Comparative Pharmacology of Cefaclor and Cephalexin

Two cephalosporin antibiotics, cefaclor and cephalexin, were administered orally to healthy, adult male volunteers for comparison of their pharmacological properties. In doses of 250 mg orally, cefaclor produced a peak serum concentration of 6.01 ± 0.55 (standard deviation [SD]) μg/ml compared with 9.43 ± 2.36 μg/ml for cephalexin (P < 0.01). The half-lives were 0.58 ± 0.07 (SD) h and 0.80 ± 0.12 (SD) h, and elimination constants were 1.22 ± 0.15 and 0.88 ± 0.13 h⁻¹ for cefaclor and cephalexin, respectively (P < 0.001). Neither drug showed accumulation over the dosing period, and both were well tolerated.     

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.     

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     

Pharmacokinetics of Antituberculosis Drugs in HIV-Positive and HIV-Negative Adults in Malawi

Limited data address the impact of HIV coinfection on the pharmacokinetics (PK) of antituberculosis drugs in sub-Saharan Africa. A total of 47 Malawian adults underwent rich pharmacokinetic sampling at 0, 0.5, 1, 2, 3, 4, 6, 8, and 24 h postdose. Of the subjects, 51% were male, their mean age was 34 years, and 65% were HIV-positive with a mean CD4 count of 268 cells/μl. Antituberculosis drugs were administered as fixed-dose combinations (150 mg rifampin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol) according to recommended weight bands. Plasma drug concentrations were determined by high-performance liquid chromatography (rifampin and pyrazinamide) or liquid chromatography-mass spectrometry (isoniazid and ethambutol). Data were analyzed by noncompartmental methods and analysis of variance of log-transformed summary parameters. The pharmacokinetic parameters were as follows (median [interquartile range]): for rifampin, maximum concentration of drug in plasma (C_max) of 4.129 μg/ml (2.474 to 5.596 μg/ml), area under the curve from 0 to 24 h (AUC_0–∞) of 21.32 μg/ml · h (13.57 to 28.60 μg/ml · h), and half-life of 2.45 h (1.86 to 3.08 h); for isoniazid, C_max of 3.97 μg/ml (2.979 to 4.544 μg/ml), AUC_0–24 of 22.5 (14.75 to 34.59 μg/ml · h), and half-life of 3.93 h (3.18 to 4.73 h); for pyrazinamide, C_max of 34.21 μg/ml (30.00 to 41.60 μg/ml), AUC_0–24 of 386.6 μg/ml · h (320.0 to 463.7 μg/ml · h), and half-life of 6.821 h (5.71 to 8.042 h); and for ethambutol, C_max of 2.278 μg/ml (1.694 to 3.098 μg/ml), AUC_0–24 of 20.41 μg/ml · h (16.18 to 26.27 μg/ml · h), and half-life of 7.507 (6.517 to 8.696 h). The isoniazid PK data analysis suggested that around two-thirds of the participants were slow acetylators. Dose, weight, and weight-adjusted dose were not significant predictors of PK exposure, probably due to weight-banded dosing. In this first pharmacokinetic study of antituberculosis drugs in Malawian adults, measures of pharmacokinetic exposure were comparable with those of other studies for all first-line drugs except for rifampin, for which the C_max and AUC_0–24 values were notably lower. Contrary to some earlier observations, HIV status did not significantly affect the AUC of any of the drugs. Increasing the dose of rifampin might be beneficial in African adults, irrespective of HIV status. Current co-trimoxazole prophylaxis was associated with an increase in the half-life of isoniazid of 41% (P = 0.022). Possible competitive interactions between isoniazid and sulfamethoxazole mediated by the N-acetyltransferase pathway should therefore be explored further.     

