Assessment of thimerosal effects in sublethal concentrations on zebrafish (Danio rerio) embryos exploring NMR-based metabolomics profile.

Thimerosal, a preservative commonly used in the pharmaceutical and cosmetic industry, has raised concerns regarding its potentially toxic effects as an organic mercury compound. Within this context, using an NMR-based metabolomics profile and chemometric analysis, zebrafish embryos were used as an in vivo model to study the effects of thimerosal in metabolic profiles after exposure to sublethal concentrations of the mercury compound. The thimerosal concentrations of 40 and 80 nM were employed, corresponding to 40% and 80% of the LC50, respectively, for zebrafish embryos. The most significant alterations in the metabolic profile included changes in carbohydrates, amino acids, nucleotides, trimethylamine-N-oxide, ethanolamine, betaine, and ethanol. Furthermore, thimerosal exposure affects various metabolic pathways, impairing the nervous system, disrupting protein metabolism, and potentially causing oxidative damage. Therefore, adopting a metabolomics approach in this investigation provided insights into the potentially implicated metabolic pathways contributing to the deleterious effects of thimerosal in biological systems.

Biological evaluation of 1,3-benzodioxole acids points to 3,4-(methylenedioxy) cinnamic acid as a potential larvicide against Aedes aegypti (Diptera: Culicidae).

Aedes aegypti serves as the primary vector for viruses like dengue, Chikungunya, Zika, and yellow fever, posing a significant public health challenge in Brazil. Given the absence of approved vaccines for these diseases, effective mosquito control becomes paramount in preventing outbreaks. However, currently available chemical insecticides face issues related to toxicity and the emergence of resistance, necessitating the exploration of new active compounds. Drawing inspiration from natural products, we identified the 1,3-benzodioxole group as a key pharmacophore associated with insecticidal activity. Therefore, this study aimed to synthesize and assess the larvicidal activity of 1,3-benzodioxole acids against Ae. aegypti, as well as their toxicity in mammals. Among the compounds evaluated, 3,4-(methylenedioxy) cinnamic acid (compound 4) demonstrated larvicidal activity. It exhibited LC50 and LC90 values of 28.9 ± 5.6 and 162.7 ± 26.2 µM, respectively, after 24 h of exposure. For reference, the positive control, temephos, displayed both LC50 and LC90 values below 10.94 µM. These findings underline the significance of the 3,4-methylenedioxy substituent on the aromatic ring and the presence of a double bond in the aliphatic chain for biological activity. Furthermore, compound 4 exhibited no cytotoxicity towards human peripheral blood mononuclear cells, even at concentrations up to 5200 µM. Lastly, in mice treated with 2000 mg kg-1, compound 4 showed mild behavioral effects and displayed no structural signs of toxicity in vital organs such as the kidney, liver, spleen, and lungs.

Potentiating-antibiotic activity and absorption, distribution, metabolism, excretion and toxicity properties (ADMET) analysis of synthetic thiadiazines against multi-drug resistant (MDR) strains.

BACKGROUND: Thiadiazines are heterocyclic compounds that contain two nitrogen atoms and one sulfur atom in their structure. These synthetic molecules have several relevant pharmacological activities, such as antifungal, antibacterial, and antiparasitic. OBJECTIVES: The present study aimed to evaluate the possible in vitro and in silico interactions of compounds derived from thiadiazines. METHODS: The compounds were initially synthesized, purified, and confirmed through HPLC methodology. Multi-drug resistant bacterial strains of Staphylococcus aureus 10 and Pseudomonas aeruginosa 24 were used to evaluate the direct and modifying antibiotic activity of thiadiazine derivatives. ADMET assays (absorption, distribution, metabolism, excretion, and toxicity) were conducted, which evaluated the influence of the compounds against thousands of macromolecules considered as bioactive targets. RESULTS: There were modifications in the chemical synthesis in carbon 4 or 3 in one of the aromatic rings of the structure where different ions were added, ensuring a variability of products. It was possible to observe results that indicate the possibility of these compounds acting through the cyclooxygenase 2 mechanism, which, in addition to being involved in inflammatory responses, also acts by helping sodium reabsorption. The amine group present in thiadiazine analogs confers hydrophilic characteristics to the substances, but this primary characteristic has been altered due to alterations and insertions of other ligands. The characteristics of the analogs generally allow easy intestinal absorption, reduce possible hepatic toxic effects, and enable possible neurological and anti-inflammatory action. The antibacterial activity tests showed a slight direct action, mainly of the IJ23 analog. Some compounds were able to modify the action of the antibiotics gentamicin and norfloxacin against multi-drug resistant strains, indicating a possible synergistic action. CONCLUSIONS: Among all the results obtained in the study, the relevance of thiadiazine analogs as possible coadjuvant drugs in the antibacterial, anti-inflammatory, and neurological action with low toxicity is clear. Need for further studies to verify these effects in living organisms is not ruled out.

