Synthesis, in vitro and in silico evaluation of gallamide and selenogallamide derivatives as inhibitors of the SARS-CoV-2 main protease.

The present work reports the inhibitory effect of amides derived from gallic acid (gallamides) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro), along with cytotoxicity evaluation and molecular docking studies. In addition to gallamides, other relevant compounds were also synthesized and evaluated against Mpro, making a total of 25 compounds. Eight compounds presented solubility issues during the inhibitory assay and one showed no inhibitory activity. Compounds 3a, 3b, and 3f showed the highest enzymatic inhibition with IC50 = 0.26 ± 0.19 µM, 0.80 ± 0.38 µM, and 2.87 ± 1.17 µM, respectively. Selenogallamide 6a exhibited IC50 values of 5.42 ± 2.89 µM and a comparison with its nonselenylated congener 3c shows that the insertion of the chalcogen moiety improved the inhibitory capacity of the compound by approximately 10 times. Regarding the cellular toxicity in THP-1 and Vero cells, compounds 3e and 3g, showed moderate cytotoxicity in Vero cells, while for THP-1 both were nontoxic, with CC50 > 150 µM. Derivative 3d showed moderate cytotoxicity against both cell lines, whereas 6d was moderatly toxic to THP-1. Other compounds analyzed do not induce substantial cellular toxicity at the concentrations tested. The molecular docking results for compounds 3a, 3b, and 3f show that hydrogen bonding interactions involving the hydroxyl groups (OH) of the gallate moiety are relevant, as well as the carbonyl group.

Highly Enantioselective Lewis Acid Catalyzed Conjugate Addition of Imidazo[1,2-a]pyridines to α,ß-Unsaturated 2-Acylimidazoles under Mild Conditions.

A highly enantioselective protocol for the conjugate addition of 2-arylimidazo[1,2-a]pyridines and other imidazo derivatives to α,ß-unsaturated 2-acylimidazoles is described. The method uses a previously reported chiral-at-metal rhodium catalyst and provides the corresponding adducts in yields of 25-98% with enantioselectivities up to er > 99:1. Additionally, the transformation proceeds under mild conditions using ethanol as the solvent at room temperature.

Inhibitory effects against SARSCoV-2 main protease (Mpro) of biflavonoids and benzophenones from the fruit of Platonia insignis.

The SARS-CoV-2 mutation and the limitation of the approved drug against COVID-19 are still a challenge in many country healthcare systems and need to be affronted despite the set of vaccines to prevent this viral infection. To contribute to the identification of new antiviral agents, the present study focused on natural products from an edible fruit with potential inhibitory effects against the SARS-CoV-2 main protease (Mpro). First, LC-ESIMS analysis of Platonia insignis fruits was performed and showed the presence of biflavonoids and benzophenones in the seed and pulp, respectively. Then, maceration and chromatographic purification led to the identification of two triglycerides (1 and 2) alongside chamaejasmine (3) and volkensiflavone (4) from the seed and isogarcinol (5) and cycloxanthochymol (6), from the pulp. Compounds 1-6 after evaluating their inhibitory against Mpro, displayed from no to significant activity. Compound 5 was the most potent with an IC50 value of 0.72 µM and was more active than the positive control, Ebselen (IC50 of 3.4 µM). It displayed weak and no cytotoxicity against THP-1 (CC50 of 116.2 µM) and Vero cell lines, respectively. Other active compounds showed no cytotoxicity against THP-1. and Vero cell lines. Molecular docking studies revealed interactions in the catalytic pocket between compound 5 and amino acid residues that composed the catalytic dyads (His 41 and Cyst 145).

Synthesis of the Brivaracetam Employing Asymmetric Photocatalysis and Continuous Flow Conditions.

An original total synthesis of the antiepileptic drug brivaracetam (BRV) is reported. The key step in the synthesis consists of an enantioselective photochemical Giese addition, promoted by visible-light and the chiral bifunctional photocatalyst Δ-RhS. Continuous flow conditions were employed to improve the efficiency and allow an easy scale-up of the enantioselective photochemical reaction step. The intermediate obtained from the photochemical step was converted into BRV by two different pathways, followed by one alkylation and amidation, thus giving the desired active pharmaceutical ingredients (API) in 44% overall yield, 9:1 diastereoisomeric ratio (dr) and >99:1 enantiomeric ratio (er).