Discovery of quinolone derivatives as antimycobacterial agents

Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (M. tuberculosis), is an important public health issue. Current first-line drugs administered to TB patients have been in use for over 40 years, whereas second-line drugs display strong side effects and poor compliance. Additionally, designing effective regimens to treat patients infected with multi- and extremely-drug-resistant (MDR and XDR) strains of TB is challenging. In this report, we screened our compound library and identified compound 1 with antituberculosis activity and a minimal inhibitory concentration (MIC) against M. tuberculosis of 20 μg mL⁻¹. Structure optimization and the structure–activity relationship of 1 as the lead compound enabled the design and synthesis of a series of quinolone derivatives, 6a1–6a2, 6b1–6b36, 6c1, 6d1–6d14, 7a1–7a2, 7b1–7b2, 7c1, 8a1–8a5, 9a1–9a4 and 10a1–10a6. These compounds were evaluated in vitro for anti-tubercular activity against the M. tuberculosis H₃₇Rv strain. Among them, compounds 6b6, 6b12 and 6b21 exhibited MIC values in the range of 1.2–3 μg mL⁻¹ and showed excellent activity against the tested MDR-TB strain (MIC: 3, 2.9 and 0.9 μg mL⁻¹, respectively). All three compounds were non-toxic toward A549 and Vero cells (>100 and >50 μg mL⁻¹, respectively). In addition, an antibacterial spectrum test carried out using compound 6b21 showed that this compound specifically inhibits M. tuberculosis. These can serve as a new starting point for the development of anti-TB agents with therapeutic potential.

6b21: MIC against M. tb H₃₇Rv = 1.2 μg mL⁻¹, MIC against drug-resistant strains = 0.9 μg mL⁻¹, solubility = 132 μg mL⁻¹, non-cytotoxicity.     

Differential Release of Lipoteichoic and Teichoic Acids from Streptococcus pneumoniae as a Result of Exposure to β-Lactam Antibiotics, Rifamycins, Trovafloxacin, and Quinupristin-Dalfopristin

The release of lipoteichoic acid (LTA) and teichoic acid (TA) from a Streptococcus pneumoniae type 3 strain during exposure to ceftriaxone, meropenem, rifampin, rifabutin, quinupristin-dalfopristin, and trovafloxacin in tryptic soy broth was monitored by a newly developed enzyme-linked immunosorbent assay. At a concentration of 10 μg/ml, a rapid and intense release of LTA and TA occurred during exposure to ceftriaxone (3,248 ± 1,688 ng/ml at 3 h and 3,827 ± 2,133 ng/ml at 12 h) and meropenem (2,464 ± 1,081 ng/ml at 3 h and 2,900 ± 1,364 ng/ml at 12 h). Three hours after exposure to rifampin, rifabutin, quinupristin-dalfopristin, and trovafloxacin, mean LTA and TA concentrations of less than 460 ng/ml were observed (for each group, P < 0.01 versus the concentrations after exposure to ceftriaxone). After 12 h of treatment, the LTA and TA concentrations were 463 ± 126 ng/ml after exposure to rifampin, 669 ± 303 ng/ml after exposure to rifabutin, and 1,236 ± 772 ng/ml after exposure to quinupristin-dalfopristin (for each group, P < 0.05 versus the concentrations after exposure to ceftriaxone) and 1,745 ± 1,185 ng/ml after exposure to trovafloxacin (P = 0.12 versus the concentration after exposure to ceftriaxone). At 10 μg/ml, bactericidal antibacterial agents that do not primarily affect cell wall synthesis reduced the amount of LTA and TA released during their cidal action against S. pneumoniae in comparison with the amount released after exposure to β-lactams. Larger quantities of LTA and TA were released after treatment with low concentrations (1× the MIC and 1× the minimum bactericidal concentration) than after no treatment for all antibacterial agents except the rifamycins. This does not support the concept of using a low first antibiotic dose to prevent the release of proinflammatory cell wall components.     

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.     

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.     

Combined algicidal effect of urocanic acid,N-acetylhistamine and l-histidine to harmful alga Phaeocystis globosa

The algicidal compounds produced by Bacillus sp. strain B1 against Phaeocystis globosa, one of the main red-tide algae, were isolated and identified in a previous study as urocanic acid (uro), l-histidine (his) and N-acetylhistamine (ace). The 96 h median effective concentration EC₅₀ values indicated the algicidal effect order of uro (8 μg mL⁻¹) > ace (16 μg mL⁻¹) > his (23 μg mL⁻¹). The interaction between uro and ace had a synergistic effect on Phaeocystis globosa, accelerated the increase in its intracellular reactive oxygen species (ROS) levels, and further decreased the activities of antioxidases after 96 h, causing destruction of cell membrane integrity and nuclear structure. However, the other two binary mixtures uro + his and ace + his were both antagonistic to Phaeocystis globosa. The increase in the level of ROS indicated that the algal cells suffered from oxidative damage. The surplus ROS induced the increase in malondialdehyde (MDA) content and activities of antioxidant enzymes including superoxide dismutase (SOD) and catalase (CAT), all of which reached maxima after 72 h treatment. Transmission electron microscopy (TEM) analysis revealed that these nitrogen-containing compounds caused destruction of cell membrane integrity, chloroplasts and nuclear structure. The present study will provide useful information for the combined effect of algicidal compounds on the harmful alga Phaeocystis globosa. This is the first report to explore single and combined algicidal effects of three nitrogen-containing compounds against the harmful alga Phaeocystis globosa.