Natural Compounds as Inhibitors of Aß Peptide and Tau Aggregation.

Neurodegenerative conditions like Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) encompass disorders characterized by the degeneration of neurons in specific circumstances. The quest for novel agents to influence these diseases, particularly AD, has unearthed various natural compounds displaying multifaceted activities and diverse pharmacological mechanisms. Given the ongoing extensive study of pathways associated with the accumulation of neurofibrillary aggregates and amyloid plaques, this paper aims to comprehensively review around 130 studies exploring natural products. These studies focus on inhibiting the formation of amyloid plaques and tau protein tangles, with the objective of potentially alleviating or delaying AD.

BACE-1 Inhibitors Targeting Alzheimer's Disease.

The accumulation of amyloid-ß (Aß) is the main event related to Alzheimer's disease (AD) progression. Over the years, several disease-modulating approaches have been reported, but without clinical success. The amyloid cascade hypothesis evolved and proposed essential targets such as tau protein aggregation and modulation of ß-secretase (ß-site amyloid precursor protein cleaving enzyme 1 - BACE-1) and γ-secretase proteases. BACE-1 cuts the amyloid precursor protein (APP) to release the C99 fragment, giving rise to several Aß peptide species during the subsequent γ-secretase cleavage. In this way, BACE-1 has emerged as a clinically validated and attractive target in medicinal chemistry, as it plays a crucial role in the rate of Aß generation. In this review, we report the main results of candidates in clinical trials such as E2609, MK8931, and AZD-3293, in addition to highlighting the pharmacokinetic and pharmacodynamic-related effects of the inhibitors already reported. The current status of developing new peptidomimetic, non-peptidomimetic, naturally occurring, and other class inhibitors are demonstrated, considering their main limitations and lessons learned. The goal is to provide a broad and complete approach to the subject, exploring new chemical classes and perspectives.

The influence of N-alkyl chains in benzoyl-thiourea derivatives on urease inhibition: Soil studies and biophysical and theoretical investigations on the mechanism of interaction.

Ureases are enzymes produced by fungi, plants, and bacteria associated with agricultural and clinical problems. The urea hydrolysis in NH3 and CO2 leads to the loss of N-urea fertilizers in soils and changes the human stomach microenvironment, favoring the colonization of H. pylori. In this sense, it is necessary to evaluate potential enzyme inhibitors to mitigate the effects of their activities and respond to scientific and market demands to produce fertilizers with enhanced efficiency. Thus, biophysical and theoretical studies were carried out to evaluate the influence of the N-alkyl chain in benzoyl-thiourea derivatives on urease enzyme inhibition. A screening based on IC50, binding constants, and theoretical studies demonstrated that BTU1 without the N-alkyl chain (R = H) was more active than other compounds, so the magnitude of the interaction was determined as BTU1 > BTU2 > BTU3 > BTU4 > BTU5, corresponding to progressively increased chain length. Thus, BTU1 was selected for interaction and soil application essays. The binding constants (Kb) for the supramolecular urease-BTU1 complex ranged from 7.95 to 5.71 × 103 M-1 at different temperatures (22, 30, and 38 °C), indicating that the preferential forces responsible for the stabilization of the complex are hydrogen bonds and van der Waals forces (ΔH = -15.84 kJ mol-1 and ΔS = -36.61 J mol-1 K-1). Theoretical and experimental results (thermodynamics, synchronous fluorescence, and competition assay) agree and indicate that BTU1 is a mixed inhibitor. Finally, urease inhibition was evaluated in the four soil samples, where BTU1 was as efficient as NBPT (based on ANOVA two-way and Tukey test with 95% confidence), with an average inhibition of 20% of urease activity. Thus, the biophysics and theoretical studies are strategies for evaluating potential inhibitors and showed that increasing the N-alkyl chain in benzoyl-thiourea derivatives did not favor urease inhibition.

