Development of novel montmorillonite-based sustained release system for oral bromopride delivery.

The drug delivery systems are an important strategy of pharmaceutical technology to modulate undesirable properties, increasing efficacy, and reducing the side effects of active pharmaceutical ingredients (API). The sustained release is a type of controlled-release system that provides a suitable drug level in the blood through a slow release rate. An interesting alternative to achieve a controlled release is the application of carrier materials such as polymers, cyclodextrins, and clays. Sodium montmorillonite (Na-MMT) is a biocompatible natural clay that allows the insertion of organic compounds in interlamellar space, owing to its high cation exchange capacity and large internal surface area. Bromopride (BPD) is an aminated compound with antiemetic properties classified as class II (low solubility, high permeability) of the Biopharmaceutical Classification System (BCS). Herein, the aim of the study was the development and investigation of a drug delivery system formed by intercalation of BPD with Na-MMT. The results indicate the successful intercalation of this API with the lamellar silicate, meanwhile, there was no evidence of BPD intercalation in organic montmorillonite. The Na-MMT/BPD molecular complex exhibits a sustained release in performed assays. Molecular dynamics simulations suggested that BPD molecules interact with the montmorillonite layer through ion-dipole interactions and also between BPD molecules, forming hydrogen bonds web into montmorillonite interlayer space. The new drug delivery system showed an alternative to achieve the BPD sustained release, which may improve its pharmacological performance in therapeutic applications.

Using in vivo animal models for studying SARS-CoV-2.

INTRODUCTION: The search for an animal model capable of reproducing the physiopathology of the COVID-19, and also suitable for evaluating the efficacy and safety of new drugs has become a challenge for many researchers. AREAS COVERED: This work reviews the current animal models for in vivo tests with SARS-CoV-2 as well as the challenges involved in the safety and efficacy trials. EXPERT OPINION: Studies have reported the use of nonhuman primates, ferrets, mice, Syrian hamsters, lagomorphs, mink, and zebrafish in experiments that aimed to understand the course of COVID-19 or test vaccines and other drugs. In contrast, the assays with animal hyperimmune sera have only been used in in vitro assays. Finding an animal that faithfully reproduces all the characteristics of the disease in humans is difficult. Some models may be more complex to work with, such as monkeys, or require genetic manipulation so that they can express the human ACE2 receptor, as in the case of mice. Although some models are more promising, possibly the use of more than one animal model represents the best scenario. Therefore, further studies are needed to establish an ideal animal model to help in the development of other treatment strategies besides vaccines.

Ethylhexyl methoxycinnamate and butyl methoxydibenzoylmethane: Toxicological effects on marine biota and human concerns.

Ethylhexyl methoxycinnamate (EHMC) (CAS number: 5466-77-3) and butyl methoxydibenzoylmethane (BMDM) (CAS number: 70356-09-1) are important sunscreens. However, frequent application of large amounts of these compounds may reflect serious environmental impact, once it enters the environment through indirect release via wastewater treatment or immediate release during water activities. In this article, we reviewed the toxicological effects of EHMC and BMDM on aquatic ecosystems and the human consequences. According to the literature, EHMC and BMDM have been detected in water samples and sediments worldwide. Consequently, these compounds are also present in several marine organisms like fish, invertebrates, coral reefs, marine mammals, and other species, due to its bioaccumulation potential. Studies show that these chemicals are capable of damaging the aquatic beings in different ways. Further, bioaccumulation studies have shown that EHMC biomagnifies through trophic levels, which makes human seafood consumption a concern because the higher position in the trophic chain, the more elevate levels of ultraviolet (UV) filters are detected, and it is established that EHMC present adverse effects on the human organism. In contrast, there are no studies on the BMDM bioaccumulation and biomagnification potential. Different strategies can be adopted to avoid the damage caused by sunscreens in the environment and human organism. Two of them include the use of natural photoprotectors, such as polyphenols, in association with UV filters in sunscreens and the development of new and safer UV filters. Overall, this review shows the importance of studying the impacts of sunscreens in nature and developing safer sunscreens and formulations to safeguard marine fauna, ecosystems, and humans.

