Bioactive Bismuth Compounds: Is Their Toxicity a Barrier to Therapeutic Use?

Bismuth compounds are considered relatively non-toxic, with their low solubility in aqueous solutions (e.g., biological fluids) being the major contributing factor to this property. Bismuth derivatives are widely used for the treatment of peptic ulcers, functional dyspepsia, and chronic gastritis. Moreover, the properties of bismuth compounds have also been extensively explored in two main fields of action: antimicrobial and anticancer. Despite the clinical interest of bismuth-based drugs, several side effects have also been reported. In fact, excessive acute ingestion of bismuth, or abuse for an extended period of time, can lead to toxicity. However, evidence has demonstrated that the discontinuation of these compounds usually reverses their toxic effects. Notwithstanding, the continuously growing use of bismuth products suggests that it is indeed part of our environment and our daily lives, which urges a more in-depth review and investigation into its possible undesired activities. Therefore, this review aims to update the pharmaco-toxicological properties of bismuth compounds. A special focus will be given to in vitro, in vivo, and clinical studies exploring their toxicity.

Novel 4-Azapregnene Derivatives as Potential Anticancer Agents: Synthesis, Antiproliferative Activity and Molecular Docking Studies.

A series of novel 21E-arylidene-4-azapregn-5-ene steroids has been successfully designed, synthesized and structurally characterized, and their antiproliferative activity was evaluated in four different cell lines. Within this group, the 21E-(pyridin-3-yl)methylidene derivative exhibited significant cytotoxic activity in hormone-dependent cells LNCaP (IC50 = 10.20 µM) and T47-D cells (IC50 = 1.33 µM). In PC-3 androgen-independent cells, the steroid 21E-p-nitrophenylidene-4-azapregn-5-ene was the most potent of this series (IC50 = 3.29 µM). Considering these results, the 21E-(pyridin-3-yl)methylidene derivative was chosen for further biological studies on T47-D and LNCaP cells, and it was shown that this azasteroid seems to lead T47-D cells to apoptotic death. Finally, molecular docking studies were performed to explore the affinity of these 4-azapregnene derivatives to several steroid targets, namely 5α-reductase type 2, estrogen receptor α, androgen receptor and CYP17A1. In general, compounds presented higher affinity to 5α-reductase type 2 and estrogen receptor α.

Development of Phenothiazine Hybrids with Potential Medicinal Interest: A Review.

The molecular hybridization approach has been used to develop compounds with improved efficacy by combining two or more pharmacophores of bioactive scaffolds. In this context, hybridization of various relevant pharmacophores with phenothiazine derivatives has resulted in pertinent compounds with diverse biological activities, interacting with specific or multiple targets. In fact, the development of new drugs or drug candidates based on phenothiazine system has been a promising approach due to the diverse activities associated with this tricyclic system, traditionally present in compounds with antipsychotic, antihistaminic and antimuscarinic effects. Actually, the pharmacological actions of phenothiazine hybrids include promising antibacterial, antifungal, anticancer, anti-inflammatory, antimalarial, analgesic and multi-drug resistance reversal properties. The present review summarizes the progress in the development of phenothiazine hybrids and their biological activity.

An Insight into Symmetrical Cyanine Dyes as Promising Selective Antiproliferative Agents in Caco-2 Colorectal Cancer Cells.

Cancer remains one of the diseases with the highest worldwide incidence. Several cytotoxic approaches have been used over the years to overcome this public health threat, such as chemotherapy, radiotherapy, and photodynamic therapy (PDT). Cyanine dyes are a class of compounds that have been extensively studied as PDT sensitisers; nevertheless, their antiproliferative potential in the absence of a light source has been scarcely explored. Herein, the synthesis of eighteen symmetric mono-, tri-, and heptamethine cyanine dyes and their evaluation as potential anticancer agents is described. The influences of the heterocyclic nature, counterion, and methine chain length on the antiproliferative effects and selectivities were analysed, and relevant structure-activity relationship data were gathered. The impact of light on the cytotoxic activity of the most promising dye was also assessed and discussed. Most of the monomethine and trimethine cyanine dyes under study demonstrated a high antiproliferative effect on human tumour cell lines of colorectal (Caco-2), breast (MCF-7), and prostate (PC-3) cancer at the initial screening (10 µM). However, concentration-viability curves showed higher potency and selectivity for the Caco-2 cell line. A monomethine cyanine dye derived from benzoxazole was the most promising compound (IC50 for Caco-2 = 0.67 µM and a selectivity index of 20.9 for Caco-2 versus normal human dermal fibroblasts (NHDF)) and led to Caco-2 cell cycle arrest at the G0/G1 phase. Complementary in silico studies predicted good intestinal absorption and oral bioavailability for this cyanine dye.

