 ± 0.52 μg mL⁻¹, while metabolites 2–7 were identified as non-cytotoxic. Compounds 1–7 showed no cytotoxicity against MCF-7 (breast cancer), NCI-H460 (lung cancer), and HeLa (cervical cancer) cell lines.

Fungal transformation of methasterone resulted in six products (2–7). 2–5, and 7 were identified as new. Substrate 1 showed remarkable anti-inflammatory activity but was cytotoxic. Products 2 and 7 showed moderate activity but were non-cytotoxic.     

A vanillin-based copper(ii) metal complex with a DNA-mediated apoptotic activity

Vanillin (vanH) is the major component of vanilla and one of the most widely used flavoring agents. In this work the complex [Cu(phen)(van)₂] was prepared and characterized by structural (X-ray), spectroscopic (IR, UV-Vis, EPR) and electrochemical techniques. This compound showed an octahedral geometry with an unusual arrangement of the vanillin ligands, where the methoxy groups of the vanillinate ions are coordinated opposite to each other. The compound promoted DNA cleavage in the presence of glutathione (GSH) and H₂O₂. At 40 μmol L⁻¹ of complex with GSH (10 mmol L⁻¹), there is a complete cleavage of DNA to nicked form II, while only at 10 μmol L⁻¹ of this complex with H₂O₂ (1 mmol L⁻¹) an extensive cleavage leading to form III took place. Additionally, we have evidences of superoxide generation upon reaction with GSH. Therefore, DNA fragmentation occurs likely through an oxidative pathway. MTT assays indicated that the complex is highly cytotoxic against three distinct cell lines: B16–F10 (IC₅₀ = 3.39 ± 0.61 μmol L⁻¹), HUH-7 (IC₅₀ = 4.22 ± 0.31 μmol L⁻¹) and 786-0 (IC₅₀ = 10.38 ± 0.91 μmol L⁻¹). Flow cytometry studies conducted with 786-0 cell line indicated cell death might occur by apoptosis. Cell cycle progression evaluated at 5 and 10 μmol L⁻¹ resulted in a clear increase of 786-0 cells at G1 phase and depletion of G2/M, while higher doses showed an expressive increase of sub-G1 phase. Altogether, these results pointed out to a promising biological activity and potential as an anti-cancer agent.

Proposed catalytic cycle for ROS production in the vicinity of DNA after reduction of [Cu(phen)(van)₂] by glutathion.     

Chemical constituents from Carica papaya Linn. leaves as potential cytotoxic,EGFRwt and aromatase (CYP19A) inhibitors; a study supported by molecular docking

The phytochemical investigation of the hydromethanolic extract of Carica papaya Linn. leaves (Caricaceae) resulted in the isolation and characterization of ten compounds, namely; carpaine (1), methyl gallate (2), loliolide (3), rutin (4), clitorin (5), kaempferol-3-O-neohesperidoside (6), isoquercetin (7), nicotiflorin (8) and isorhamnetin-3-O-β-d-glucopyranoside (9). The compounds 2, 3, 5–7 and 9 were isolated for the first time from the genus Carica. An in vitro breast cancer cytotoxicity study was evaluated with an MCF-7 cell line using the MTT assay. Methyl gallate and clitorin demonstrated the most potent cytotoxic activities with an IC₅₀ of 1.11 ± 0.06 and 2.47 ± 0.14 μM, respectively. Moreover, methyl gallate and nicotiflorin exhibited potential EGFR^wt kinase inhibition activities with an IC₅₀ of 37.3 ± 1.9 and 41.08 ± 2.1 nM, respectively, compared with the positive control erlotinib (IC₅₀ = 35.94 ± 1.8 nM). On the other hand, clitorin and nicotiflorin displayed the strongest aromatase kinase inhibition activities with an IC₅₀ of 77.41 ± 4.53 and 92.84 ± 5.44 nM, respectively. Clitorin was comparable to the efficacy of the standard drug letrozole (IC₅₀ = 77.72 ± 4.55). Additionally, molecular docking simulations of the isolated compounds to EGFR and human placental aromatase cytochrome P450 (CYP19A1) were evaluated. Methyl gallate linked with the EGFR receptor through hydrogen bonding with a pose score of −4.5287 kcal mol⁻¹ and RMSD value of 1.69 Å. Clitorin showed the strongest interaction with aromatase (CYP19A1) for the breast cancer receptor with a posing score of −14.2074 and RMSD value of 1.56 Å. Compounds (1–3) possessed a good bioavailability score with a 0.55 value.

The phytochemical investigation of the hydromethanolic extract of Carica papaya Linn. leaves (Caricaceae) resulted in the isolation and characterization of ten compounds.     

