Proposal of novel natural inhibitors of severe acute respiratory syndrome coronavirus 2 main protease: Molecular docking and ab initio fragment molecular orbital calculations.

This paper proposes natural drug candidate compounds for the treatment of coronavirus disease 2019 (COVID-19). We investigated the binding properties between the compounds in the Moringa oleifera plant and the main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 using molecular docking and ab initio fragment molecular orbital calculations. Among the 12 compounds, niaziminin was found to bind the strongest to Mpro. We furthermore proposed novel compounds based on niaziminin and investigated their binding properties to Mpro. The results reveal that the introduction of a hydroxyl group into niaziminin enhances its binding affinity to Mpro. These niaziminin derivatives can be promising candidate drugs for the treatment of COVID-19.

Brassinin, a brassica-derived phytochemical, regulates monocyte-to-macrophage differentiation and inflammatory responses in human monocytes and murine macrophages.

OBJECTIVES: The effects and molecular mechanisms of brassinin (BR), an indole phytoalexin from cruciferous vegetables, on monocyte-to-macrophage differentiation and inflammatory responses were investigated in this study. METHODS: Inflammatory responses from RAW264.7 cells and THP-1 were stimulated by lipopolysaccharide (1 µg/ml), and monocyte-to-macrophage differentiation of THP-1 was induced by phorbol myristate acetate (50 ng/ml). The production of inflammatory mediators was determined by ELISA, Western blot or real-time PCR. Reactive oxygen species were examined by DCFH-DA assay. KEY FINDINGS: Brassinin at 50 µm suppressed lipopolysaccharide-induced production of nitric oxide synthase, cyclooxygenase-2, prostaglandin E2 and reactive oxygen species by 90%, 69%, 52% and 41%, respectively, in RAW264.7 cells. In THP-1 cells, BR inhibited phorbol myristate acetate-induced monocyte-to-macrophage differentiation by suppressing cluster of differentiation molecule ß and CD36. In addition, BR suppressed translocation of nuclear factor 'kappa-light-chain-enhancer' of activated B cells (NF-κB) into the nucleus. However, BR activated the nuclear factor erythroid-derived 2-like 2 (Nrf2) and its target molecules hemoxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1), with an increase in nuclear translocation of Nrf2. CONCLUSIONS: Brassinin suppressed monocyte-to-macrophage differentiation and inflammatory responses by differentially regulating Nrf2 and NF-κB signallings.

Determination of Carbamates and Thiocarbamates in Water, Soil and Sediment of the Formoso River, TO, Brazil.

Considering the increase in agricultural production in Brazil, the use of pesticides for this production, and that there are no studies on pesticides in the region, the presence of carbamates and thiocarbamates was investigated in different environmental compartments of the Formoso River, TO, Brazil, by UHPLC/MS/MS. The collections were made on the banks of this river, in the area of influence of the agricultural project. The active principles were not found in the soil and sediment samples, only the propoxur principle was found in the water, reaching values of up to 0.025 µg L-1 . It was found that the biodiversity of the Tocantinense savannah is under threat, because even though only one of the substances surveyed, propoxur and its derivatives, has been detected, they are substances of high toxicity and tendency to contaminate surface and groundwater to varying degrees and irreversible damage to different species.

Potential Angiotensin Converting Enzyme Inhibitors from Moringa oleifera.