Highlights on Steroidal Arylidene Derivatives as a Source of Pharmacologically Active Compounds: A Review.

Steroids constitute a unique class of chemical compounds, playing an important role in physiopathological processes, and have high pharmacological interest. Additionally, steroids have been associated with a relatively low toxicity and high bioavailability. Nowadays, multiple steroidal derivatives are clinically available for the treatment of numerous diseases. Moreover, different structural modifications on their skeleton have been explored, aiming to develop compounds with new and improved pharmacological properties. Thus, steroidal arylidene derivatives emerged as a relevant example of these modifications. This family of compounds has been mainly described as 17ß-hydroxysteroid dehydrogenase type 1 and aromatase inhibitors, as well as neuroprotective and anticancer agents. Besides, due to their straightforward preparation and intrinsic chemical reactivity, steroidal arylidene derivatives are important synthetic intermediates for the preparation of other compounds, particularly bearing heterocyclic systems. In fact, starting from arylidenesteroids, it was possible to develop bioactive steroidal pyrazolines, pyrazoles, pyrimidines, pyridines, spiro-pyrrolidines, amongst others. Most of these products have also been studied as anti-inflammatory and anticancer agents, as well as 5α-reductase and aromatase inhibitors. This work aims to provide a comprehensive overview of steroidal arylidene derivatives described in the literature, highlighting their bioactivities and importance as synthetic intermediates for other pharmacologically active compounds.

Recent Developments in New Therapeutic Agents against Alzheimer and Parkinson Diseases: In-Silico Approaches.

Neurodegenerative diseases (ND), including Alzheimer's (AD) and Parkinson's Disease (PD), are becoming increasingly more common and are recognized as a social problem in modern societies. These disorders are characterized by a progressive neurodegeneration and are considered one of the main causes of disability and mortality worldwide. Currently, there is no existing cure for AD nor PD and the clinically used drugs aim only at symptomatic relief, and are not capable of stopping neurodegeneration. Over the last years, several drug candidates reached clinical trials phases, but they were suspended, mainly because of the unsatisfactory pharmacological benefits. Recently, the number of compounds developed using in silico approaches has been increasing at a promising rate, mainly evaluating the affinity for several macromolecular targets and applying filters to exclude compounds with potentially unfavorable pharmacokinetics. Thus, in this review, an overview of the current therapeutics in use for these two ND, the main targets in drug development, and the primary studies published in the last five years that used in silico approaches to design novel drug candidates for AD and PD treatment will be presented. In addition, future perspectives for the treatment of these ND will also be briefly discussed.

New Estrone Oxime Derivatives: Synthesis, Cytotoxic Evaluation and Docking Studies.

The interest in the introduction of the oxime group in molecules aiming to improve their biological effects is increasing. This work aimed to develop new steroidal oximes of the estrane series with potential antitumor interest. For this, several oximes were synthesized by reaction of hydroxylamine with the 17-ketone of estrone derivatives. Then, their cytotoxicity was evaluated in six cell lines. An estrogenicity assay, a cell cycle distribution analysis and a fluorescence microscopy study with Hoechst 3358 staining were performed with the most promising compound. In addition, molecular docking studies against estrogen receptor α, steroid sulfatase, 17ß-hydroxysteroid dehydrogenase type 1 and ß-tubulin were also accomplished. The 2-nitroestrone oxime showed higher cytotoxicity than the parent compound on MCF-7 cancer cells. Furthermore, the oximes bearing halogen groups in A-ring evidenced selectivity for HepaRG cells. Remarkably, the Δ9,11-estrone oxime was the most cytotoxic and arrested LNCaP cells in the G2/M phase. Fluorescence microscopy studies showed the presence of condensed DNA typical of prophase and condensed and fragmented nuclei characteristic of apoptosis. However, this oxime promoted the proliferation of T47-D cells. Interestingly, molecular docking studies estimated a strong interaction between Δ9,11-estrone oxime and estrogen receptor α and ß-tubulin, which may account for the described effects.