Design,synthesis, and bioactivity evaluation of antitumor sorafenib analogues

Malignant tumors are a serious threat to human health and are generally treated with chemical therapy. This chemical therapy uses agents that act on signal transduction pathway mechanism of tumor with good selectivity and low toxicity. Sorafenib is a multikinase target inhibitor with good tumor inhibitory activity and a protein kinase inhibitor. In this research, a novel series of sorafenib analogues and derivatives were designed, synthesized, and evaluated as tumor inhibitors. These compounds used sorafenib as the lead compound and achieved modifications using bioisosteres and the alkyl principle. The in vitro the results showed that compounds 3c, 3d, 3h, 3n, 3r, and 3z had good inhibitory effects on human cervical cancer cells (Hela), while compounds 3t and 3v had good inhibitory effects on human lung cancer cells (H1975 and A549). Among these, compound 3d had an inhibitory activity (IC₅₀) of 0.56 ± 0.04 μmol L⁻¹ against Hela cells (human cervical cancer), the compound 3t had an IC₅₀ of 2.34 ± 0.07 μmol L⁻¹ against H1975 cells (human lung cancer), and compound 3v had an IC₅₀ of 1.35 ± 0.03 μmol L⁻¹ against A549 cells (human lung cancer). The in vivo results showed that these compounds had good antitumor effects and low acute toxicity.

Malignant tumors are a serious threat to human health and are generally treated with chemical therapy.     

The protective potential of a Fraxinus xanthoxyloides ethyl acetate fraction against CCl4-induced oxidative stress in the cardiac tissue of rats

Secondary metabolites present in medicinal plants offer a golden opportunity to fight different ailments, such as cancer, infections, diabetes, neurodegenerative and cardiovascular diseases, etc. The traditional use of various parts of Fraxinus xanthoxyloides is known to serve as a cure for pneumonia, pain, jaundice, malaria, fracturing of bones, and internal wounds. The aim of this research was to validate the antioxidant and cardio-protective properties of F. xanthoxyloides leaves. The antioxidant potential was evaluated by employing different assays on the crude methanol extract, as well as its derived fractions. The extract/fraction that showed significant activity was further investigated for the presence of phytochemicals using high performance liquid chromatography-diode array detector (HPLC-DAD) analysis and also for cardio-protective potential. In the case of the antioxidant potential, the ethyl acetate fraction (FXE) was demonstrated to have the most potent total antioxidant (26.3 ± 2.4 AAE μg mg⁻¹), hydroxyl ion scavenging (IC₅₀ = 7.9 ± 0.9 μg mg⁻¹), ferrous ion chelating (IC₅₀ = 28.2 ± 2.7 μg mg⁻¹) and nitric oxide scavenging (IC₅₀ = 32.5 ± 2.9 μg mg⁻¹) effects among all of the extract/fractions, whereas in the case of DPPH (IC₅₀ = 17.5 ± 2.7 μg mg⁻¹) and the reducing power assay (16.7 ± 2.8 GAE μg mg⁻¹), promising antioxidant potential was shown by the n-butanol fraction. The presence of different concentrations of rutin, caffeic acid, catechin, and gallic acid was observed in the high performance liquid chromatography (HPLC) profile of FXE. Furthermore, in in vivo experimentation, the oral administration of FXE and silymarin significantly restored the CCl₄-induced increase in the levels of creatine kinase, creatine kinase-MB, cholesterol and triacylglycerides when compared with the untreated group. FXE and silymarin treatment also restored the levels of the tissue antioxidant enzymes, for example glutathione-S-transferase, glutathione reductase, catalase, peroxidase and superoxide dismutase. Furthermore, significantly lower levels of reduced glutathione and enhanced levels of lipid peroxides, hydrogen peroxide, comet length and DNA damages were observed after CCl₄ administration in the cardiac tissue of rats. FXE was able to restore these biochemical parameters, as well as the histological status of heart tissue. Based upon the present investigation, we concluded that F. xanthoxyloides leaves may have cardio-protective potential similar to silymarin against CCl₄ induced injuries owing to its antioxidant constituents.

Secondary metabolites present in medicinal plants offer a golden opportunity to fight different ailments, such as cancer, infections, diabetes, neurodegenerative and cardiovascular diseases, etc.     