Ultrastructure of Phaeocystis globosa cells after treatment with EC₅₀ value for 72 h: (a) control, (b) ace (16 μg mL⁻¹), (c) uro (8 μg mL⁻¹), (d) uro + ace (1 : 1 TU, 8 : 16 μg mL⁻¹) Chl, chloroplast; CW, cell wall; N, nucleus; PM, plasma membrane.     

Novel chalcone derivatives containing a 1,2,4-triazine moiety: design,synthesis, antibacterial and antiviral activities

A series of novel chalcone derivatives containing the 1,2,4-triazine moiety were synthesized and their structures were confirmed by ¹H NMR, ¹³C NMR and elemental analyses. Antiviral bioassays revealed that most of the compounds exhibited good antiviral activity against tobacco mosaic virus (TMV) at a concentration of 500 μg mL⁻¹. The designated compound 4l was 50% effective in terms of curative and protective activities against TMV with 50% effective concentrations (EC₅₀) of 10.9 and 79.4 μg mL⁻¹, which were better than those of ningnanmycin (81.4 and 82.2 μg mL⁻¹). Microscale thermophoresis (MST) also showed that the binding of compound 4l to coat protein (TMV-CP) yielded a K_d value of 0.275 ± 0.160 μmol L⁻¹, which was better than that of ningnanmycin (0.523 ± 0.250 μmol L⁻¹). At the same time, molecular docking studies for 4l with TMV-CP (PDB code:1EI7) showed that the compound was embedded well in the pocket between the two subunits of TMV-CP. Meanwhile, compound 4a demonstrated excellent antibacterial activities against Ralstonia solanacearum (R. solanacearum), with an EC₅₀ value of 0.1 μg mL⁻¹, which was better than that of thiodiazole-copper (36.1 μg mL⁻¹) and bismerthiazol (49.5 μg mL⁻¹). The compounds act by causing folding and deformation of the bacterial cell membrane as observed using scanning electron microscopy (SEM). The chalcone derivatives thus synthesized could become potential alternative templates for novel antiviral and antibacterial agents.

A series of novel chalcone derivatives containing the 1,2,4-triazine moiety were synthesized and their structures were confirmed by ¹H NMR, ¹³C NMR and elemental analyses.     

In vitro kinetic release study,antimicrobial activity and in vivo toxicity profile of a kojic acid ester-based nanoemulsion for topical application

Nanoemulsions have emerged as novel vehicles for drug delivery that allow sustained or controlled release for topical application. In this study, kojic acid ester-based nanoemulsion (KAE-NA) was analyzed for in vitro permeation evaluation, kinetic release study, in vitro antimicrobial activity and in vivo toxicity profile on embryonic zebrafish (Danio rerio). Based on KAE-NA in vitro permeation evaluation, the percentage of permeation was significantly improved from 4.94% at 1 h to 59.64% at 8 h of application. The permeation rate of KAE-NA at 8 h was 4659.50 μg cm⁻² h⁻¹ (initial concentration, C₀ = 2000 μg mL⁻¹) with a permeability coefficient (K_p) value of 0.48 cm h⁻¹. The kinetic release analysis showed the Korsmeyer–Peppas model was the best fitted kinetic model with high linearity [R² = 0.9964]. Antimicrobial activity of KAE-NA was studied against the skin pathogen bacteria Staphylococcus aureus ATCC 43300. The results indicated that the inhibition zone size of the KAE-NA (8.00 ± 0.0 mm) was slightly bigger than that of its active ingredient, kojic acid ester (6.5 ± 0.0 mm). The toxicity profile of KAE-NA on embryonic zebrafish revealed less toxicity with LC₅₀ (50% lethal concentration) more than 500 μg mL⁻¹. The survival rate of the embryonic zebrafish was more than 80% when treated at doses ranging from 7.81–250 μg mL⁻¹ and showed normal development throughout the experiment without any observed deformation. Hence, KAE-NA proved to be less toxic on the embryonic zebrafish.