Synthesis and process optimization of symmetric and unsymmetric barbiturates C5-coupled with 2,1-benzisoxazoles.

Benzisoxazoles represent an important pharmacophore in medicinal chemistry. Recently, an unexpected formation of symmetric 3-substituted 2,1-benzisoxazoles through reduction of 5-(2-nitrobenzylidene)barbiturates has been described. This reductive intramolecular heterocyclization probably involves a nitroso intermediary. To improve the previous reaction conditions, the nature of the reducing agent and additives, reaction time and solvents were evaluated. By applying the optimized conditions, several symmetric and unsymmetric barbiturates C5-coupled with 2,1-benzisoxazoles were prepared with an yield of 52-87%. From this set, seven compounds were novel and the unsymmetric nature of the (thio)barbituric acid moiety was explored. For that, the total synthesis, starting from the respective urea or thiourea, was successfully performed, and 11 thiobarbiturates, benzylidene barbiturate and thiobarbiturate precursors are described.

Nimesulide analogues: From anti-inflammatory to antitumor agents.

Nimesulide is a nonsteroidal anti-inflammatory drug possessing analgesic and antipyretic properties. This drug is considered a selective cyclooxygenase-2 (COX-2) inhibitor and, more recently, has been associated to antitumor activity. Thus, numerous works have been developed to modify the nimesulide skeleton aiming to develop new and more potent and selective COX-2 inhibitors as well as potential anticancer agents. This review intends to provide an overview on analogues of nimesulide, including the general synthetic approaches used for their preparation and structural diversification and their main anti-inflammatory and/or antitumor properties.

Considerations and Pitfalls in Selecting the Drug Vehicles for Evaluation of New Drug Candidates: Focus on in vivo Pharmaco-Toxicological Assays Based on the Rotarod Performance Test.

Purpose - During the discovery and development of new drugs, compounds with low aqueous solubility pose special challenges in their pharmacological evaluation and, therefore, the selection of appropriate vehicles to administer the compounds of interest is determinant for the quality of the results generated during the in vivo non-clinical studies. This work aimed to evaluate the motor deficit (as a surrogate of neurotoxicity) of several administration/delivery vehicles through the rotarod performance test. Methods - Trained male CD-1 mice were intraperitoneally administered with the following vehicles: dimethyl sulfoxide (DMSO), aqueous sodium chloride (NaCl) 0.9%, aqueous carboxymethylcellulose (CMC) 0.5%, polyethylene glycol (PEG)-400, propylene glycol (PG), and solutions of these vehicles containing 5% and 10% DMSO. Results - It was observed that the aqueous vehicles (NaCl 0.9% and CMC 0.5%) did not affect the performance of the animals on the rod. On the other hand, a vehicle consisting solely of DMSO led to significant motor impairment and only a small improvement was recorded over time. Additionally, a strong neuromotor toxicity was observed in the early evaluation points of the experiment using vehicles constituted by PG and PEG-400 or by mixtures of PG/DMSO (5% and 10%) and PEG-400/DMSO (5% and 10%). Conclusion - This study provides useful data about the neurotoxicity inherent to several vehicles frequently used in non-clinical pharmaco-toxicological assays, aiming to draw especial attention to the need of a careful selection of drug vehicles in order to avoid the impact of such confounding variables on the accuracy of the results and in decision-making processes. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Novel 4-acetamide-2-alkylthio-N-acetanilides resembling nimesulide: Synthesis, cell viability evaluation and in silico studies.

