Benzocarbazoledinones as SARS-CoV-2 Replication Inhibitors: Synthesis, Cell-Based Studies, Enzyme Inhibition, Molecular Modeling, and Pharmacokinetics Insights.

Endemic and pandemic viruses represent significant public health challenges, leading to substantial morbidity and mortality over time. The COVID-19 pandemic has underscored the urgent need for the development and discovery of new, potent antiviral agents. In this study, we present the synthesis and anti-SARS-CoV-2 activity of a series of benzocarbazoledinones, assessed using cell-based screening assays.

Synthesis and evaluation of hybrid sulfonamide-chalcones with potential antileishmanial activity.

Leishmaniasis is an emerging tropical infectious disease caused by a protozoan parasite of the genus Leishmania. In this work, the molecular hybridization between a trimethoxy chalcone and a sulfonamide group was used to generate a series of sulfonamide-chalcones. A series of eight sulfonamide-chalcone hybrids were made with good yields (up to 95%).

Indications for carotid Doppler ultrasound in asymptomatic patients - are we ordering it correctly?

Background: Carotid arteries are frequently the site of pathologies, the most common being atherosclerosis, which may result in the formation of plaques, causing stenosis. Doppler ultrasound is currently the exam of choice for assessment of the carotid arteries in asymptomatic patients to screen for and diagnose vascular lesions. Current guidelines recommend screening patients who have risk factors for carotid stenosis and who are able and willing to undergo medical treatment and/or carotid intervention.

Aurones: A Promising Scaffold to Inhibit SARS-CoV-2 Replication.

Aurones are a small subgroup of flavonoids in which the basic C-C-C skeleton is arranged as ()-2-benzylidenebenzofuran-3(2)-one. These compounds are structural isomers of flavones and flavonols, natural products reported as potent inhibitors of SARS-CoV-2 replication. Herein, we report the design, synthesis, and anti-SARS-CoV-2 activity of a series of 25 aurones bearing different oxygenated groups (OH, OCH, OCHOCH, OCHO, OCFH, and OCHCHR) at the A- and/or B-rings using cell-based screening assays.

Low doses of 3-phenyl-lawsone or meglumine antimoniate delivery by tattooing route are successful in reducing parasite load in cutaneous lesions of () -infected hamsters.

Current therapeutic ways adopted for the treatment of leishmaniasis are toxic and expensive including parasite resistance is a growing problem. Given this scenario, it is urgent to explore treatment alternatives for leishmaniasis. The aim of this study was to evaluate the effect of 3-phenyl-lawsone (3-PL) naphthoquinone on () infection, both and , using two local routes of administration: subcutaneous (higher dose) and tattoo (lower dose).

From Spanish Flu to Syndemic COVID-19: long-standing sanitarian vulnerability of Manaus, warnings from the Brazilian rainforest gateway.

A second deadlier wave of COVID-19 and the causes of the recent public health collapse of Manaus are compared with the Spanish flu events in that city, and Brazil. Historic sanitarian problems, and its hub position in the Brazilian airway network are combined drivers of deadly events related to COVID-19. These drivers were amplified by misleading governance, highly transmissible variants, and relaxation of social distancing.

Worldwide COVID-19 spreading explained: traveling numbers as a primary driver for the pandemic.

The spread of SARS-CoV-2 and the distribution of cases worldwide followed no clear biogeographic, climatic, or cultural trend. Conversely, the internationally busiest cities in all countries tended to be the hardest hit, suggesting a basic, mathematically neutral pattern of the new coronavirus early dissemination. We tested whether the number of flight passengers per time and the number of international frontiers could explain the number of cases of COVID-19 worldwide by a stepwise regression.

Oncotherapy: A Decision Support System to Validate Oncological Treatments.

Making therapy decisions in oncology is a challenging task in the medical precision era. Oncotherapy is a decision support system that provides oncologists with suitable therapies for the patient within the national guidelines. The system is capable, on the one hand, to help the oncologist to maximize fitting therapy to the patient and, on the other hand, to provide control tools for the country's sanitary authorities.

Lapachol and synthetic derivatives: in vitro and in vivo activities against Bothrops snake venoms.