Inhibitory effects of 190 compounds against SARS-CoV-2 Mpr o protein: Molecular docking interactions.

COVID-19 has caused many deaths since the first outbreak in 2019. The burden on healthcare systems around the world has been reduced by the success of vaccines. However, population adherence and the occurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants are still challenging tasks to be affronted. In addition, the newly approved drug presents some limitations in terms of side effects and drug interference, highlighting the importance of searching for new antiviral agents against SARS-CoV-2. The SARS-CoV-2 main protease (Mpr o ) represents a versatile target to search for new drug candidates due to its essential role in proteolytic activities responsible for the virus replication. In this work, a series of 190 compounds, composed of 27 natural ones and 163 synthetic compounds, were screened in vitro for their inhibitory effects against SARS-CoV-2 Mpro . Twenty-five compounds inhibited Mpro with inhibitory constant values (Ki ) between 23.2 and 241 µM. Among them, a thiosemicarbazone derivative was the most active compound. Molecular docking studies using Protein Data Bank ID 5RG1, 5RG2, and 5RG3 crystal structures of Mpro revealed important interactions identified as hydrophobic, hydrogen bonding and steric interactions with amino acid residues in the active site cavity. Overall, our findings indicate the described thiosemicarbazones as good candidates to be further explored to develop antiviral leads against SARS-CoV-2. Moreover, the studies showed the importance of careful evaluation of test results to detect and exclude false-positive findings.

Studies of Cytotoxicity Effects, SARS-CoV-2 Main Protease Inhibition, and in Silico Interactions of Synthetic Chalcones.

SARS-CoV-2 main protease (Mpro ) plays an essential role in proteolysis cleavage that promotes coronavirus replication. Thus, attenuating the activity of this enzyme represents a strategy to develop antiviral agents. We report inhibitory effects against Mpro of 40 synthetic chalcones, and cytotoxicity activities, hemolysis, and in silico interactions of active compounds. Seven of them bearing a (E)-3-(furan-2-yl)-1-arylprop-2-en-1-one skeleton (10, 28, and 35-39) showed enzyme inhibition with IC50 ranging from 13.76 and 36.13 µM. Except for 35 and 36, other active compounds were not cytotoxic up to 150 µM against THP-1 and Vero cell lines. Compounds 10, and 35-39 showed no hemolysis while 28 was weakly hemotoxic at 150 µM. Moreover, molecular docking showed interactions between compound 10 and Mpro (PDBID 5RG2 and 5RG3) with proximity to cys145 and His41, suggesting a covalent binding. Products of the reaction between chalcones and cyclohexanethiol indicated that this binding could be a Michael addition type.

Decarboxylative ring-opening of 2-oxazolidinones: a facile and modular synthesis of ß-chalcogen amines.

We report herein the synthesis of primary and secondary ß-chalcogen amines through the regioselective ring-opening reaction of non-activated 2-oxazolidinones promoted by in situ generated chalcogenolate anions. The developed one-step protocol enabled the preparation of ß-selenoamines, ß-telluroamines and ß-thioamines with appreciable structural diversity and in yields of up to 95%.

An Adaptive Mapping Method Using Spectral Envelope Approach for DNA Spectral Analysis.

The digital signal processing approaches were investigated as a preliminary indicator for discriminating between the protein coding and non-coding regions of DNA. This is because a three-base periodicity (TBP) has already been proven to exist in protein-coding regions arising from the length of codons (three nucleic acids). This demonstrates that there is a prominent peak in the energy spectrum of a DNA coding sequence at frequency 13 rad/sample. However, because DNA sequences are symbolic sequences, these should be mapped into one or more signals such that the hidden information is highlighted. We propose, therefore, two new algorithms for computing adaptive mappings and, by using them, finding periodicities. Both such algorithms are based on the spectral envelope approach. This adaptive approach is essentially important since a single mapping for any DNA sequence may ignore its intrinsic properties. Finally, the improved performance of the new methods is verified by using them with synthetic and real DNA sequences as compared to the classical methods, especially the minimum entropy mapping (MEM) spectrum, which is also an adaptive method. We demonstrated that our method is both more accurate and more responsive than all its counterparts. This is especially important in this application since it reduces the risks of a coding sequence being missed.

Natural Products with Tandem Anti-inflammatory, Immunomodulatory and Anti-SARS-CoV/2 Effects: A Drug Discovery Perspective against SARS-CoV-2.