Preclinical data on morpholine (3,5-di-tertbutyl-4-hydroxyphenyl) methanone induced anxiolysis.

Trimetozine is used to be indicated for the treatment of mental illnesses, particularly anxiety. The present study provides data on the pharmacological profile of trimetozine derivative morpholine (3,5-di-tert-butyl-4-hydroxyphenyl) methanone (LQFM289) which was designed from molecular hybridization of trimetozine lead compound and 2,6-di-tert-butyl-hydroxytoluene to develop new anxiolytic drugs. Here, we conduct molecular dynamics simulations, docking studies, receptor binding assays, and in silico ADMET profiling of LQFM289 before its behavioral and biochemical assessment in mice within the dose range of 5-20 mg/kg. The docking of LQFM289 showed strong interactions with the benzodiazepine binding sites and matched well with receptor binding data. With the ADMET profile of this trimetozine derivative that predicts a high intestinal absorption and permeability to blood-brain barrier without being inhibited by the permeability glycoprotein, the oral administration of LQFM289 10 mg/kg consistently induced anxiolytic-like behavior of the mice exposed to the open field and light-dark box apparatus without eliciting motor incoordination in the wire, rotarod, and chimney tests. A decrease in the wire and rotarod´s fall latency coupled with an increase in the chimney test´s climbing time and a decrease in the number of crossings in the open field apparatus at the dose of 20 mg/kg of this trimetozine derivative suggest sedative or motor coordination impairment at this highest dose. The attenuation of the anxiolytic-like effects of LQFM289 (10 mg/kg) by flumazenil pretreatment implicates the participation of benzodiazepine binding sites. The lowering of corticosterone and tumor necrosis factor alpha (cytokine) in LQFM289-treated mice at a single oral (acute) dose of 10 mg/kg suggests that the anxiolytic-like effect of this compound also involves the recruitment of non-benzodiazepine binding sites/GABAergic molecular machinery.

Biological activities and physicochemical characterization of alkaline lignins obtained from branches and leaves of Buchenavia viridiflora with potential pharmaceutical and biomedical applications.

In this work, we investigated in vitro different biological activities of alkaline lignins extracted from the species Buchenavia viridiflora, a tree from the Amazon rainforest used as a wood product. The chemical composition results for the twig and leaves were, respectively (%): cellulose (30.88 and 24. 28), hemicellulose (21.62 and 23.03), lignin (29.93 and 25.46), extractives (13.06 and 20.52), and ash (4.51 and 6.72). The yield was higher for the lignin of the branches (67.9 %) when compared to the leaves (60.2 %). Lignins are of the GSH type, low molecular weight and thermally stable. They promoted moderate to low antioxidant activity, highlighting the lignin of the branches, which presented an IC50 of 884.56 µg/mL for the DPPH assay and an IC50 of 14.08 µg/mL for ABTS. In the cytotoxicity assays, they showed low toxicity against macrophage cells (IC50 28.47 and 22.58 µg/mL). In addition, they were not cytotoxic against splenocytes and erythrocytes at concentrations ranging from 100 to 6.25 µg/mL. These were able to promote splenocyte proliferation and induce the production of anti-inflammatory cytokines. And inhibit the growth of tumor cells with IC50 ranging from 12.63 to values >100 µg/mL and microbial at a concentration of 512 µg/mL. Finally, they showed antiparasitic activity by inhibiting the growth of chloroquine-sensitive and resistant Plasmodium falciparum strains. These findings reinforce that the lignins in this study are promising for potential pharmaceutical and biomedical applications.

Medicinal Chemistry of Inhibitors Targeting Resistant Bacteria.