Since nimesulide, a nonsteroidal anti-inflammatory drug, is known to be a selective inhibitor of cyclooxygenase-2 and shows activity against cancer cells, there has been much interest in developing related molecules with enhanced anticancer properties. Taking in consideration structural features of nimesulide analogues ten new ortho-(akylthio)-N-alkylacetanilides were synthesized and fully characterized. The antiproliferative effect of these acetanilides was evaluated against human breast (MCF-7) and prostate (LNCaP) cancer cell lines as well as normal human dermal fibroblasts (NHDF). In particular, acetoacetanilides with methylcyclohexyl and/or 2,4-dimethylbenzyl groups linked to amide group and/or to sulfur atom had interesting cytotoxicities against human breast cancer cells. Moreover, these groups caused an increase in the antiproliferative effect against both cancer cells. Docking studies revealed the possibility of these acetoacetanilides to be potential ligands of the androgen receptor, though hormone-independent mechanisms may be involved in antiproliferative effects shown by these acetoacetanilides. In addition, 3D-QSAR studies demonstrated that the cytotoxic activity against the human breast cancer cell line was dependent on both bulkiness and electrostatic nature of the N- and S-alkyl groups of acetoacetanilides.

3,3'-Diamino-N-methyldipropylamine as a versatile affinity ligand.

Currently, in biomedicine and biotechnology fields, there is a growing need to develop and produce biomolecules with a high degree of purity. To accomplish this goal, new purification methods are being developed looking for higher performance, efficiency, selectivity, and cost-effectiveness. Affinity chromatography is considered one of the most highly selective methods for biomolecules purification. The purpose of this work is to explore a new type of a structurally simple ligand immobilized onto an agarose matrix to be used in affinity chromatography. The ligand in this study, 3,3'-diamino-N-methyldipropylamine has shown low toxicity and low cost of preparation. Moreover, the ability of the ligand to be used in affinity chromatography to purify proteins and nucleic acids was verified. An increasing sodium chloride gradient, using salt concentrations up to 500 mM, was suitable to accomplish the purification of these biomolecules, meaning that the new support allows the recovery of target biomolecules under mild conditions. Thus, the 3,3'-diamino-N-methyldipropylamine ligand is shown to be a useful and versatile tool in chromatographic experiments, with very good results either for proteins or supercoiled plasmid isoform purification.

Anticancer steroids: linking natural and semi-synthetic compounds.

Steroids, a widespread class of natural organic compounds occurring in animals, plants and fungi, have shown great therapeutic value for a broad array of pathologies. The present overview is focused on the anticancer activity of steroids, which is very representative of a rich structural molecular diversity and ability to interact with various biological targets and pathways. This review encompasses the most relevant discoveries on steroid anticancer drugs and leads through the last decade and comprises 668 references.

Medication and the Risk of Falls: An Analysis of Adverse Drug Reactions Reported to the Portuguese Pharmacovigilance System.

Falls are not always considered direct adverse drug reactions (ADRs). However, due to their mechanism of action, certain drugs increase the risk of falls. This retrospective study aimed to evaluate the association between drugs and the risk of falls. An analysis of ADR reports submitted to a national pharmacovigilance database from 1992 to 2021 was performed using terms from the MedDRA dictionary. This included the word "fall" and terms related to conditions potentially predisposing patients to falls. The analysis involved examining the sex and age distribution of the population. Reports were assessed for seriousness, the class of the suspected drug, and the characterisation of fall events when they occurred. Over this period, 2217 cases were reported, with the majority occurring among females (60.71%) and the age group of 18-64 years old (38.43%). Most reports were classified as serious across all age groups, and immunomodulators (16.78%) were the most frequently reported pharmacotherapeutic class of suspected drugs. Falls were reported as ADRs in 343 cases, with fractures being the most commonly reported injuries (24.45%). In conclusion, falls can pose a significant health problem. Therefore, continuously monitoring drugs is crucial to minimise fall-associated risk factors.

Fighting Epilepsy with Nanomedicines-Is This the Right Weapon?