BACKGROUND: COVID-19 is still causing long-term health consequences, mass deaths, and collapsing healthcare systems around the world. There are no efficient drugs for its treatment. However, previous studies revealed that SARS-CoV-2 and SARS-CoV have 96% and 86.5% similarities in cysteine proteases (3CLpro) and papain-like protease (PLpro) sequences, respectively. This resemblance could be important in the search for drug candidates with antiviral effects against SARS-CoV-2. OBJECTIVE: This paper is a compilation of natural products that inhibit SARS-CoV 3CLpro and PLpro and, concomitantly, reduce inflammation and/or modulate the immune system as a perspective strategy for COVID-19 drug discovery. It also presents in silico studies performed on these selected natural products using SARS-CoV-2 3CLpro and PLpro as targets to propose a list of hit compounds. METHODS: The plant metabolites were selected in the literature based on their biological activities on SARS-CoV proteins, inflammatory mediators, and immune response. The consensus docking analysis was performed using four different packages. RESULTS: Seventy-nine compounds reported in the literature with inhibitory effects on SARS-CoV proteins were reported as anti-inflammatory agents. Fourteen of them showed immunomodulatory effects in previous studies. Five and six of these compounds showed significant in silico consensus as drug candidates that can inhibit PLpro and 3CLpro, respectively. Our findings corroborated recent results reported on anti-SARS-CoV-2 in the literature. CONCLUSION: This study revealed that amentoflavone, rubranoside B, savinin, psoralidin, hirsutenone, and papyriflavonol A are good drug candidates for the search of antibiotics against COVID-19.

Efficacy of Phytopharmaceuticals From the Amazonian Plant Libidibia ferrea for Wound Healing in Dogs.

We comparatively evaluate two distinct formulations containing 5% of Jucá (Libidibia ferrea) for wound healing in dogs. An excision model study was performed in 11 dogs with three dermal wounds in each animal, which were treated with: (1) topical phytopharmaceutical based on Carbopol (PyC) containing 5% Jucá ethanolic extract; (2) topical phytopharmaceutical based on Astrocaryum murumuru butter (PyM) containing 5% Jucá ethanolic extract; and (3) commercial ointment (control). Wound treatment was carried out on alternated days starting at day (D) one until D21. Macroscopic (all time-points) and histological (D0 and D21) analyses were performed. The antimicrobial activity of Jucá was evaluated through Minimal Inhibitory Concentration (MIC). Phytochemical analysis of Jucá revealed 3.1% phenolic compound content expressed in rutin and the presence of hydrolyzable tannins and flavonoids. The mean wound retraction was 33.7 ± 5.5, 34.0 ± 4.7, and 28.4 ± 4.9 % for PyC, PyM, and control groups, respectively, with higher wound retraction for both herbal-treated groups compared to the control (P < 0.05). Alcoholic extract of Jucá had antimicrobial activity against the microorganisms Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Candida krusei at different degrees, with MIC ranging from 250 to 16.625 µg/ml. Microscopic evaluation showed that the phytotherapic formulations contributed to better dermal wound healing through wound fibroplasia. The alcoholic extract of Jucá pods has great potential for wound healing in dogs and can be used in the development of commercially viable phytotherapic formulations.

Exploiting nonlinearity of the speech production system for voice disorder assessment by recurrence quantification analysis.

This work summarizes the research related to digital speech signal processing with recurrence quantification analysis (RQA) applied to voice disorder assessment. The main motivation for these studies is the fact that RQA is able to exploit the nonlinear dynamical nature of the speech production system. Due to the use of recurrence quantification measures to represent the behavior of speech signals, promising results were obtained in the characterization and classification of laryngeal pathologies and voice disorders. These contributions may help one to evaluate the usability and efficiency of RQA in vocal disorder assessment.

Visible-Light-Activated Catalytic Enantioselective ß-Alkylation of α,ß-Unsaturated 2-Acyl Imidazoles Using Hantzsch Esters as Radical Reservoirs.

An efficient and practical method for the enantioselective ß-functionalization of α,ß-unsaturated 2-acyl imidazoles is described. The method uses a previously devised chiral-at-metal rhodium catalyst (Λ-RhS, 4 mol %) along with Hantzsch ester derivatives as alkyl radical sources. The rhodium complex exerts a dual role as the visible-light-absorbing unit upon substrate binding and as the asymmetric catalyst. The method provides up to quantitative yields with excellent enantioselectivities up to 98% ee and can be classified as a redox-neutral, electron-transfer-catalyzed reaction.