The discovery of antibiotics was a revolutionary feat that provided countless health benefits. The identification of penicillin by Alexander Fleming initiated the era of antibiotics, represented by constant discoveries that enabled effective treatments for the different classes of diseases caused by bacteria. However, the indiscriminate use of these drugs allowed the emergence of resistance mechanisms of these microorganisms against the available drugs. In addition, the constant discoveries in the 20th century generated a shortage of new molecules, worrying health agencies and professionals about the appearance of multidrug-resistant strains against available drugs. In this context, the advances of recent years in molecular biology and microbiology have allowed new perspectives in drug design and development, using the findings related to the mechanisms of bacterial resistance to generate new drugs that are not affected by such mechanisms and supply new molecules to be used to treat resistant bacterial infections. Besides, a promising strategy against bacterial resistance is the combination of drugs through adjuvants, providing new expectations in designing new antibiotics and new antimicrobial therapies. Thus, this manuscript will address the main mechanisms of bacterial resistance under the understanding of medicinal chemistry, showing the main active compounds against efflux mechanisms, and also the application of the use of drug delivery systems, and finally, the main potential natural products as adjuvants or with promising activity against resistant strains.

Computer-Aided Drug Design of Anti-inflammatory Agents Targeting Microsomal Prostaglandin E2 Synthase-1 (mPGES-1).

Inflammation is a natural reaction to external stimuli to protect the organism. However, if it is exaggerated, it can cause severe physiopathological damage, linked to diseases like rheumatoid arthritis, cancer, diabetes, allergies, and infections. Inflammation is mainly characterized by pain, increased temperature, flushing, and edema, which can be controlled using anti-inflammatory drugs. In this context, prostaglandin E2 (PGE2) inhibition has been targeted for designing new compounds with anti-inflammatory properties. It is a bioactive lipid overproduced during an inflammatory process, in which its increased production is carried out mainly by COX-1, COX-2, and microsomal prostaglandin E2 synthase-1 (mPGES-1). Recently, studies have demonstrated that mPGES-1 inhibition is a safe strategy for developing anti-inflammatory agents, which could protect against pain, acute inflammation, arthritis, autoimmune diseases, and different types of cancers. Thus, in recent years, computer-aided drug design (CADD) approaches have been increasingly used to design new inhibitors, decreasing costs and increasing the probability of discovering active substances. Finally, this review will cover all aspects involving high-throughput virtual screening, molecular docking, dynamics, fragment-based drug design, and quantitative structure-activity relationship in seeking new promising mPGES-1 inhibitors.

Molecular Modeling Targeting Transmembrane Serine Protease 2 (TMPRSS2) as an Alternative Drug Target Against Coronaviruses.

Since December 2019, the new Coronavirus disease (COVID-19) caused by the etiological agent SARS-CoV-2 has been responsible for several cases worldwide, becoming pandemic in March 2020. Pharmaceutical companies and academics have joined their efforts to discover new therapies to control the disease since there are no specific drugs to combat this emerging virus. Thus, several tar-gets have been explored; among them, the transmembrane protease serine 2 (TMPRSS2) has gained greater interest in the scientific community. In this context, this review will describe the importance of TMPRSS2 protease and the significant advances in virtual screening focused on discovering new inhibitors. In this review, it was observed that molecular modeling methods could be powerful tools in identifying new molecules against SARS-CoV-2. Thus, this review could be used to guide re-searchers worldwide to explore the biological and clinical potential of compounds that could be promising drug candidates against SARS-CoV-2, acting by inhibition of TMPRSS2 protein.

The new psychoactive substances 25H-NBOMe and 25H-NBOH induce abnormal development in the zebrafish embryo and interact in the DNA major groove.

Toxicological effects of 25H-NBOMe and 25H-NBOH recreational drugs on zebrafish embryos and larvae at the end of 96 h exposure period were demonstrated. 25H-NBOH and 25H-NBOMe caused high embryo mortality at 80 and 100 µg mL-1, respectively. According to the decrease in the concentration tested, lethality decreased while non-lethal effects were predominant up to 10 and 50 µg mL-1 of 25H-NBOH and 25H-NBOMe, respectively, including spine malformation, egg hatching delay, body malformation, otolith malformation, pericardial edema, and blood clotting. We can disclose that these drugs have an affinity for DNA in vitro using biophysical spectroscopic assays and molecular modeling methods. The experiments demonstrated that 25H-NBOH and 25H-NBOMe bind to the unclassical major groove of ctDNA with a binding constant of 27.00 × 104 M-1 and 5.27 × 104 M-1, respectively. Furthermore, these interactions lead to conformational changes in the DNA structure. Therefore, the results observed in the zebrafish embryos and DNA may be correlated.