BACKGROUND: Hypertension is the chronic medical condition and it affected billions of people worldwide. Natural medicines are the main alternatives to treatment for a majority of people suffering from hypertension. Niazicin-A, Niazimin-A, and Niaziminin-B compounds from Moringa oleifera ethanolic leave extract were reported to have potent antihypertensive activity. OBJECTIVE: These compounds were targeted with Angiotensin-converting enzyme [ACE] which is one of the main regulatory enzymes of the renin-angiotensin system. METHODS: Protein-ligand docking of these compounds with [ACE] [both domain N and C] was conceded out through Autodock vina and visualization was done by chimera. Pharmacokinetics study of these compounds was predicted by ADME-Toxicity Prediction. RESULTS: Niazicin-A, Niazimin-A, and Niaziminin-B showed high binding affinity with ACE and partially blocked the active sites of the enzyme. Niazicin-A, Niazimin-A and Niaziminin-B showed the estimated free binding energy of -7.6kcal/mol kcal/mol, -8.8kcal/mol and -8.0kcal/mol respectively with C-domain of ACE and -7.9kcal/mol, -8.5kcal/mol and -7.7kcal/mol respectively with N-domain of ACE. The compounds showed better binding energy with angiotensinconverting enzyme in comparison to Captopril -5.5kcal/mol and -5.6kcal/mol and Enalapril [standard] -8.4kcal/mol and -7.5kcal/mol with C and N domain, respectively. CONCLUSION: Computationally, the selected bioactive molecules have shown better binding energy to known standard drugs which have been already known for inhibition of ACE and can further act as a pharmacophore for in vitro and in vivo studies in the development of alternative medicine.

Inhibition of the ß-carbonic anhydrase from the dandruff-producing fungus Malassezia globosa with monothiocarbamates.

A series of monothiocarbamates (MTCs) was investigated for the inhibition of the ß-class carbonic anhydrase (CAs, EC 4.2.1.1) from the fungal parasite Malassezia globosa, MgCA. These MTCs incorporate various scaffolds, among which aliphatic amine with 1-4 carbons atom in their molecule, morpholine, piperazine, as well as phenethylamine and benzylamine derivatives. All the reported MTCs displayed a better efficacy in inhibiting MgCA compared to the clinically used sulphonamide drug acetazolamide (KI of 74 µM), with KIs spanning between 1.85 and 18.9 µM. The homology model of the enzyme previously reported by us was used to rationalize the results by docking some of these MTCs within the fungal CA active site. This study might be useful to enrich the knowledge of the MgCA inhibition profile, eliciting novel ideas pertaining the design of modulators with potential efficacy in combatting dandruff or other fungal infections.

Design of polymer-brush-grafted magnetic nanoparticles for highly efficient water remediation.

Highly efficient removal of mercury(II) ions (Hg(II)) from water has been reported by employing polymer-brush-functionalized magnetic nanoparticles (MNPs). Surface-initiated conventional radical polymerization (SI-cRP) was used to grow poly(2-aminoethyl methacrylate hydrochloride) (poly-AEMA·HCl) polymer chains on magnetite nanoparticles (Fe3O4), followed by the transformation of pendant amino groups into dithiocarbamate (DTC) groups, which showed high chelating affinity toward Hg(II) ions. This polymer-brush-based DTC-functionalized MNP (MNPs-polyAEMA·DTC) platform showed the complete removal of Hg(II) from aqueous solutions. The Hg(II) ion removal capacity and efficiency of MNPs-polyAEMA·DTC were compared with its monolayer analogue, which was derived from the direct transformation of amino groups of (3-aminopropyl) triethoxysilane (APTES)-functionalized MNPs (MNPs-APTES) to DTC functional groups (MNPs-DTC). The surface chemical modifications and higher chelating functional group density, in the case of MNPs-polyAEMA·DTC, were ascertained by transmission electron microscopy (TEM), thermogravimetric analysis (TGA), physical property measurement system (PPMS), attenuated total reflectance infrared (ATR-IR) spectroscopy, and X-ray photoelectron spectroscopy (XPS). The Hg(II) ion removal capacity and efficiency of monolayer and polymer-brush-based DTC-functionalized MNPs (MNPs-DTC and MNPs-polyAEMA·DTC, respectively) were evaluated and compared by studying the effect of various factors on the percentage removal of Hg(II) such as adsorbent amount, temperature, and contact time. Furthermore, the adsorption behavior of MNPs-DTC and MNPs-polyAEMA·DTC was analyzed by applying Langmuir and Freundlich adsorption isotherm models. In addition, the adsorption thermodynamics, as well as the adsorption kinetics, were also evaluated in detail. The higher surface functional group density of MNPs-polyAEMA·DTC led to superior remediation characteristics toward Hg(II) ions than its monolayer analogue.