Auditory Stimuli Coding by Postsynaptic Potential and Local Field Potential Features.

The relation between physical stimuli and neurophysiological responses, such as action potentials (spikes) and Local Field Potentials (LFP), has recently been experimented in order to explain how neurons encode auditory information. However, none of these experiments presented analyses with postsynaptic potentials (PSPs). In the present study, we have estimated information values between auditory stimuli and amplitudes/latencies of PSPs and LFPs in anesthetized rats in vivo. To obtain these values, a new method of information estimation was used. This method produced more accurate estimates than those obtained by using the traditional binning method; a fact that was corroborated by simulated data. The traditional binning method could not certainly impart such accuracy even when adjusted by quadratic extrapolation. We found that the information obtained from LFP amplitude variation was significantly greater than the information obtained from PSP amplitude variation. This confirms the fact that LFP reflects the action of many PSPs. Results have shown that the auditory cortex codes more information of stimuli frequency with slow oscillations in groups of neurons than it does with slow oscillations in neurons separately.

NIR bacteriochlorin chromophores accessed by Heck and Sonogashira cross-coupling reactions on a tetrabromobacteriochlorin derivative.

The synthesis of a new tetrabromobacteriochlorin BCBr4 is reported having the 3,4-dibromo-1H-pyrrole-2-carbaldehyde (10) as the major precursor. The BCBr4 was successfully employed in Pd cross-coupling reactions with methyl acrylate, phenyl acetylene and 4-ethynylanisole. In all three cases, the desired tetra-coupled products were obtained in good to excellent yields, and present a significant red shift in the UV-Vis bands above 800 nm. DFT and TD-DFT theoretical analyses of the NIR bacteriochlorin chromophores were performed in order to evaluate the effect of ß substitution on their electronic structures.

Co-Deposition of Gold Nanoparticles and Metalloporphyrin Using the Langmuir-Blodgett (LB) Technique for Surface-Enhanced Raman Scattering (SERS).

The synergistic effect produced by metallic nanoparticles when incorporated into different systems empowers a research field that is growing rapidly. In addition, organometallic materials are at the center of intensive research with diverse applications such as light-emitting devices, transistors, solar cells, and sensors. The Langmuir-Blodgett (LB) technique has proven to be suitable to address challenges inherent to organic devices, since the film properties can be tuned at the molecular level. Here we report a strategy to incorporate gold nanoparticles (AuNPs) into the LB film by co-deposition in order to achieve surface-enhanced Raman scattering (SERS) of the zinc(II)-protoporphyrin (IX) dimethyl ester (ZnPPIX-DME). Prior to the LB co-deposition, the properties of the Langmuir monolayer of ZnPPIX-DME at the air-water interface, containing AuNPs in the subphase, are studied through the surface-pressure versus mean molecular area (π-A) isotherms. The ZnPPIX-DME+AuNPs π-A isotherm presented a significant shift to higher molecular area, suggesting an interaction between both ZnPPIX-DME molecules and AuNPs. Those interactions are a key factor allowing the co-deposition of both AuNPs and ZnPPIX-DME molecules onto a solid substrate, thus forming the LB film. SERS of ZnPPIX-DME was successfully attained, ensuring the spatial distribution of the AuNPs. Higher enhancement factors were found at AuNP aggregates, as a result of the intense local electromagnetic field found in the metal nanoparticle aggregates. The main vibrational bands observed in the SERS spectra suggest a physical adsorption of the ZnPPIX-DME onto the surface of AuNPs. The latter is not only in agreement with the interactions pointed out by the π-A isotherms but also suggests that this interaction is kept upon LB film co-deposition.

Unsymmetrical 1,5-diaryl-3-oxo-1,4-pentadienyls and their evaluation as antiparasitic agents.

In this work the synthesis and antiparasitical activity of new 1,5-diaryl-3-oxo-1,4-pentadienyl derivatives are described. First, compounds 1a, 1b, 1c and 1d were prepared by acid-catalyzed aldol reaction between 2-butanone and benzaldehyde, anisaldehyde, p-N,N-dimethylaminobenzaldehyde and p-nitrobenzaldehyde. Reacting each of the methyl ketones 1a, 1b, 1c and 1d with the p-substituted benzaldehydes under basic-catalyzed aldol reaction, we further prepared compounds 2a-2p. All twenty compounds were evaluated for antiproliferative activity, particularly for promastigote of Leishmania amazonensis and epimastigote of Trypanosoma cruzi. All compounds showed good activity while nitro compounds 2i and 2k showed inhibition activity at a few µM.