Cruzain and Rhodesain Inhibitors: Last Decade of Advances in Seeking for New Compounds Against American and African Trypanosomiases.

Neglected tropical diseases (NTDs) are a group of approximately 20 diseases that affect part of the population in Sub- and Tropical countries. In the past, pharmaceutical industries and governmental agencies have invested in the control, elimination and eradication of such diseases. Among these diseases, Chagas disease (CD) and Human African trypanosomiasis (HAT) are a public health problem, mainly in the countries from the American continent and sub-Saharan African. In this context, the search for new therapeutic alternatives against such diseases has been growing in recent years, presenting cysteine proteases as the main strategy to discover new anti-trypanosomal drugs. Thus, cruzain and rhodesain enzymes are targets widely studied, since the cruzain is present in all stages of the parasite's life, related to the stages of proliferation and differentiation and infection of macrophages; while the rhodesain is related to the immune defense process. In addition, knowledge about the amino acid sequences and availability of X-ray complexes have stimulated the drug searching against these targets, mainly through molecular modeling studies. Thus, this review manuscript will be addressed to cruzain and rhodesain inhibitors developed in the last 10 years, which could provide basis for new lead compounds in the discovery of new trypanocidal drugs. We found 117 studies involving inhibitors of cruzain and rhodesain, being thiosemicarbazones, semicarbazones, N-acylhydrazones, thiazoles-hydrazone, thiazolidinones-hydrazones, oxadiazoles, triazoles, triazines, imidazoles, peptidomimetic, and others. All references were obtained using "cruzain" or "rhodesain" and "inhibitor" as keywords in Science Direct, Bentham Science, PubMed, Espacenet, Springer, ACS Publisher, Wiley, Taylor and Francis, and MDPI (Multidisciplinary Digital Publishing Institute) databases. Finally, we highlighted all these chemical classes of molecules to provide valuable information that could be used to design new inhibitors against Chagas disease and sleeping sickness in the future.

Drug Repurposing: A Strategy for Discovering Inhibitors against Emerging Viral Infections.

BACKGROUND: Viral diseases are responsible for several deaths around the world. Over the past few years, the world has seen several outbreaks caused by viral diseases that, for a long time, seemed to possess no risk. These are diseases that have been forgotten for a long time and, until nowadays, there are no approved drugs or vaccines, leading the pharmaceutical industry and several research groups to run out of time in the search for new pharmacological treatments or prevention methods. In this context, drug repurposing proves to be a fast and economically viable technique, considering the fact that it uses drugs that have a well-established safety profile. Thus, in this review, we present the main advances in drug repurposing and their benefit for searching new treatments against emerging viral diseases. METHODS: We conducted a search in the bibliographic databases (Science Direct, Bentham Science, PubMed, Springer, ACS Publisher, Wiley, and NIH's COVID-19 Portfolio) using the keywords "drug repurposing", "emerging viral infections" and each of the diseases reported here (CoV; ZIKV; DENV; CHIKV; EBOV and MARV) as an inclusion/exclusion criterion. A subjective analysis was performed regarding the quality of the works for inclusion in this manuscript. Thus, the selected works were those that presented drugs repositioned against the emerging viral diseases presented here by means of computational, high-throughput screening or phenotype-based strategies, with no time limit and of relevant scientific value. RESULTS: 291 papers were selected, 24 of which were CHIKV; 52 for ZIKV; 43 for DENV; 35 for EBOV; 10 for MARV; and 56 for CoV and the rest (72 papers) related to the drugs repurposing and emerging viral diseases. Among CoV-related articles, most were published in 2020 (31 papers), updating the current topic. Besides, between the years 2003 - 2005, 10 articles were created, and from 2011 - 2015, there were 7 articles, portraying the outbreaks that occurred at that time. For ZIKV, similar to CoV, most publications were during the period of outbreaks between the years 2016 - 2017 (23 articles). Similarly, most CHIKV (13 papers) and DENV (14 papers) publications occur at the same time interval. For EBOV (13 papers) and MARV (4 papers), they were between the years 2015 - 2016. Through this review, several drugs were highlighted that can be evolved in vivo and clinical trials as possible used against these pathogens showed that remdesivir represent potential treatments against CoV. Furthermore, ribavirin may also be a potential treatment against CHIKV; sofosbuvir against ZIKV; celgosivir against DENV, and favipiravir against EBOV and MARV, representing new hopes against these pathogens. CONCLUSION: The conclusions of this review manuscript show the potential of the drug repurposing strategy in the discovery of new pharmaceutical products, as from this approach, drugs could be used against emerging viral diseases. Thus, this strategy deserves more attention among research groups and is a promising approach to the discovery of new drugs against emerging viral diseases and also other diseases.