Insights into the failure of the potential, neutral myocardial imaging agent TcN-NOET: physicochemical identification of by-products and degradation species.

INTRODUCTION: The neutral complex [(99m)Tc(N)(NOEt)(2)], often referred to as TcN-NOET [NOEt=N-ethoxy,N-ethyldithiocarbamate(1-)], was proposed several years ago as a myocardial imaging agent. Despite some favorable clinical properties evidenced during phase I and phase II studies, the overall results of the European and American phase III clinical studies have been judged insufficient for a successful approval process by the regulatory agencies. METHODS: Non-carrier-added and carrier-added experiments using short-lived (99m)Tc and long-lived (99g)Tc have been utilized to prepare a series of bis-substituted [Tc(N)(DTC)(2)] complexes [DTC=dithiocarbamate(1-)]. They have been purified by means of chromatographic techniques (high-performance liquid chromatography and thin-layer chromatography) and identified via double detection (UV-vis and radiometry) by comparison with authenticated samples of (99g)Tc compounds prepared by conventional coordination chemistry procedures. RESULTS: The molecular structure of the lipophilic, neutral complex cis-[Tc(N)(NOEt)(2)] has been assigned by comparison with similar nitrido-Tc(V) complexes already reported in the literature. Novel bis-substituted nitrido-Tc complexes containing hydrolyzed portions of coordinated NOEt, namely, N-ethyldithiocarbamate [NHEt(1-)] and N-hydroxy, N-ethyldithiocarbamate [NOHEt(1-)], have been prepared and characterized by means of multinuclear nuclear magnetic resonance spectroscopy and mass spectrometry. CONCLUSIONS: Despite the identification of these "hydrolyzed" species, it is still unclear whether the failure to reach the clinical goal of the perfusion tracer [(99m)Tc(N)(NOEt)(2)] is related to the degradation processes evidenced in this study or is the result of the mediocre imaging properties of the tracer.

Cytotoxic thiocarbamate derivatives of boldine.

Two new boldine derivatives: the 3-thiocarbamateboldine (3) and the 2,9-O,O-diacetyl-3-thiocarbamateboldine (4) have been synthesized and their cytotoxicity evaluated.

Acid modified diatomaceous earth--a sorbent material for thin layer chromatography.

Natural diatomaceous earth (DE) is modified by flux calcination and refluxing with acid. To characterize natural DE, modified DE's [flux calcinated (FC)DE and FCDE-I] and silica gel 60GF(254) (Si-60GF(254)) are analyzed microscopically, physically, and chemically by various techniques. FCDE-I and Si-60GF(254) are investigated for their usefulness in the stationary phase of thin layer chromatography (TLC) both individually and in composition. Sodium diethyldithiocarbamate (DEDTC) and ammonium pyrrolidinedithiocarbamate (PyDTC) are prepared as Co or Cu (M) complexes [M(DEDTC)(2) and M(PyDTC)(2), respectively]. These complexes and their mixtures are run on thin layers of Si-60GF(254) and FCDE-I individually, and on various FCDE-I and Si-60GF(254) mixtures. Pure toluene and various toluene-cyclohexane mixtures (3:1, 1:1, 1:2, 1:3, v/v) are used as mobile phases for the running the complexes. The best analytical separations of both M(DEDTC)(2) and M(PyDTC)(2) complexes are obtained when using pure toluene and toluene-cyclohexane (3:1, 1:1, v/v) as mobile phases on FCDE-I-Si-60GF(254) (1:3, 1:1, w/w) layers as stationary phases. This study shows that it is possible to qualitatively analyze and to satisfactorily separate a mixture Cu(2+) and Co(2+) cations on cited chromatographic systems.

Preliminary feasibility study for the use of an adsorption/bio-regeneration system for molinate removal from effluents.