Facing Racism and Sexism in Science by Fighting Against Social Implicit Bias: A Latina and Black Woman's Perspective.

The editors of several major journals have recently asserted the importance of combating racism and sexism in science. This is especially relevant now, as the COVID-19 pandemic may have led to a widening of the gender and racial/ethnicity gaps. Implicit bias is a crucial component in this fight. Negative stereotypes that are socially constructed in a given culture are frequently associated with implicit bias (which is unconscious or not perceived). In the present article, we point to scientific evidence that shows the presence of implicit bias in the academic community, contributing to strongly damaging unconscious evaluations and judgments of individuals or groups. Additionally, we suggest several actions aimed at (1) editors and reviewers of scientific journals (2) people in positions of power within funding agencies and research institutions, and (3) members of selection committees to mitigate this effect. These recommendations are based on the experience of a group of Latinx American scientists comprising Black and Latina women, teachers, and undergraduate students who participate in women in science working group at universities in the state of Rio de Janeiro, Brazil. With this article, we hope to contribute to reflections, actions, and the development of institutional policies that enable and consolidate diversity in science and reduce disparities based on gender and race/ethnicity.

Biotechnological Potential of Eugenol and Thymol Derivatives Against Staphylococcus aureus from Bovine Mastitis.

Bovine mastitis is an infectious disease that affects the mammary gland of dairy cattle with considerable economic losses. Staphylococcus aureus is the main microorganism involved in this highly contagious process, and the treatment is only using antibiotics. Currently, the search for new treatment and/or compounds is still in need due to microbial resistance. In this work, we evaluated the potential of eugenol and thymol derivatives against S. aureus strains from bovine mastitis. On that purpose, nine derivatives were synthesized from eugenol and thymol (1-9), and tested against 15 strains of S. aureus from subclinical bovine mastitis. Initially, the strains were evaluated for the biofilm production profile, and those with strong adherence were selected to the antimicrobial sensitivity determination in the Minimum Inhibitory Concentration (MIC) assays. Herein the compounds toxicity was also evaluated by in silico analysis using Osiris DataWarrior® software. The results showed that 60% of the strains were considered strongly adherent and three strains (S. aureus 4271, 4745 and 4746) were selected for the MIC tests. Among the nine eugenol and thymol derivatives tested, four were active against the evaluated strains (MIC = 32 µg mL-1) within CLSI standard values. In silico analysis showed that all derivatives had cLopP < 5, cLogS > - 4 and TPSA < 140 Å2, and similar theoretical toxicity parameters to some antibiotics currently on the market. These molecules also showed negative drug-likeness values, pointing to the originality of these structures and theoretical feasibility on escaping of resistance mechanism and act against resistant strains. Thus, these eugenol derivatives may be considered as promising for the development of new treatments against bovine mastitis and future exploring on this purpose.

COVID-19: Innovative Antiviral Drugs Required for Long-Term Prevention and Control of Coronavirus Diseases.

The COVID-19 pandemic has had global catastrophic effects on financial markets, jobs and peoples' lives. Future prevention/therapy of COVID-19 will rely heavily on vaccine development and attempts to repurpose drugs previously used for other microbial diseases. Little attention, however, has been paid to possible difficulties and delays in producing these drugs. Sometimes, unfortunately, these endeavours have been politicized and if these two approaches founder in any way or resistance subsequently occurs, then the world will be left once again to the mercy of these devastating viral pandemics. This review, therefore, briefly outlines the challenges in the development of vaccines and repurposed antiviral drugs, which will hopefully lead to new treatments for COVID-19. It also concludes, however, that the armoury against COVID-19 urgently needs to be enlarging due to the potential severity and likely future reoccurrence of new emergent viruses. Therefore, serious consideration is given to alternative ways of preventing and controlling these pathogens that have received scant attention from the media in the present pandemic. The development of innovative, broad-spectrum, antiviral drugs from natural products is therefore particularly advocated with the challenges involved by new regulatory and scientific initiatives.