Chemical and biological study of aplysiatoxin derivatives showing inhibition of potassium channel Kv1.5

Three new aplysiatoxins, neo-debromoaplysiatoxin D (1), oscillatoxin E (2) and oscillatoxin F (3), accompanied by four known analogues (4–7), were identified from the marine cyanobacterium Lyngbya sp. Structural frames differ amongst these metabolites, and therefore we classified compounds 1 and 4–6 as aplysiatoxins as they possess 6/12/6 and 6/10/6 tricyclic ring systems featuring a macrolactone ring, and compounds 2, 3 and 7 as oscillatoxins that feature a hexane-tetrahydropyran in a spirobicyclic system. Bioactivity experiments showed that compounds 1 and 4–6 presented significant expression of phosphor-PKCδ whereas compounds 2, 5 and 7 showed the most potent blocking activity against potassium channel Kv1.5 with IC₅₀ values of 0.79 ± 0.032 μM, 1.28 ± 0.080 μM and 1.47 ± 0.138 μM, respectively. Molecular docking analysis supplementing the binding interaction of oscillatoxin E (2) and oscillatoxin F (3) with Kv1.5 showed oscillatoxin E (2) with a strong binding affinity of −37.645 kcal mol⁻¹ and oscillatoxin F (3) with a weaker affinity of −32.217 kcal mol⁻¹, further supporting the experimental data.

New aplysiatoxin derivative (oscillatoxin E) exhibiting potent blocking activity against potassium channel Kv1.5 is consistent with molecular docking analysis.     

Inhibitory effect of phenolic extract from squirting cucumber (Ecballium elaterium (L.) A. Rich) seed oil on integrin-mediated cell adhesion,migration and angiogenesis

Integrin targeted therapies by natural bioactive compounds have attracted attention in the field of oncology and cancer treatment. This study evaluates the potential of phenolic extract from the medicinal herb Ecballium elaterium L. seed oil (PEO) to inhibit the adhesion and migration of the highly invasive human fibrosarcoma cell line HT1080. At safe concentrations (up to 40 μg mL⁻¹), results show that PEO dose-dependently inhibits adhesion and migration of HT1080 to fibronectin (IC₅₀ = 18 μg mL⁻¹) and fibrinogen (IC₅₀ = 12.86 μg mL⁻¹). These observations were associated with the reduction of cell motility and migration velocity as revealed in the Boyden chamber and random motility using two-dimensional assays, respectively. Additional experiments using integrin blocking antibodies showed that PEO at the highest safe concentration (40 μg mL⁻¹) competitively inhibited the attachment of HT1080 cell to anti-αvβ3 (>98%), anti-α5β1 (>86%), and to a lesser extent anti-α2 (>50%) immobilized antibodies, suggesting that αvβ3 and α5β1 integrins were selectively targeted by PEO. Moreover, PEO specifically targeted these integrins in human microvascular endothelial cells (HMEC-1) and dose-dependently blocked the in vitro tubulogenesis. In the CAM model, PEO inhibited the VEGF-induced neoangiogenesis confirming its anti-angiogenic effect. Collectively, these results indicate that PEO holds promise for the development of natural integrin-targeted therapies against fibrosarcoma.

Phenolic extract from Ecballium elaterium inhibits integrin-mediated adhesion and migration, and hinders VGEF-induced angiogenesis.     

Uracil derivatives as HIV-1 capsid protein inhibitors: design,in silico,in vitro and cytotoxicity studies

A series of novel uracil derivatives such as bispyrimidine dione and tetrapyrimidine dione derivatives were designed based on the existing four-point pharmacophore model as effective HIV capsid protein inhibitors. The compounds were initially docked with an HIV capsid protein monomer to rationalize the ideas of design and to find the potential binding modes. The successful design and computational studies led to the synthesis of bispyrimidine dione and tetrapyrimidine dione derivatives from uracil and aromatic aldehydes in the presence of HCl using novel methodology. The in vitro evaluation in HIV p24 assay revealed five potential uracil derivatives with IC₅₀ values ranging from 191.5 μg ml⁻¹ to 62.5 μg ml⁻¹. The meta-chloro substituted uracil compound 9a showed promising activity with an IC₅₀ value of 62.5 μg ml⁻¹ which is well correlated with the computational studies. As expected, all the active compounds were noncytotoxic in BA/F3 and Mo7e cell lines highlighting the thoughtful design. The structure activity relationship indicates the position priority and lower log P values as the possible cause of inhibitory potential of the uracil compounds.

The paper describes the design, synthesis, computational and biological validation of a series of novel uracil derivatives as effective HIV capsid protein inhibitors.     

Biochemical and kinetic characterization of laccase and manganese peroxidase from novel Klebsiella pneumoniae strains and their application in bioethanol production