Epilepsy is a chronic and complex condition and is one of the most common neurological diseases, affecting about 50 million people worldwide. Pharmacological therapy has been, and is likely to remain, the main treatment approach for this disease. Although a large number of new antiseizure drugs (ASDs) has been introduced into the market in the last few years, many patients suffer from uncontrolled seizures, demanding the development of more effective therapies. Nanomedicines have emerged as a promising approach to deliver drugs to the brain, potentiating their therapeutic index. Moreover, nanomedicine has applied the knowledge of nanoscience, not only in disease treatment but also in prevention and diagnosis. In the current review, the general features and therapeutic management of epilepsy will be addressed, as well as the main barriers to overcome to obtain better antiseizure therapies. Furthermore, the role of nanomedicines as a valuable tool to selectively deliver drugs will be discussed, considering the ability of nanocarriers to deal with the less favourable physical-chemical properties of some ASDs, enhance their brain penetration, reduce the adverse effects, and circumvent the concerning drug resistance.

Resveratrol as an Inhibitor of the NorA Efflux Pump and Resistance Modulator in Staphylococcus aureus.

Staphylococcus aureus can exhibit resistance to various antibiotics. Among its resistance mechanisms, the active efflux of antibiotics can be seen as relevant. This study aimed to evaluate the ability of resveratrol to modulate norfloxacin resistance in S. aureus. The antimicrobial activity of resveratrol was assessed using the broth microdilution method to determine the minimum inhibitory concentration (MIC). Then, the modulatory effect of resveratrol was evaluated using the MIC determination for the antibiotic or ethidium bromide in the presence and absence of resveratrol at a sub-MIC level. The MIC of norfloxacin against S. aureus SA1199B (NorA-overexpressing strain) decreased 16-fold when in the presence of resveratrol, with a similar behavior being observed for ethidium bromide. An evaluation of the ethidium bromide accumulation was also performed, showing that in the presence of resveratrol, the SA1199B strain had augmented fluorescence due to the accumulation of ethidium bromide. Altogether, the results suggested that resveratrol may act by inhibiting NorA. These in vitro data were supported by docking results, with interactions between resveratrol and the NorA efflux pump predicted to be favorable. Our findings demonstrated that resveratrol may modulate norfloxacin resistance through the inhibition of NorA, increasing the effectiveness of this antibiotic against S. aureus.

Design, synthesis, and biological evaluation of new arjunolic acid derivatives as anticancer agents.

Arjunolic acid (AA) is a pentacyclic triterpenoid with promising anticancer properties. A series of novel AA derivatives containing a pentameric A-ring with an enal moiety, combined with additional modifications at C-28, were designed and prepared. The biological activity on the viability of human cancer and non-tumor cell lines was evaluated in order to identify the most promising derivatives. Additionally, a preliminary study of the structure-activity relationship was carried out. The most active derivative, derivative 26, also showed the best selectivity between malignant cells and non-malignant fibroblasts. For compound 26, the anticancer molecular mechanism of action in PANC-1 cells was further studied and the results showed that this derivative induced a cell-cycle arrest at G0/G1 phase and significantly inhibited the wound closure rate of PANC-1 cancer cells in a concentration-dependent manner. Additionally, compound 26 synergistically increased the cytotoxicity of Gemcitabine, especially at a concentration of 0.24 µM. Moreover, a preliminary pharmacological study indicated that at lower doses this compound did not demonstrate toxicity in vivo. Taken together, these findings suggest that compound 26 may be a valuable compound for the development of new pancreatic anticancer treatment, and further studies are needed to explore its full potential.

Synthesis, In Vitro Biological Evaluation of Antiproliferative and Neuroprotective Effects and In Silico Studies of Novel 16E-Arylidene-5α,6α-epoxyepiandrosterone Derivatives.