Nanoemulsions have emerged as novel vehicles for drug delivery that allow sustained or controlled release for topical application.     

Kitazin-pea interaction: understanding the fungicide induced nodule alteration,cytotoxicity, oxidative damage and toxicity alleviation by Rhizobium leguminosarum

Realizing the severity of fungicidal toxicity to legumes and importance of fungicide tolerant rhizobia in legume production, kitazin tolerant (2400 μg mL⁻¹) strain RP1 was recovered from pea nodules and was identified as Rhizobium leguminosarum (accession no. {"type":"entrez-nucleotide","attrs":{"text":"KY940047","term_id":"1339307653","term_text":"KY940047"}}KY940047). R. leguminosarum produced indole acetic acid (80.5 ± 2.5 mL⁻¹), siderophores: salicylic acid (54 ± 7.3 μg mL⁻¹) and 2,3-dihydoxybenzoic acid (31.9 ± 2.7 μg mL⁻¹), α-ketobutyrate (51 ± 3.2 per mg per protein per hour), solubilized insoluble phosphate (29.5 ± 1.8 μg mL⁻¹) and secreted 29.5 + 2.6 μg mL⁻¹ exopolysaccharides, which, however, decreased consistently with gradually increasing kitazin concentrations. Beyond the tolerance level, kitazin caused structural damage and altered membrane integrity of RP1, as revealed under scanning (SEM) and confocal (CLSM) electron microscopy. Phytotoxicity of kitazin to peas was obvious under both in vitro and in vivo conditions. A significant reduction of 23, 68, 57 and 50% in germination, seedling vigor index, plumule length and radicle length was found at 2× kitazin compared to the control. Cellular damage and cytotoxicity induced by kitazin in membrane altered root cells was detected with acridine orange/propidium iodide (AO/PI) and Evans blue dye. A maximum increase of 1.72, 5.2, 9.3 and 1.72, 5.2, 9.3-fold in red and blue fluorescence was quantified at 1×, 2×, and 3× doses of kitazin, respectively. In contrast, application of R. leguminosarum RP1 alleviated toxicity and enhanced the length of plant organs, dry biomass, symbiotic attributes, photosynthetic pigments, nutrient uptake and grain features of peas comparatively uninoculated and fungicide-treated plants. Additionally, strain RP1 expressively reduced the antioxidant enzymes peroxidase, ascorbate peroxidase, guaiacol peroxidase, catalase and malondialdehyde contents by 10, 2.2, 11, 20 and 4% compared to stressed plants raised at 192 μg kg⁻¹ soil. Moreover, a decline of 19, 21 and 20% in proline content extracted from roots, shoots and grains, respectively was recorded for R. leguminosarum inoculated pea plants grown with 96 μg kg⁻¹ kitazin. Also, the SEM and CLSM of roots revealed the bacterial colonization. In conclusion, R. leguminosarum tolerated a higher level of kitazin, secreted plant growth promoting (PGP) bioactive molecules even under fungicide stress and significantly increased the performance of peas while reducing the levels of proline and antioxidant enzymes. So, it can safely be suggested to legume growers that RP1 strain could inexpensively be explored as an efficient biofertilizer for enhancing the production of legumes especially peas while growing even under fungicide (kitazin) enriched soils.

Realizing the severity of fungicidal toxicity to legumes and the importance of fungicide tolerant rhizobia in legume production, kitazin tolerant strain RP1 was recovered from pea nodules and was identified as Rhizobium leguminosarum.     

α-Glucosidase inhibitors from Chinese bayberry (Morella rubra Sieb. et Zucc.) fruit: molecular docking and interaction mechanism of flavonols with different B-ring hydroxylations