Background: It is known that local tissue injuries incurred by snakebites are quickly instilled causing extensive, irreversible, tissue destruction that may include loss of limb function or even amputation. Such injuries are not completely neutralized by the available antivenins, which in general are focused on halting systemic effects. Therefore it is prudent to investigate the potential antiophidic effects of natural and synthetic compounds, perhaps combining them with serum therapy, to potentially attenuate or eliminate the adverse local and systemic effects of snake venom.

Second-generation pterocarpanquinones: synthesis and antileishmanial activity.

Background: Despite the development of new therapies for leishmaniasis, among the 200 countries or territories reporting to the WHO, 87 were identified as endemic for Tegumentary Leishmaniasis and 75 as endemic for Visceral Leishmaniasis. The identification of antileishmanial drug candidates is essential to fill the drug discovery pipeline for leishmaniasis. In the hit molecule LQB-118 selected, the first generation of pterocarpanquinones was effective and safe against experimental visceral and cutaneous leishmaniasis via oral delivery.

Anti-inflammatory properties of pterocarpanquinone LQB-118 in mice.

Pterocarpanquinone (+/-)-LQB-118 presents antineoplastic and antiparasitic properties and also shows great inhibitory effect on TNF-α release in vitro. Here, its anti-inflammatory activity was evaluated in a lipopolysaccharide (LPS)-induced lung inflammation model in C57BL/6 mice. LPS inhalation induced a marked neutrophil infiltration to the lungs which was reduced by intraperitoneal treatment with (+/-)-LQB-118 in a similar manner to that of dexamethasone and even better than that of acetylsalicylic acid.

Further evidence that naphthoquinone inhibits Toxoplasma gondii growth in vitro.

Toxoplasmosis is a widely disseminated disease caused by Toxoplasma gondii, an intracellular protozoan parasite. Standard treatment causes many side effects, such as depletion of bone marrow cells, skin rashes and gastrointestinal implications. Therefore, it is necessary to find chemotherapeutic alternatives for the treatment of this disease.

Pterocarpanquinone LQB-118 induces apoptosis in Leishmania (Viannia) braziliensis and controls lesions in infected hamsters.

Previous results demonstrate that the hybrid synthetic pterocarpanquinone LQB-118 presents antileishmanial activity against Leishmania amazonensis in a mouse model. The aim of the present study was to use a hamster model to investigate whether LQB-118 presents antileishmanial activity against Leishmania (Viannia) braziliensis, which is the major Leishmania species related to American tegumentary leishmaniasis. The in vitro antileishmanial activity of LQB-118 on L.

Plasmodium ovale malaria in Brazil: report of an imported case with a prolonged incubation period.

We report the first case of imported Plasmodium ovale in Brazil, confirmed using both conventional microscopy and PCR-based protocols. The patient was a 36-year-old Brazilian male who had been working as a miner in Cabinda Province, Angola. Based on his travel history, the parasite was dormant for at least two years.

LQB-118, an orally active pterocarpanquinone, induces selective oxidative stress and apoptosis in Leishmania amazonensis.

Objectives: The pterocarpanquinone LQB-118, previously demonstrated to be effective in vivo via oral delivery, was investigated for its mechanism in selective parasite killing.

Methods: Oxidative stress in Leishmania amazonensis was analysed by evaluating reactive oxygen species (ROS) production (2',7'-dichlorodihydrofluorescein diacetate) and the loss of mitochondrial membrane potential (ΔΨm) using rhodamine, JC-1 and MitoCapture. Ultrastructural analysis was performed using transmission electron microscopy (TEM).

The pterocarpanquinone LQB 118 induces apoptosis in tumor cells through the intrinsic pathway and the endoplasmic reticulum stress pathway.

LQB 118 is a pterocarpanquinone compound synthesized by our group. It has already been shown that it acts against different leukemia cell lines. However, little is known about the pathway through which this compound induces the death of these cells.

The therapeutical potential of a novel pterocarpanquinone LQB-118 to target inhibitor of apoptosis proteins in acute myeloid leukemia cells.

Acute myeloid leukemia (AML) is a challenging neoplasm that despite therapeutic advances requires efforts to overcome the multidrug resistance (MDR) phenotype, the major cause of relapse. The pterocarpanquinone LQB-118 is a new compound that induces apoptosis in leukemia cells. The objective of this work was to analyze the role of LQB-118 in inhibiting the inhibitor of apoptosis proteins (IAPs), XIAP and survivin, as well as in modulating the subcellular localization of NFκB, in comparison with idarubicin.