Steroids constitute an important class of pharmacologically active molecules, playing key roles in human physiology. Within this group, 16E-arylideneandrostane derivatives have been reported as potent anti-cancer agents for the treatment of leukemia, breast and prostate cancers, and brain tumors. Additionally, 5α,6α-epoxycholesterol is an oxysterol with several biological activities, including regulation of cell proliferation and cholesterol homeostasis. Interestingly, pregnenolone derivatives combining these two modifications were described as potential neuroprotective agents. In this research, novel 16E-arylidene-5α,6α-epoxyepiandrosterone derivatives were synthesized from dehydroepiandrosterone by aldol condensation with different aldehydes followed by a diastereoselective 5α,6α-epoxidation. Their cytotoxicity was evaluated on tumoral and non-tumoral cell lines by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Furthermore, the assessment of the neuroprotective activity of these derivatives was performed in a dopaminergic neuronal cell line (N27), at basal conditions, and in the presence of the neurotoxin 6-hydroxydopamine (6-OHDA). Interestingly, some of these steroids had selective cytotoxic effects in tumoral cell lines, with an IC50 of 3.47 µM for the 2,3-dichlorophenyl derivative in the breast cancer cell line (MCF-7). The effects of this functionalized epoxide on cell proliferation (Ki67 staining), cell necrosis (propidium iodide staining), as well as the analysis of the nuclear area and near neighbor distance in MCF-7 cells, were analyzed. From this set of biological studies, strong evidence of the activation of apoptosis was found. In contrast, no significant neuroprotection against 6-OHDA-induced neurotoxicity was observed for the less cytotoxic steroids in N27 cells. Lastly, molecular docking simulations were achieved to verify the potential affinity of these compounds against important targets of steroidal drugs (androgen receptor, estrogen receptor α, and 5α-reductase type 2, 17α-hydroxylase-17,20-lyase and aromatase enzymes). This in silico study predicted a strong affinity between most novel steroidal derivatives and 5α-reductase and 17α-hydroxylase-17,20-lyase enzymes.

Innovative Aqueous Nanoemulsion Prepared by Phase Inversion Emulsification with Exceptional Homogeneity.

Formulating low-solubility or low-permeability drugs is a challenge, particularly with the low administration volumes required in intranasal drug delivery. Nanoemulsions (NE) can solve both issues, but their production and physical stability can be challenging, particularly when a high proportion of lipids is necessary. Hence, the aim of the present work was to develop a NE with good solubilization capacity for lipophilic drugs like simvastatin and able to promote the absorption of drugs with low permeability like fosphenytoin. Compositions with high proportion of two lipids were screened and characterized. Surprisingly, one of the compositions did not require high energy methods for high droplet size homogeneity. To better understand formulation factors important for this feature, several related compositions were evaluated, and their relative cytotoxicity was screened. Optimized compositions contained a high proportion of propylene glycol monocaprylate NF, formed very homogenous NE using a low-energy phase inversion method, solubilized simvastatin at high drug strength, and promoted a faster intranasal absorption of the hydrophilic prodrug fosphenytoin. Hence, a new highly homogeneous NE obtained by a simple low-energy method was successfully developed, which is a potential alternative for industrial application for the solubilization and protection of lipophilic actives, as well as (co-)administration of hydrophilic molecules.

New Scaffolds of Proteasome Inhibitors: Boosting Anticancer Potential by Exploiting the Synergy of In Silico and In Vitro Methodologies.

Cancer is a complex multifactorial disease whose pathophysiology involves multiple metabolic pathways, including the ubiquitin-proteasome system, for which several proteasome inhibitors have already been approved for clinical use. However, the resistance to existing therapies and the occurrence of severe adverse effects is still a concern. The purpose of this study was the discovery of novel scaffolds of proteasome inhibitors with anticancer activity, aiming to overcome the limitations of the existing proteasome inhibitors. Thus, a structure-based virtual screening protocol was developed using the structure of the human 20S proteasome, and 246 compounds from virtual databases were selected for in vitro evaluation, namely proteasome inhibition assays and cell viability assays. Compound 4 (JHG58) was shortlisted as the best hit compound based on its potential in terms of proteasome inhibitory activity and its ability to induce cell death (both with IC50 values in the low micromolar range). Molecular docking studies revealed that compound 4 interacts with key residues, namely with the catalytic Thr1, Ala20, Thr21, Lys33, and Asp125 at the chymotrypsin-like catalytic active site. The hit compound is a good candidate for additional optimization through a hit-to-lead campaign.