Inhibition of α-glucosidase alleviates postprandial high glycemic levels in diabetic or prediabetic population. In Chinese bayberry fruit, myricetin, quercetin and kaempferol are main flavonols, which differ only in their hydroxylation on the B-ring. Kaempferol (4′-OH) showed high IC₅₀ (65.36 ± 0.27 μmol L⁻¹) against α-glucosidase, while quercetin (3′,4′-OH) exhibited stronger inhibition (46.91 ± 0.54 μmol L⁻¹) and myricetin (3′,4′,5′-OH) possessed the strongest inhibitory activity (33.20 ± 0.43 μmol L⁻¹). Molecular docking analysis illustrated that these flavonols could insert to the active cavity of α-glucosidase. Adjacent hydroxyl groups at B-ring of myricetin and quercetin positively contributed to form hydrogen bonds that were important to the stability of flavonol–enzyme complex, while kaempferol had no adjacent hydroxyl groups. Such observation was further validated by molecular dynamics simulations, and in good consistency with in vitro kinetic analysis and fluorescence spectroscopy analysis. Among three flavonols tested, myricetin possessed the strongest inhibition effects on α-glucosidase with the lowest dissociation constant (K_i = 15.56 μmol L⁻¹) of myricetin-α-glucosidase, largest fluorescence quenching constant (K_sv) of (14.26 ± 0.03) × 10⁴ L mol⁻¹ and highest binding constant (K_a) of (1.38 ± 0.03) × 10⁵ L mol⁻¹ at 298 K with the enzyme. Bio-Layer Interferometry (BLI) and circular dichroism (CD) analysis further confirmed that myricetin had high affinity to α-glucosidase and induced conformational changes of enzyme. Therefore, myricetin, quercetin and kaempferol are all excellent dietary α-glucosidase inhibitors and their inhibitory activities are enhanced by increasing number of hydroxyl groups on B-ring.

Inhibition of α-glucosidase alleviates postprandial high glycemic levels in diabetic or prediabetic population.     

Suppressive Role of B Cells in Chronic Colitis of T Cell Receptor α Mutant Mice

The role of antibodies (Abs) in the development of chronic colitis in T cell receptor (TCR)-α^−/− mice was explored by creating double mutant mice (TCR-α^−/− × immunoglobulin (Ig)μ^−/−), which lack B cells. TCR-α^−/− × Igμ^−/− mice spontaneously developed colitis at an earlier age, and the colitis was more severe than in TCR-α^−/− mice. Colitis was induced in recombination-activating gene-1 (RAG-1^−/−) mice by the transfer of mesenteric lymph node (MLN) cells from TCR-α^−/− × Igμ^−/− mice. When purified B cells from TCR-α^−/− mice were mixed with MLN cells before cell transfer, colitis did not develop in RAG-1^−/− mice. Administration of the purified Ig from TCR-α^−/− mice and a mixture of monoclonal autoAbs reactive with colonic epithelial cells led to attenuation of colitis in TCR-α^−/− × Igμ^−/− mice. Apoptotic cells were increased in the colon, MLN, and spleen of TCR-α^−/− × Igμ^−/− mice as compared to Igμ^−/− mice and TCR-α^−/− mice. Administration of the purified Ig from TCR-α^−/− mice into TCR-α^−/− × Igμ^−/− mice led to decrease in the number of apoptotic cells. These findings suggest that although B cells are not required for the initiation of colitis, B cells and Igs (autoAbs) can suppress colitis, presumably by affecting the clearance of apoptotic cells.     

Photocatalysis,photoinduced enhanced anti-bacterial functions and development of a selective m-tolyl hydrazine sensor based on mixed Ag·NiMn2O4 nanomaterials

In this work, a tri-metal based nanocomposite was synthesized and characterized. A detailed investigation of the photocatalytic dye degradation efficiency of the nanocomposite under visible light showed promising results in a wide pH range, both acidic and basic medium. Studies on anti-bacterial activity against seven pathogenic bacteria, including both Gram positive and Gram negative species, were conducted in the presence and absence of light and compared with the standard antibiotic gentamicin. The minimum inhibitory concentration (MIC) values of Ag·NiMn₂O₄ against multidrug-resistant (MDR) pathogens ranged from 0.008 to 0.65 μg μL⁻¹, while the minimum bactericidal concentration (MBC) was found to be 0.0016 μg μL⁻¹. The nanomaterial, Ag·NiMn₂O₄ was deposited onto the surface of a glassy carbon electrode (GCE; 0.0316 cm²) as a thin film to fabricate the chemical sensor probe. The proposed sensor showed linear current (vs. concentration) response to m-THyd (m-tolyl hydrazine) from 1.0 pM to 0.01 mM, which is denoted as the linear dynamic range (LDR). The estimated sensitivity and detection limit of the m-THyd sensor were found to be 47.275 μA μM⁻¹ cm⁻² and 0.97 ± 0.05 pM, respectively. As a potential sensor, it is reliable due to its good reproducibility, rapid response, higher sensitivity, working stability for long duration and efficiency in the analysis of real environmental samples.