A new type of pterocarpanquinone that affects Toxoplasma gondii tachyzoites in vitro.

Toxoplasma gondii, the agent of Toxoplasmosis, is an obligate intracellular protozoan able to infect a wide range of vertebrate cells, including nonprofessional and professional phagocytes. Therefore, drugs must have intracellular activities in order to control this parasite. The most common therapy for Toxoplasmosis is the combination of sulfadiazine and pyrimethamine.

Effectiveness of the local or oral delivery of the novel naphthopterocarpanquinone LQB-118 against cutaneous leishmaniasis.

Objectives: This paper describes the antileishmanial properties of LQB-118, a new compound designed by molecular hybridization, orally active in Leishmania amazonensis-infected BALB/c mice.

Methods: In vitro antileishmanial activity was determined in L. amazonensis-infected macrophages.

Palladium-catalyzed tandem Heck-lactonization from o-iodophenols and enoates: synthesis of coumarins and the study of the mechanism by electrospray ionization mass spectrometry.

The tandem Heck-lactonization reaction between enoates Z-1a,b, E-1a, E-2a-d, Z-2e, 2f, and o-iodophenols (4a-f) was studied in the presence of substoichiometric amounts of Pd(OAc)(2) or PdCl(2), under experimental conditions favoring the cationic mechanism (conditions A, B, and C), leading to coumarins 5a-f and 6a-e. Moderate to excellent yields were obtained under aqueous conditions (conditions A and B). Using electrospray ionization for transferring ions directly from solution to the gas phase, and mass spectrometry for structural assignments, key cationic palladium intermediates have been successfully intercepted and structurally characterized for the first time for this type of reaction.

LQB-118, a pterocarpanquinone structurally related to lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone]: a novel class of agent with high apoptotic effect in chronic myeloid leukemia cells.

Despite the relevant therapeutic progresses obtained with imatinib, clinical resistance to this drug has emerged and reemerged after cytogenetic remission in a group of patients with chronic myeloid leukemia (CML). Therefore, novel treatment strategies are needed. In this study, we evaluated the anti-CML activity and mechanisms of action of LQB-118, a pterocarpanquinone structurally related to lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone].

New pterocarpanquinones: synthesis, antineoplasic activity on cultured human malignant cell lines and TNF-alpha modulation in human PBMC cells.

A new pterocarpanquinone (5a) was synthesized through a palladium catalyzed oxyarylation reaction and was transformed, through electrophilic substitution reaction, into derivatives 5b-d. These compounds showed to be active against human leukemic cell lines and human lung cancer cell lines. Even multidrug resistant cells were sensitive to 5a, which presented low toxicity toward peripheral blood mononuclear cells (PBMC) cells and decreased the production of TNF-alpha by these cells.

Ability of a synthetic coumestan to antagonize Bothrops snake venom activities.

We investigated a synthetic coumestan named LQB93 and similar compounds abilities to antagonize activities of Bothrops jararacussu and Bothrops jararaca crude venoms in different protocols. The antimyotoxic activity was evaluated in vitro by the rate of release of creatine kinase (CK) from isolated mouse extensor digitorum longus muscle (EDL) induced by B. jararacussu (25 g/ml).

Comparison of the cytotoxic effect of lapachol, alpha-lapachone and pentacyclic 1,4-naphthoquinones on human leukemic cells.

The pentacyclic 1,4-naphthoquinones 1a-d were cytotoxic (IC(50) approximately 2-7 microM) to human leukemic cell lines K562 (oxidative stress-resistant), Lucena-1 (MDR phenotype) and Daudi. Fresh leukemic cells obtained from patients, some with the MDR phenotype, were also sensitive to these compounds. The pentacyclic 1,4-naphthoquinones 1a and 1c induced apoptotic cell death in cells from leukemic patients as determined by flow cytometry.

Insights into the mechanism of Na+,K+-ATPase inhibition by 2-methoxy-3,8,9-trihydroxy coumestan.

The molecular mechanisms involved in Na+,K+-ATPase inhibition by 2-methoxy-3,8,9-trihydroxy coumestan were investigated. We show that this compound decreases the free sulfydryl groups present in the enzyme and that its inhibitory effect is prevented by dithiothreitol and other two sulfydryl containing reagents. We propose a redox cycle culminating with the irreversible oxidation of sulfydryl groups essential for the catalytic activity of this enzyme and of two other related P-type ATPases.