This work studies the feasibility of the use of a combined physical-biological remediation procedure for treatment of effluents contaminated with molinate, where the herbicide is removed through adsorption and biodegraded in a subsequent stage, with the regeneration of the adsorbent. In order to select the most adequate absorbent for molinate, different materials were tested, namely pine bark, activated carbon and resin Amberlite XAD-4. Activated carbon and resin Amberlite XAD-4 were the most efficient on the removal of molinate from solutions, although the activated carbon used proved not to be bio-regenerable. It was also observed that factors such as temperature, pH, and conductivity did not affect significantly molinate adsorption onto resin Amberlite XAD-4. Resin Amberlite XAD-4 was successfully bio-regenerated, being observed that biodegradation was mainly dependent on spontaneous desorption of the molinate. After bio-regeneration, the resin could be re-utilised as adsorbent.

Tryptophan-derived sulfur-containing phytoalexins--a general overview.

Phytoalexins are low molecular weight antimicrobial compounds that are synthesized and accumulated in plants after their exposure to pathogenic microorganisms (bacteria, fungi, viruses and protozoans). They are extensively studied now as promising antifungal, potentially anticancer and plant diseases controlling agents. The article pertains to a group of indole-derived phytoalexins--brassinins, containing at least one sulfur atom in the side chain or in the ring(s), isolated from the cruciferous plants. Up today more than 20 compounds, closely related biogenetically, but exhibiting diversified biological activity have been identified. The survey summerises most promising recent results pertaining practical application of brassinins and camalexins.

Niaziminin, a thiocarbamate from the leaves of Moringa oleifera, holds a strict structural requirement for inhibition of tumor-promoter-induced Epstein-Barr virus activation.

Three known thiocarbamate (TC)- and isothiocyanate (ITC)-related compounds have been isolated from the leaves of Moringa oleifera, a traditional herb in southeast Asia, as inhibitors of tumor promoter teleocidin B-4-induced Epstein-Barr virus (EBV) activation in Raji cells. Interestingly, only niaziminin among 10 TCs including 8 synthetic ones showed considerable inhibition against EBV activation. The structure-activity relationships indicated that the presence of an acetoxy group at the 4'-position of niaziminin is important and indispensable for inhibition. On the other hand, among the ITC-related compounds, naturally occurring 4-[(4'-O-acetyl-alpha-L-rhamnosyloxy)benzyl]ITC and commercially available allyl- and benzyl-ITC significantly inhibited activation, suggesting that the isothiocyano group is a critical structural factor for activity.

Identification and quantification of the N-acetylcysteine conjugate of allyl isothiocyanate in human urine after ingestion of mustard.

Allyl isothiocyanate (AITC) is a constituent of cruciferous vegetables. It occurs widely in the human diet as a natural ingredient or food additive. AITC possesses numerous biochemical and physiological activities. It is cytotoxic and tumorigenic at high doses and also is a modulator of enzymes involved in metabolism of xenobiotics, including carcinogens. It is plausible that the wide consumption of dietary AITC may have profound effects on human health. To facilitate investigations of the effects of dietary AITC in humans, a method of measuring its uptake is needed. In this study, a urinary marker was developed for quantifying AITC uptake in humans. Four adult volunteers were asked to eat a meal containing brown mustard as the source of AITC. The 48-h urine samples were collected from these individuals and analyzed by reverse phase high performance liquid chromatography. A major urinary metabolite was found, which was identified as N-acetyl-S-(N-allylthiocarbamoyl)-L-cysteine, the N-acetylcysteine conjugate of AITC, by comparing its retention time and UV, nuclear magnetic resonance, and mass spectra with those of the synthetic standard. After ingestion of mustard, the AITC conjugate was detected in urine collected from 0 to 12 h. No conjugate was found in urine samples collected after 12 h. The major portion of this metabolite was excreted within 8 h. The average total excretion of AITC conjugate was 5.4 +/- 1.7 (SD) mg after consumption of 10 g of mustard and 12.8 +/- 2.0 mg when 20 g of mustard was consumed. Thus, a dose-dependent excretion of this metabolite was demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)