Photocatalytic dye degradation efficiency of Ag·NiMn₂O₄ at pH 4 was 91%; at pH 9, 77% and 95% in presence of H₂O₂ and at pH 7, 50%. Assembled Ag·NiMn₂O₄ nanomaterials/binder/GCE, as m-THyd sensor showed considerable sensitivity, DL, LDR, response time, reproducibility etc.     

Chemical and biological studies on the soft coral Nephthea sp.

Soft corals belonging to the family Nephtheidae have been appreciated as marine sources of diverse metabolites with promising anticancer potential. In view of that, the current work investigates the anti-proliferative potential of the crude extract, different fractions, and green synthesized silver nanoparticles (AgNPs) of the Red Sea soft coral, Nephthea sp. against a panel of tumor cell lines. The metabolic pool of the soft coral under study was also explored via an LC-HR-ESI-MS metabolomics approach, followed by molecular docking analysis of the characterized metabolites against the target proteins, EGFR, VEGFR, and HER2 (erbB2) that are known to be involved in cancer cell proliferation, growth, and survival. Overall, the n-butanol fraction of Nephthea sp. exhibited the highest inhibitory activities against MCF7 (breast cancer) and A549 (lung cancer) cell lines, with interesting IC₅₀ values of 2.30 ± 0.07 and 3.12 ± 0.10 μg ml⁻¹, respectively, whereas the maximum growth inhibition of HL60 (leukemia) cells was recorded by the total extract (IC₅₀ = 2.78 ± 0.09 μg ml⁻¹). More interestingly, the anti-proliferative potential of the total soft coral extract was evidently improved when packaged in the form of biogenic AgNPs, particularly against A549 and MCF7 tumor cells, showing IC₅₀ values of 0.72 ± 0.06 and 9.32 ± 0.57 μg ml⁻¹, respectively. On the other hand, metabolic profiling of Nephthea sp. resulted in the annotation of structurally diverse terpenoids, some of which displayed considerable binding affinities and molecular interactions with the studied target proteins, suggesting their possible contribution to the anti-proliferative properties of Nephthea sp. via inhibition of tyrosine kinases, especially the EGFR type. Taken together, the present findings highlighted the relevance of Nephthea sp. to future anticancer drug discovery and provided a base for further work on the green synthesis of a range of bioactive NPs from marine soft corals.

The cytotoxic potential of the crude extract, different fractions, and green synthesized nanoparticles of the soft coral Nephthea sp. was studied, supported by LC-HR-ESI-MS metabolomics analysis and molecular docking of the dereplicated compounds.     

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.     

Binuclear and tetranuclear Zn(ii) complexes with thiosemicarbazones: synthesis,X-ray crystal structures,ATP-sensing,DNA-binding,phosphatase activity and theoretical calculations

Two Zinc(ii) complexes [Zn₄(L¹)₄]·2H₂O (1) and [Zn₂(L²)₂]·2H₂O (2) of pyruvaldehydethiosemicarbazone ligands are reported. The complexes were characterized by elemental analysis, IR, NMR, UV-vis spectroscopy and by single-crystal X-ray crystallography. X-ray crystal structure determinations of the complexes show that though Zn : ligand stoichiometry is 1 : 1 in both the complexes, the molecular unit is tetranuclear for 1 and binuclear for 2. Both the complexes show selective sensing of ATP at pH 7.4 (0.01 M HEPES) in CH₃CN–H₂O (9 : 1) medium in the presence of other anions like AcO⁻, NO₃⁻, F⁻, Cl⁻, H₂PO₄⁻, HPO₄²⁻ and P₂O₇²⁻. The UV-titration experiments of complexes 1 and 2 with ATP results in binding constants of 2.0(±0.07) × 10⁴ M⁻¹ and 7.1(±0.05) × 10³ M⁻¹ respectively. The calculated detection limits of 6.7 μM and 1.7 μM for 1 and 2 respectively suggest that the complexes are sensitive detectors of ATP. High selectivity of the complexes is confirmed by the addition of ATP in presence of an excess of other anions. DFT studies confirm that the ATP complexes are more favorable than those with the other inorganic phosphate anions, in agreement with the experimental results. Phosphatase like activity of both complexes is investigated spectrophotometrically using 4-nitrophenylphosphate (NPP) as a substrate, indicating the complexes possess significant phosphate ester hydrolytic efficiency. The kinetics for the hydrolysis of the substrate NPP was studied by the initial rate method at 25 °C. Michaelis–Menten derived kinetic parameters indicate that rate of hydrolysis of the P–O bond by complex 1 is much greater than that of complex 2, the k_cat values being 212(±5) and 38(±2) h⁻¹ respectively. The DNA binding studies of the complexes were investigated using electronic absorption spectroscopy and fluorescence quenching. The absorption spectral titrations of the complexes with DNA indicate that the CT-DNA binding affinity (K_b) of complex 1 (2.10(±0.07) × 10⁶ M⁻¹) is slightly greater than that of 2 (1.11(±0.04) × 10⁶ M⁻¹). From fluorescence spectra the apparent binding constant (K_app) values were calculated and they are found to be 5.41(±0.01) × 10⁵ M⁻¹ for 1 and 3.93(±0.02) × 10⁵ M⁻¹ for 2. The molecular dynamics simulation demonstrates that the Zn(ii) complex 1 is a good intercalator of DNA.

