Abietane Diterpenes from Medusantha martiusii and Their Anti-Neuroinflammatory Activity.

Seven new abietane diterpenoids, comprising medusanthol A-G (1-3, 5, 7-9) and two previously identified analogs (4 and 6), were isolated from the hexane extract of the aerial parts of Medusantha martiusii. The structures of the compounds were elucidated by HRESIMS, 1D/2D NMR spectroscopic data, IR spectroscopy, NMR calculations with DP4+ probability analysis, and ECD calculations. The anti-neuroinflammatory potential of compounds 1-7 was evaluated by determining their ability to inhibit the production of nitric oxide (NO) and the proinflammatory cytokine TNF-α in BV2 microglia stimulated with LPS and IFN-γ. Compounds 1-4 and 7 exhibited decreased NO levels at a concentration of 12.5 µM. Compound 1 demonstrated strong activity with an IC50 of 3.12 µM, and compound 2 had an IC50 of 15.53 µM; both compounds effectively reduced NO levels compared to the positive control quercetin (IC50 11.8 µM). Additionally, both compounds significantly decreased TNF-α levels, indicating their potential as promising anti-neuroinflammatory agents.

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

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

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

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

Semisynthetic Sesquiterpene Lactones Generated by the Sensibility of Glaucolide B to Lewis and Brønsted-Lowry Acids and Bases: Cytotoxicity and Anti-Inflammatory Activities.

Sesquiterpene lactone (SL) subtypes including hirsutinolide and cadinanolide have a controversial genesis. Metabolites of these classes are either described as natural products or as artifacts produced via the influence of solvents, chromatographic mobile phases, and adsorbents used in phytochemical studies. Based on this divergence, and to better understand the sensibility of these metabolites, different pH conditions were used to prepare semisynthetic SLs and evaluate the anti-inflammatory and antiproliferative activities. Therefore, glaucolide B (1) was treated with various Brønsted-Lowry and Lewis acids and bases-the same approach was applied to some of its derivatives-allowing us to obtain 14 semisynthetic SL derivatives, 10 of which are hereby reported for the first time. Hirsutinolide derivatives 7a (CC50 = 5.0 µM; SI = 2.5) and 7b (CC50 = 11.2 µM; SI = 2.5) and the germacranolide derivative 8a (CC50 = 3.1 µM; SI = 3.0) revealed significant cytotoxic activity and selectivity against human melanoma SK-MEL-28 cells when compared with that against non-tumoral HUVEC cells. Additionally, compounds 7a and 7c.1 showed strongly reduced interleukin-6 (IL-6) and nitrite (NOx) release in pre-treated M1 macrophages J774A.1 when stimulated with lipopolysaccharide. Despite the fact that hirsutinolide and cadinanolide SLs may be produced via plant metabolism, this study shows that acidic and alkaline extraction and solid-phase purification processes can promote their formation.

Targeted Isolation of Anti-inflammatory Lignans from Justicia aequilabris by Molecular Networking Approach.

Herein, the isolation of secondary metabolites from the aerial parts of Justicia aequilabris guided by HPLC-MSn and molecular networking analyses is reported. Twenty-two known compounds were dereplicated. Three new lignans (aequilabrines A-C (1-3)) and three known compounds (lariciresinol-4'-O-ß-glucose (4), roseoside (5), and allantoin (6)) were obtained. The anti-inflammatory activity of compounds 1-3 was evaluated in vitro by inhibiting the nitric oxide production (NO) and pro-inflammatory activity on the cytokine IL-1ß. Compounds 2 and 3 showed significant inhibitory activity against NO production, with IC50 values of 9.1 and 7.3 µM, respectively. The maximum inhibition of IL-1ß production was 23.5% (1), 27.3% (2), and 32.5% (3).

PTML modeling for peptide discovery: in silico design of non-hemolytic peptides with antihypertensive activity.