Extended regimens of the contraceptive vaginal ring: evaluation of clinical aspects.

BACKGROUND: Oral contraceptives used for extended periods of time have been extensively studied because of their potential benefits; however, there have been few publications on extended regimens of vaginal contraceptive rings. The aim of this study was to evaluate the clinical symptoms, body weight and blood pressure changes in women using the vaginal ring continuously over a 1-year period. STUDY DESIGN: This prospective cohort evaluated clinical aspects (dysmenorrhea, headache, breast tenderness, leg pain and irritability), body weight and blood pressure changes in 75 women (18-37 years of age) using a vaginal ring releasing 120 mcg of etonogestrel and 15 mcg of ethinyl estradiol daily, over a continuous period of 84 days, followed by a 7-day ring-free interval, during 1 year. The chi-square, Wilcoxon and paired t tests were used to analyze differences in the outcomes of interest. RESULTS: Compared to pre-enrollment status, at the end of the study period, the patients reported significantly less dysmenorrhea and irritability, a nonsignificant decrease in breast tenderness, leg pain and headaches. Blood pressure measurements remained unchanged. Although weight and body mass index increased significantly among users, they remained within the expected biological variation range. CONCLUSION: The vaginal ring used on an extended regimen is a well-tolerated contraceptive method and also offers noncontraceptive benefits.

MRI segmentation using dialectical optimization.

Biology, Psychology and Social Sciences are intrinsically connected to the very roots of the development of algorithms and methods in Computational Intelligence, as it is easily seen in approaches like genetic algorithms, evolutionary programming and particle swarm optimization. In this work we propose a new optimization method based on dialectics using fuzzy membership functions to model the influence of interactions between integrating poles in the status of each pole. Poles are the basic units composing dialectical systems. In order to validate our proposal we designed a segmentation method based on the optimization of k-means using dialectics for the segmentation of MR images. As a case study we used 181 MR synthetic multispectral images composed by proton density, T(1)- and T(2)-weighted synthetic brain images of 181 slices with 1 mm, resolution of 1 mm(3), for a normal brain and a noiseless MR tomographic system without field inhomogeneities, amounting a total of 543 images, generated by the simulator BrainWeb [2]. Our principal target here is comparing our proposal to k-means, fuzzy c-means, and Kohonen's self-organized maps, concerning the quantization error, we proved that our method can improved results obtained using k-means.

Synthesis of phthalocyanines-ALA conjugates: water-soluble compounds with low aggregation.

Syntheses of two water-soluble phthalocyanines (Pc) containing 5-aminolevulinic acid (ALA) linked to the core structure are described. These compounds were prepared by using original functionalizations, and they present remarkable structural and photophysical features, indicating that they could be applied to photodynamic therapy (PDT).

Hepatitis C is less aggressive in hemodialysis patients than in nonuremic patients.

BACKGROUND AND OBJECTIVES: The severity of liver disease among hepatitis C patients on hemodialysis is controversial. The aim of this study was to compare the clinical, biochemical, and liver histologic characteristics of hepatitis C virus (HCV) in hemodialysis patients and in those with normal renal function. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A case-control study was carried out with 36 HCV patients on hemodialysis and 37 HCV patients with normal renal function matched for gender, age at infection, and estimated time of infection. RESULTS: HCV patients on hemodialysis had lower levels of alanine aminotransferase and lower viral load. Hepatic fibrosis was significantly higher in the patients with normal renal function (73%) than in hemodialysis patients (47.2%, P < 0.025); the same was observed for inflammatory activity (control group 59.5% versus hemodialysis patients 27.7%, P = 0.003). In addition, the risk of tissue inflammation was four times lower in hemodialysis patients (odds ratio = 0.23, P < 0.004), and severe inflammatory activity on biopsy was the only independent risk factor for fibrosis (P < 0.001). CONCLUSIONS: The lower biochemical and inflammatory activities observed in hemodialysis patients suggest that hemodialysis and uremia may have a protective role against progression of the disease caused by HCV.