A binuclear and a tetranuclear zinc(ii) of pyruvaldehyde thiosemicarbazone show selective sensing of ATP at pH 7.4 (0.01 M HEPES) in CH₃CN–H₂O (9 : 1) medium. The DNA binding and phosphatase activities of the complexes are also reported.     

Chemical structure and biological properties of a polysaccharide isolated from Pleurotus sajor-caju

Herein, a polysaccharide obtained from Pleurotus sajor-caju was fractionated via anion-exchange column chromatography and purified using gel permeation column chromatography. The chemical characterization of the polysaccharide indicated that it contained 90.16% total carbohydrate, 0% protein, 12.7% ash and 5.2% moisture; on the other hand, the carbon, hydrogen and nitrogen contents were found to be 31.53, 4.28 and 3.01%, respectively. The polysaccharide has the molecular weight of 79 kDa; the chemical structure of the polysaccharide is →6)α-d-Glc^iv(1→6)α-d-Glcⁱⁱⁱ(1→6)β-d-Glcⁱⁱ(1→6)α-d-Glcⁱ(1→units. The polysaccharide exhibited the DPPH radical scavenging activity of 21.67–68.35% at 10–160 μg ml⁻¹, ABTS radical scavenging activity of 16.01–70.09% at 25–125 μg ml⁻¹, superoxide radical scavenging activity of 24.31–73.64% at 50–250 μg ml⁻¹, hydroxyl radical scavenging activity of 16.64–63.51% at 25–125 μg ml⁻¹ and reducing power of 0.366–1.678% at 10–120 μg ml; further evaluation of the polysaccharide revealed its anticancer activity of 18.61–63.21% at 100–500 μg ml⁻¹ concentration against the AGS human gastric carcinoma cell line. The active principle of the polysaccharide may be used in the food and pharmacological industry in the future.

Herein, a polysaccharide obtained from Pleurotus sajor-caju was fractionated via anion-exchange column chromatography and purified using gel permeation column chromatography.     

Simple,fast and environmentally friendly method to determine ciprofloxacin in wastewater samples based on an impedimetric immunosensor

In this study an impedimetric immunosensor was developed in order to determine ciprofloxacin (CIP) in wastewater samples, an emergent contaminant widely found in wastewater. To achieve this, an anti-ciprofloxacin antibody was immobilized on the surface of a printed carbon electrode. Then, the developed immunosensor was applied in wastewater samples from Université Laval residences (Québec, Canada) through the load transfer resistance (R_ct) using [Fe(CN)₆]^3−/4− as a redox probe, and the average CIP concentration was found to be 2.90 × 10⁻⁴ μg mL⁻¹. The observed R_ct changes presented a linear relationship from CIP concentrations of 10⁻⁵ to 1.0 μg mL⁻¹, with detection and quantification limits of 2.50 × 10⁻⁶ and 7.90 × 10⁻⁶ μg mL⁻¹, respectively. The immunosensor presented high selectivity and repeatability, as well as a good recovery rate in wastewater samples (97%). Significant interference with other compounds was not observed. The proposed method requires only 30 μL of sample without the use of organic solvents or preceding sample preparation and/or extraction techniques. Moreover, the method is fast: only 20 min of incubation followed by 2 min of analysis time was sufficient to obtain the CIP concentration. The method''s estimated cost is U$ 2.00 per sample.

In this study an impedimetric immunosensor was developed in order to determine ciprofloxacin (CIP) in wastewater samples, an emergent contaminant widely found in wastewater samples.