Hypertension is a medical condition that affects millions of people worldwide. Despite the high efficacy of the current antihypertensive drugs, they are associated with serious side effects. Peptides constitute attractive options for chemical therapy against hypertension, and computational models can accelerate the design of antihypertensive peptides. Yet, to the best of our knowledge, all the in silico models predict only the antihypertensive activity of peptides while neglecting their inherent toxic potential to red blood cells. In this work, we report the first sequence-based model that combines perturbation theory and machine learning through multilayer perceptron networks (SB-PTML-MLP) to enable the simultaneous screening of antihypertensive activity and hemotoxicity of peptides. We have interpreted the molecular descriptors present in the model from a physicochemical and structural point of view. By strictly following such interpretations as guidelines, we performed two tasks. First, we selected amino acids with favorable contributions to both the increase of the antihypertensive activity and the diminution of hemotoxicity. Then, we assembled those suitable amino acids, virtually designing peptides that were predicted by the SB-PTML-MLP model as antihypertensive agents exhibiting low hemotoxicity. The potentiality of the SB-PTML-MLP model as a tool for designing potent and safe antihypertensive peptides was confirmed by predictions performed by online computational tools reported in the scientific literature. The methodology presented here can be extended to other pharmacological applications of peptides.

Milonine attenuates the lipopolysaccharide-induced acute lung injury in mice by modulating the Akt/NF-κB signaling pathways.

Acute lung injury is an inflammation that triggers acute respiratory distress syndrome with perialveolar neutrophil infiltration, alveolar-capillary barrier damage, and lung edema. Activation of the toll-like receptor 4 complex (TLR4/MD2) and its downstream signaling pathways are responsible for the cytokine storm and cause alveolar damage. Due to the complexity of this pulmonary inflammation, a defined pharmacotherapy has not been established. Thus, this study evaluated the anti-inflammatory potential of milonine, an alkaloid of Cissampelos sympodialis Eichl, in an experimental model of lung inflammation. BALB/c mice were lipopolysaccharide-challenged and treated with milonine at 2.0 mg/kg. Twenty-four hours later, the bronchoalveolar fluid, peripheral blood, and lungs were collected for cellular and molecular analysis. The milonine treatment decreased the cell migration (mainly neutrophils) to the alveoli, the pulmonary edema, and the cytokine levels (IL-1ß, IL-6, TNF-α). The systemic IL-6 level was also reduced. The milonine docking analysis demonstrated hydrophobic interaction at TLR4/MD2 groove with Ile124 and Phe126 amino acids. Indeed, the alkaloid downregulated the kinase-Akt and NF-κB through TLR4/MD2. Therefore, milonine is an effective inflammatory modulator being a potential molecule for the treatment of lung inflammation.

The SistematX Web Portal of Natural Products: An Update.

Natural products and their secondary metabolites are promising starting points for the development of drug prototypes and new drugs, as many current treatments for numerous diseases are directly or indirectly related to such compounds. State-of-the-art, curated, integrated, and frequently updated databases of secondary metabolites are thus highly relevant to drug discovery. The SistematX Web Portal, introduced in 2018, is undergoing development to address this need and documents crucial information about plant secondary metabolites, including the exact location of the species from which the compounds were isolated. SistematX also allows registered users to log in to the data management area and gain access to administrative pages. This study reports recent updates and modifications to the SistematX Web Portal, including a batch download option, the generation and visualization of 1H and 13C nuclear magnetic resonance spectra, and the calculation of physicochemical (drug-like and lead-like) properties and biological activity profiles. The SistematX Web Portal is freely available at http://sistematx.ufpb.br.

Bioactive Compounds from the Aerial Parts of Evolvulus linarioides.