COVID-19 and Hyperimmune sera: A feasible plan B to fight against coronavirus.

Since the very beginning of the COVID-19 pandemic, different treatment strategies have been explored. These mainly involve the development of antimicrobial, antiviral, and/or anti-inflammatory agents as well as vaccine production. However, other potential options should be more avidly investigated since vaccine production on a worldwide level, and the anti-vaccination movement, also known as anti-vax or vaccine hesitancy by many communities, are still real obstacles without a ready solution. This review presents recent findings on the potential therapeutic advantages of heterologous serotherapy for the treatment of COVID-19. We present not only the effective use in animal models of hyperimmune sera against this coronavirus but also strategies, and protocols for the production of anti-SARS-CoV-2 sera. Promising antigens are also indicated such as the receptor-binding domain (RBD) in SARS-CoV-2 S protein, which is already in phase 2/3 clinical trial, and the trimeric protein S, which was shown to be up to 150 times more potent than the serum from convalescent donors. Due to the high death rate, the treatment for those currently infected with coronavirus cannot be ignored. Therefore, the potential use of anti-SARS-CoV-2 hyperimmune sera should be carefully but urgently evaluated in phase 2/3 clinical studies.

Efficient Synthesis and Antibacterial Profile of Bis(2-hydroxynaphthalene- 1,4-dione).

BACKGROUND: Antibacterial resistance is a serious public health problem infecting millions in the global population. Currently, there are few antimicrobials on the market against resistant bacterial infections. Therefore, there is an urgent need for new therapeutic options against these strains. OBJECTIVE: In this study, we synthesized and evaluated ten Bis(2-hydroxynaphthalene-1,4-dione) against Gram-positive strains, including a hospital Methicillin-resistant (MRSA), and Gram-negative strains. METHODS: The compounds were prepared by condensation of aldehydes and lawsone in the presence of different L-aminoacids as catalysts in very good yields. The compounds were submitted to antibacterial analysis through disk diffusion and Minimal Inhibitory Concentration (MIC) assays. RESULTS: L-aminoacids have been shown to be efficient catalysts in the preparation of Bis(2- hydroxynaphthalene-1,4-dione) from 2-hydroxy-1,4-naphthoquinones and arylaldehydes in excellent yields of up to 96%. The evaluation of the antibacterial profile against Gram-positive strains (Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 25923, S. epidermidis ATCC 12228) also including a hospital Methicillin-resistant S. aureus (MRSA) and Gram-negative strains (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853 and Klebsiella pneumoniae ATCC 4352), revealed that seven compounds showed antibacterial activity within the Clinical and Laboratory Standards Institute (CLSI) levels mainly against P. aeruginosa ATCC 27853 (MIC 8-128 µg/mL) and MRSA (MIC 32-128 µg/mL). In addition, the in vitro toxicity showed all derivatives with no hemolytic effects on healthy human erythrocytes. Furthermore, the derivatives showed satisfactory theoretical absorption, distribution, metabolism, excretion, toxicity (ADMET) parameters, and a similar profile to antibiotics currently in use. Finally, the in silico evaluation pointed to a structure-activity relationship related to lipophilicity for these compounds. This feature may help them in acting against Gram-negative strains, which present a rich lipid cell wall selective for several antibiotics. CONCLUSION: Our data showed the potential of this series for exploring new and more effective antibacterial activities in vivo against other resistant bacteria.

Synthesis, Biological Evaluation, and Molecular Modeling Studies of New Thiadiazole Derivatives as Potent P2X7 Receptor Inhibitors.