An Update on Staphylococcus aureus NorA Efflux Pump Inhibitors.

BACKGROUND: Methicillin-resistant and vancomycin-resistant Staphylococcus aureus are pathogens causing severe infectious diseases that pose real public health threats problems worldwide. In S. aureus, the most efficient multidrug-resistant system is the NorA efflux pump. For this reason, it is critical to identify efflux pump inhibitors. OBJECTIVE: In this paper, we present an update of the new natural and synthetic compounds that act as modulators of antibiotic resistance through the inhibition of the S. aureus NorA efflux pump. RESULTS: Several classes of compounds capable of restoring the antibiotic activity have been identified against resistant-S. aureus strains, acting as NorA efflux pump inhibitors. The most promising classes of compounds were quinolines, indoles, pyridines, phenols, and sulfur-containing heterocycles. However, the substantial degree structural diversity of these compounds makes it difficult to establish good structure- activity correlations that allow the design of compounds with more promising activities and properties. CONCLUSION: Despite substantial efforts put forth in the search for new antibiotic adjuvants that act as efflux pump inhibitors, and despite several promising results, there are currently no efflux pump inhibitors authorized for human or veterinary use, or in clinical trials. Unfortunately, it appears that infection control strategies have remained the same since the discovery of penicillin, and that most efforts remain focused on discovering new classes of antibiotics, rather than trying to prolong the life of available antibiotics, and simultaneously fighting mechanisms of bacterial resistance.

Computer-Aided Drug Design Applied to Secondary Metabolites as Anticancer Agents.

Computer-Aided Drug Design (CADD) techniques have garnered a great deal of attention in academia and industry because of their great versatility, low costs, possibilities of cost reduction in in vitro screening and in the development of synthetic steps; these techniques are compared with highthroughput screening, in particular for candidate drugs. The secondary metabolism of plants and other organisms provide substantial amounts of new chemical structures, many of which have numerous biological and pharmacological properties for virtually every existing disease, including cancer. In oncology, compounds such as vimblastine, vincristine, taxol, podophyllotoxin, captothecin and cytarabine are examples of how important natural products enhance the cancer-fighting therapeutic arsenal. In this context, this review presents an update of Ligand-Based Drug Design and Structure-Based Drug Design techniques applied to flavonoids, alkaloids and coumarins in the search of new compounds or fragments that can be used in oncology. A systematical search using various databases was performed. The search was limited to articles published in the last 10 years. The great diversity of chemical structures (coumarin, flavonoids and alkaloids) with cancer properties, associated with infinite synthetic possibilities for obtaining analogous compounds, creates a huge chemical environment with potential to be explored, and creates a major difficulty, for screening studies to select compounds with more promising activity for a selected target. CADD techniques appear to be the least expensive and most efficient alternatives to perform virtual screening studies, aiming to selected compounds with better activity profiles and better "drugability".

5-Nitro-Thiophene-Thiosemicarbazone Derivatives Present Antitumor Activity Mediated by Apoptosis and DNA Intercalation.