Laccase (lac) and manganese peroxidase (MnP) enzymes from the novel Klebsiella pneumoniae isolates, grown on lignin basic media (LBM) were purified by 80% ammonium sulphate fractionation, dialysis and DEAE-sepharose column chromatography. The optimum temperatures for laccase production were 60 °C, 50 °C and 50 °C and for MnP production were 50 °C, 70 °C and 60 °C from NITW715076_2, NITW715076_1 and NITW715076 isolates, respectively. The optimal pH for production was found to be 5 for production of both the enzymes from all the isolates. 2.8–3.5 fold enzyme purification was achieved retaining around 60–70% of the initial activity. SDS-PAGE revealed the molecular mass of laccase and MnP to be 66 kDa and 48 kDa, respectively. The substrate ABTS and MnSO₄ exhibited more specificity towards NITW715075_2 derived laccase and MnP (lac: K_m = 0.38 mM, V_max = 71.42 U ml⁻¹; MnP: K_m = 0.17 mM, V_max = 106.38 U ml⁻¹) compared to NITW715076_1 (lac: K_m = 3.97 mM, V_max = 148.8 U ml⁻¹; MnP: K_m = 0.90 mM, V_max = 114.67 U ml⁻¹) and NITW715076 (lac: K_m = 0.46 mM, V_max = 23.42 U ml⁻¹; MnP: K_m = 0.19 mM, V_max = 108.10 U ml⁻¹) derived. l-Cysteine and sodium azide imposed a strong inhibitory effect on the activities of both the enzymes. EDTA inhibited laccase and MnP activity at higher concentration. SDS strongly inhibited activity while for MnP it showed less inhibitory effect. The enzymes were employed for ethanol production from rice and wheat bran biomass which showed 39.29% improved production compared to control. After evaluating the applicability of these enzymes it can be suggested that the ligninolytic enzyme of Klebsiella pneumoniae isolates could be effectively employed in enhanced ethanol production and could be explored for other putative applications.

Upto 3 fold purified laccase and MnP from novel Klebsiella isolates, mediated ethanol production from rice and wheat bran substrates lead to almost 40% improvement in production profile.     

Retraction: One pot green preparation of Seabuckthorn silver nanoparticles (SBT@AgNPs) featuring high stability and longevity,antibacterial, antioxidant potential: a nano disinfectant future perspective

Retraction of ‘One pot green preparation of Seabuckthorn silver nanoparticles (SBT@AgNPs) featuring high stability and longevity, antibacterial, antioxidant potential: a nano disinfectant future perspective’ by Thiyagarajan Kalaiyarasan et al., RSC Adv., 2017, 7, 51130–51141, https://doi.org/10.1039/C7RA10262C.

I, the undersigned author, hereby wholly retract this RSC Advances article due to the following instances of matched/similar images that have been identified that weaken this article, which occurred due to honest human errors.Following the previous publication of a correction to correct errors in Fig. 1, 3, 7 and 9, further instances of duplicating images have been identified within the corrected Fig. 3 and 7, as well as additional errors in the original article, that undermine this article.In Fig. 3 of the correction notice:The panel for freshly prepared S. enterica MTCC-3219 2 μg ml⁻¹ 10⁻¹⁰ is identical to the panel for S. typhirmurium MTCC-3224 4 μg ml⁻¹ 10⁻⁵ after one year of storage, to the panel 1 h treated with SBT@AgNPs in Fig. 7, and to the panels E. coli MTCC No. 62 6 μg ml⁻¹ and 8 μg ml⁻¹ in Fig. 5 of ref. 1.The panel for freshly prepared S. typhirmurium MTCC-3224 6 μg ml⁻¹ 10⁻¹⁰ is identical to the panel for S. typhirmurium MTCC-3224 6 μg ml⁻¹ 10⁻¹⁰ after one year of storage and to the panel 0.5 h treated with SBT@AgNPs in Fig. 7.The panel for freshly prepared S. typhirmurium MTCC-3224 4 μg ml⁻¹ 10⁻⁵ is identical to the panel for freshly prepared S. enterica MTCC-3219 6 μg ml⁻¹ 10⁻¹⁰.The panel for freshly prepared S. typhirmurium MTCC-3224 2 μg ml⁻¹ 10⁻¹⁰ is identical to the panel for S. typhirmurium MTCC-3224 6 μg ml⁻¹ 10⁻⁵ after one year of storage.The panel for freshly prepared S. typhirmurium MTCC-3224 4 μg ml⁻¹ 10⁻¹⁰ is identical to the panel for S. typhirmurium MTCC-3224 2 μg ml⁻¹ 10⁻¹⁰ after one year of storage.The panel for S. enterica MTCC-3219 4 μg ml⁻¹ 10⁻⁵ after one year of storage is identical to the panel for S. enterica MTCC-3219 6 μg ml⁻¹ 10⁻¹⁰ after one year of storage.In Fig. 3a, a′, c and c′ of the original article, the error bars are erroneous.In Fig. 4 of the original article, both the panels for S. typhirmurium are identical.Thiyagarajan Kalaiyarasan and Vijay K. Bharti responded to all enquiries and submitted data related to the above concerns. However, to avoid any future ambiguity to the readers, the article is retracted.Vijay K. Bharti and O. P. Chaurasia were informed about the retraction of the article but have not responded.Signed: Kalaiyarasan ThiyagarajanDate: 1/6/2022Retraction endorsed by Laura Fisher, Executive Editor, RSC Advances