Twenty new 2-(1H-pyrazol-1-yl)-1,3,4-thiadiazole analogs were synthetized to develop P2X7 receptor (P2X7R) inhibitors. P2X7R inhibition in vitro was evaluated in mouse peritoneal macrophages, HEK-293 cells transfected with hP2X7R (dye uptake assay), and THP-1 cells (IL-1ß release assay). The 1-(5-phenyl-1,3,4-thiadiazol-2-yl)-1H-pyrazol-5-amine derivatives 9b, 9c, and 9f, and 2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-(4-fluorophenyl)-1,3,4-thiadiazole (11c) showed inhibitory effects with IC50 values ranging from 16 to 122 nM for reduced P2X7R-mediated dye uptake and 20 to 300 nM for IL-1ß release. In addition, the in vitro ADMET profile of the four most potent derivatives was determined to be in acceptable ranges concerning metabolic stability and cytotoxicity. Molecular docking and molecular dynamics simulation studies of the molecular complexes human P2X7R/9f and murine P2X7R/9f indicated the putative intermolecular interactions. Compound 9f showed affinity mainly for the Arg268, Lys377, and Asn266 residues. These results suggest that 2-(1H-pyrazol-1-yl)-1,3,4-thiadiazole analogs may be promising novel P2X7R inhibitors with therapeutic potential.

Synthesis and antimicrobial evaluation of amino sugar-based naphthoquinones and isoquinoline-5,8-diones and their halogenated compounds.

Antibiotic resistance has emerged as a serious global public health problem and lately very few antibiotics have been discovered and introduced into clinical practice. Therefore, there is an urgent need for the development of antibacterial compounds with new mechanism of action, especially those capable of evading known resistance mechanisms. In this work two series of glycoconjugate and non-glycoconjugate amino compounds derived from of isoquinoline-5,8-dione and 1,4-naphthoquinone and their halogenated derivatives were synthesized and evaluated for antimicrobial activity against Gram-positive (Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 25923, S. epidermidis ATCC 12228, S. simulans ATCC 27851) and Gram-negative bacteria (E. coli ATCC 25922, Proteus mirabilis ATCC 15290, K. pneumoniae ATCC 4352 and P. aeruginosa ATCC 27853) strains of clinical importance. This study revealed that glycoconjugate compounds derived from halogeno-substituted naphthoquinones were more active against Gram-negative strains, which cause infections whose treatment is even more difficult, according to the literature. These molecules were also more active than isoquinoline-5,8-dione analogues with minimum inhibitory concentration (MIC = 4-32 µg/mL) within Clinical and Laboratory Standard Institute MIC values (CLSI 0.08-256 µg/mL). Interestingly the minimal bactericidal concentration (MBC) values of the most active compounds were equal to MIC classifying them as bactericidal agents against Gram-negative bacteria. Sixteen compounds among eighteen carbohydrate-based naphthoquinones tested showed no hemolytic effects on health human erythrocytes whereas more susceptibility to hemolytic cleavage was observed when using non-glycoconjugate amino compounds. In silico Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) evaluation also pointed out that these compounds are potential for oral administration with low side effects. In general, this study indicated that these compounds should be exploited in the search for a leading substance in a project aimed at obtaining new antimicrobials more effective against Gram-negative bacteria.

Antibacterial naphthoquinone derivatives targeting resistant strain Gram-negative bacteria in biofilms.

The aims of this study were the planning, synthesis and in vitro evaluation of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones against Gram-negative and Gram-positive strains, searching for potential lead compounds against bacterial biofilm formation. A series of 12 new analogs of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones were synthesized by adding a thiol and different substituents to a ο-quinone methide using microwave irradiation. The compounds were tested against Gram-positive (Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 25923, S. simulans ATCC 27851, S. epidermidis ATCC 12228 and a hospital Methicillin-resistant S. aureus (MRSA) strain), as well as Gram-negative (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, P. aeruginosa ATCC 15442, Proteus mirabilis ATCC 15290, Serratia marcescens ATCC 14756, Klebsiella pneumoniae ATCC 4352 and Enterobacter cloacae ATCC 23355) strains, using the disk diffusion method. Ten compounds showed activity mainly against Gram-negative strains with a minimal inhibitory concentration (MIC = 4-64 µg/mL) within the Clinical and Laboratory Standards Institute (CLSI) levels. The biofilm inhibition data showed compounds, 9e, 9f, 9j and 9k, are anti-biofilm molecules when used in sub-MIC concentrations against P. aeruginosa ATCC 15442 strain. Compound (9j) inhibited biofilm formation up to 63.4% with a better profile than ciprofloxacin, which is not able to prevent biofilm formation effectively. The reduction of P. aeruginosa ATCC 15442 mature biofilms was also observed for 9e and 9k. The structure modification applied in the series resulted in 12 new naphthoquinones with antimicrobial activity against Gram-negative bacteria strains (E. coli ATCC 25922, P. aeruginosa ATCC 27853 and ATCC 15442). Four compounds decreased P. aeruginosa biofilm formation effectively.