BACKGROUND: Considering the need for the development of new antitumor drugs, associated with the great antitumor potential of thiophene and thiosemicarbazonic derivatives, in this work we promote molecular hybridization approach to synthesize new compounds with increased anticancer activity. OBJECTIVE: Investigate the antitumor activity and their likely mechanisms of action of a series of N-substituted 2-(5-nitro-thiophene)-thiosemicarbazone derivatives. METHODS: Methods were performed in vitro (cytotoxicity, cell cycle progression, morphological analysis, mitochondrial membrane potential evaluation and topoisomerase assay), spectroscopic (DNA interaction studies), and in silico studies (docking and molecular modelling). RESULTS: Most of the compounds presented significant inhibitory activity; the NCIH-292 cell line was the most resistant, and the HL-60 cell line was the most sensitive. The most promising compound was LNN-05 with IC50 values ranging from 0.5 to 1.9 µg.mL-1. The in vitro studies revealed that LNN-05 was able to depolarize (dose-dependently) the mitochondrial membrane, induceG1 phase cell cycle arrest noticeably, promote morphological cell changes associated with apoptosis in chronic human myelocytic leukaemia (K-562) cells, and presented no topoisomerase II inhibition. Spectroscopic UV-vis and molecular fluorescence studies showed that LNN compounds interact with ctDNA forming supramolecular complexes. Intercalation between nitrogenous bases was revealed through KI quenching and competitive ethidium bromide assays. Docking and Molecular Dynamics suggested that 5-nitro-thiophene-thiosemicarbazone compounds interact against the larger DNA groove, and corroborating the spectroscopic results, may assume an intercalating interaction mode. CONCLUSION: Our findings highlight 5-nitro-thiophene-thiosemicarbazone derivatives, especially LNN-05, as a promising new class of compounds for further studies to provide new anticancer therapies.

Active Essential Oils and Their Components in Use against Neglected Diseases and Arboviruses.

The term neglected diseases refers to a group of infections caused by various classes of pathogens, including protozoa, viruses, bacteria, and helminths, most often affecting impoverished populations without adequate sanitation living in close contact with infectious vectors and domestic animals. The fact that these diseases were historically not considered priorities for pharmaceutical companies made the available treatments options obsolete, precarious, outdated, and in some cases nonexistent. The use of plants for medicinal, religious, and cosmetic purposes has a history dating back to the emergence of humanity. One of the principal fractions of chemical substances found in plants are essential oils (EOs). EOs consist of a mixture of volatile and hydrophobic secondary metabolites with marked odors, composed primarily of terpenes and phenylpropanoids. They have great commercial value and were widely used in traditional medicine, by phytotherapy practitioners, and in public health services for the treatment of several conditions, including neglected diseases. In addition to the recognized cytoprotective and antioxidative activities of many of these compounds, larvicidal, insecticidal, and antiparasitic activities have been associated with the induction of oxidative stress in parasites, increasing levels of nitric oxide in the infected host, reducing parasite resistance to reactive oxygen species, and increasing lipid peroxidation, ultimately leading to serious damage to cell membranes. The hydrophobicity of these compounds also allows them to cross the membranes of parasites as well as the blood-brain barrier, collaborating in combat at the second stage of several of these infections. Based on these considerations, the aim of this review was to present an update of the potential of EOs, their fractions, and their chemical constituents, against some neglected diseases, including American and African trypanosomiasis, leishmaniasis, and arboviruses, specially dengue.

Correlation between DNA/HSA-interactions and antimalarial activity of acridine derivatives: Proposing a possible mechanism of action.

Acridines are considered an important class of compounds due to their wide variety of biological activities. In this work, we synthesized four acridine derivatives (1-4) and evaluated their biological activity against the Plasmodium falciparum W2 line, as well as studied the interaction with ctDNA and HSA using spectroscopic techniques and molecular docking. The acridine derivative 2 (IC50 = 0.90 ±â€¯0.08 µM) was more effective against P. falciparum than primaquine (IC50 = 1.70 ±â€¯0.10 µM) and similar to amsacrine (IC50 = 0.80 ±â€¯0.10 µM). In the fluorescence and UV-vis assays, it was verified that the acridine derivatives interact with ctDNA and HSA leading to a non-fluorescent supramolecular complex formation. The non-covalent binding constants ranged from 2.09 to 7.76 × 103 M-1, indicating moderate interaction with ctDNA. Through experiments with KI, fluorescence contact energy transfer and competition assays were possible to characterize the main non-covalent binding mode of the acridines evaluated with ctDNA as intercalation. The binding constants obtained showed a high linear correlation with the IC50 values against the antimalarial activity, suggesting that DNA may be the main biological target of these molecules. Finally, HSA interaction studies were performed and all evaluated compounds bind to the site II of the protein. The less active compounds (1 and 3) presented the highest affinity to HSA, indicating that the interaction with carrier protein can affect the (bio)availability of these compounds to the biological target.