Molecular modeling and dynamic simulations of agglutinin-like family members from Candida albicans: New insights into potential targets for the treatment of candidiasis.

Infections by Candida albicans in immune compromised patients cause significant morbidity and mortality. In the search for potential molecular targets for drug development, the family of agglutinin-like proteins (Als) in C. albicans have been identified due to numerous attributes associated with high virulence, most prominently due to their role in adherence. Here, molecular models of individual members of the Als family illustrated common and unique structure features. Additionally, dynamic simulations were performed to display regions of high mobility. The results showed variations between Als members in the fluctuation of the A1B1 protein loop, which is located at the entrance to the peptide binding cavity, suggesting that this feature may be a factor contributing to observed differences in affinities to ligands and adhesion properties. Molecular docking results further suggested that ligand affinity could be influenced by movements in the A1B1 loop. In addition, a new site was identified in Als in an area adjacent to the peptide binding cavity that could serve as a new binding site for the design of future anti-adhesion ligands that provide increased specificity inhibiting Als proteins from C. albicans.

Evaluation of 1,3-benzoxathiol-2-one Derivatives as Potential Antifungal Agents.

BACKGROUND: Over the last few years, fungal infections have emerged as a worrisome global public health problem. Candidiasis is a disease caused by Candida species and has been a problem worldwide mainly for immunosuppressed patients. Lately, the resistant strains and side effects have been reported as important issues for treating Candidiasis, which have to be solved by identifying new drugs. OBJECTIVE: The goal of this work was to synthesize a series of 1,3-benzoxathiol-2-one derivatives, XYbenzo[ d][1,3]oxathiol-2-ones, and evaluate their antifungal activity against five Candida species. METHODS: In vitro antifungal screening test and minimum inhibitory concentration determination were performed according to CLSI protocols using ketoconazole as the reference drug. The cytotoxicity of the most active compounds was evaluated by hemolysis and MTT (Vero cells) assays. RESULTS: Compounds 2 (XY = 6-hydroxy-5-nitro, MIC = 4-32 µg/mL) and 7 (XY = 6-acetoxy-5-nitro, MIC =16-64 µg/mL) showed good results when compared with current antifungals in CLSI values (MIC = 0.04-250 µg/mL). These compounds exhibited a safer cytotoxicity as well as a lower hemolytic profile than ketoconazole. CONCLUSION: Overall, the in vitro results pointed to the potential of compounds 2 and 7 as new antifungal prototypes to be further explored.

Hetero-Diels-Alder reactions of novel 3-triazolyl-nitrosoalkenes as an approach to functionalized 1,2,3-triazoles with antibacterial profile.

The generation and reactivity of 3-triazolyl-nitrosoalkenes are reported for the first time. The study showed that hetero-Diels-Alder reaction of these heterodienes is an interesting synthetic strategy to functionalized 1,2,3-triazoles, including 1,2,3-triazolyl-pyrroles, 1,2,3-triazolyl-dipyrromethanes and 1,2,3-triazolyl-indoles. The evaluation of the antibacterial profile against Gram-positive and Gram-negative strains revealed the new 5,5'-diethyldipyrromethane bearing a side chain incorporating a triazole and oxime moieties. The antibacterial profile detected was within the Clinical and Laboratory Standard Institute (CLSI) range and against important Staphylococcus species including Methicillin-resistant strain (S. aureus ATCC 25923, S. epidermidis ATCC 12228 and S. simulans ATCC 27851 and MRSA). Interestingly, this new 1,2,3-triazole presented hemocompatibility and low in silico toxicity profile similar to antibiotics current in use. It also has an usual antibiofilm activity against MRSA, which reinforced its potential as a new antibacterial prototype.

In Vitro Evaluation of Essential Oils Derived from Piper nigrum (Piperaceae) and Citrus limonum (Rutaceae) against the Tick Rhipicephalus (Boophilus) microplus (Acari: Ixodidae).

The present research aimed to study the chemical composition and acaricidal activity of Citrus limonum and Piper nigrum essential oils against the cattle tick Rhipicephalus microplus. GC-MS analysis of C. limonum essential oil showed limonene (50.3%), ß-pinene (14.4%), and γ-terpinene (11.7%) as the major components; P. nigrum oil was mainly composed of ß-caryophyllene (26.2%), σ-ocymene (5.8%), and α-pinene (5.5%). Acaricide activity was evaluated at concentrations of 2.5, 5.0, and 10.0% (v/v) of each plant oil, as well as 1 : 1 combination of both oils (5% : 5%, 2.5% : 2.5%, and 1.25% : 1.25% each), by immersing engorged R. microplus females for one minute. The LC90 of oils from C. limonum, P. nigrum, and the combination were 4.9%, 14.8%, and 5.1%, respectively. C. limonum essential oil caused 100% mortality of engorged females at the highest concentration (10%). P. nigrum essential oil inhibited egg-laying by up to 96% in a concentration-dependent manner, suggesting it reduces tick fecundity. When combined, the oils presented toxicity as to C. limonum oil alone, but with stronger inhibition of oviposition (5% : 5%), indicating a possible additive effect against R. microplus. The present data provide support for further investigation of novel natural products to control bovine tick infestations.

Synthesis and mechanistic evaluation of novel N'-benzylidene-carbohydrazide-1H-pyrazolo[3,4-b]pyridine derivatives as non-anionic antiplatelet agents.

Cardiovascular diseases (CVDs) account for over 17 million deaths globally each year, with atherosclerosis as the underlying cause of most CVDs. Herein we describe the synthesis and in vitro mechanistic evaluation of novel N'-benzylidene-carbohydrazide-1H-pyrazolo[3,4-b]pyridines (3-22) designed as non-anionic antiplatelet agents and presenting a 30-fold increase in potency compared to aspirin. The mechanism underlying their antiplatelet activity was elucidated by eliminating potential targets through a series of in vitro assays including light transmission aggregometry, clot retraction, and quantitative ELISA, further identifying the reduction in biosynthesis of thromboxane B2 as their main mechanism of action. The intrinsic fluorescence of the compounds permits their binding to platelet membranes to be readily monitored. In silico structure-activity relationship, molecular docking and dynamics studies support the biological profile of the series revealing the molecular basis of their activity and their potential as future molecular therapeutic agents.

Targeting CYP51 for drug design by the contributions of molecular modeling.

CYP51 is an enzyme of sterol biosynthesis pathway present in animals, plants, protozoa and fungi. This enzyme is described as an important drug target that is still of interest. Therefore, in this work, we reviewed the structure and function of CYP51 and explored the molecular modeling approaches for the development of new antifungal and antiprotozoans that target this enzyme. Crystallographic structures of CYP51 of some organisms have already been described in the literature, which enable the construction of homology models of other organisms' enzymes and molecular docking studies of new ligands. The binding mode and interactions of some new series of azoles with antifungal or antiprotozoan activities has been studied and showed important residues of the active site. Molecular modeling is an important tool to be explored for the discovery and optimization of CYP51 inhibitors with better activities, pharmacokinetics, and toxicological profiles.