Three new caryophyllane-type sesquiterpenoids, linariophyllenes A-C (1-3), two new hamamelitol derivatives, linaritols A (4) and B (5), two new chromones, linariosides A (6) and B (7), and three known chromones, cnidimol C (8), monnieriside A (9), and undulatoside A (10), were identified from the aerial parts of Evolvulus linarioides. The structures of these compounds were elucidated by NMR, MS, and IR data. The absolute configurations of compounds 1-5 and 7 were established via electronic circular dichroism data. The anti-inflammatory potential of compounds 1-5 and 7-10 was evaluated by determining their ability to inhibit the production of nitric oxide (NO) and proinflammatory cytokine IL-1ß by stimulated J774 macrophages. Compounds tested at noncytotoxic concentrations inhibited NO production by macrophages, exhibiting IC50 values between 17.8 and 66.2 µM, and inhibited IL-1ß production by stimulated macrophages by 72.7-96.2%.

BET bromodomain inhibitors: fragment-based in silico design using multi-target QSAR models.

Epigenetics has become a focus of interest in drug discovery. In this sense, bromodomain-containing proteins have emerged as potential epigenetic targets in cancer research and other therapeutic areas. Several computational approaches have been applied to the prediction of bromodomain inhibitors. Nevertheless, such approaches have several drawbacks such as the fact that they predict activity against only one bromodomain-containing protein, using structurally related compounds. Also, there are no reports focused on meaningfully analyzing the physicochemical/structural features that are necessary for the design of a bromodomain inhibitor. This work describes the development of two different multi-target models based on quantitative structure-activity relationships (mt-QSAR) for the prediction and in silico design of multi-target bromodomain inhibitors against the proteins BRD2, BRD3, and BRD4. The first model relied on linear discriminant analysis (LDA) while the second focused on artificial neural networks. Both models exhibited accuracies higher than 85% in the dataset. Several molecular fragments were extracted, and their contributions to the inhibitory activity against the three BET proteins were calculated by the LDA model. Six molecules were designed by assembling the fragments with positive contributions, and they were predicted as multi-target BET bromodomain inhibitors by the two mt-QSAR models. Molecular docking calculations converged with the predictions performed by the mt-QSAR models, suggesting that the designed molecules can exhibit potent activity against the three BET proteins. These molecules complied with the Lipinski's rule of five.

Larvicidal Compounds Extracted from Helicteres velutina K. Schum (Sterculiaceae) Evaluated against Aedes aegypti L.

Helicteres velutina K. Schum (Sterculiaceae), a member of Malvaceae sensu lato, is a Brazilian endemic plant that has been used by the indigenous tribe Pankarare as an insect repellent. A previous study has reported the isolation of terpenoids, flavonoids and pheophytins, in addition to the larvicidal activity of crude H. velutina extracts derived from the aerial components (leaves, branches/twigs, and flowers). The present study reports the biomonitoring of the effects of fractions and isolated compounds derived from H. velutina against A. aegypti fourth instar larvae. A crude ethanol extract was submitted to liquid-liquid extraction with hexane, dichloromethane, ethyl acetate and n-butanol to obtain their respective fractions. Larvicidal evaluations of the fractions were performed, and the hexane and dichloromethane fractions exhibited greater activities than the other fractions, with LC50 (50% lethal concentration) values of 3.88 and 5.80 mg/mL, respectively. The phytochemical study of these fractions resulted in the isolation and identification of 17 compounds. The molecules were subjected to a virtual screening protocol, and five molecules presented potential larvicidal activity after analyses of their applicability domains. When molecular docking was analysed, only three of these compounds showed an ability to bind with sterol carrier protein-2 (1PZ4), a protein found in the larval intestine. The compounds tiliroside and 7,4'-di-O-methyl-8-O-sulphate flavone showed in vitro larvicidal activity, with LC50 values of 0.275 mg/mL after 72 h and 0.182 mg/mL after 24 h of exposure, respectively. This is the first study to demonstrate the larvicidal activity of sulphated flavonoids against A. aegypti. Our results showed that the presence of the OSO3H group attached to C-8 of the flavonoid was crucial to the larvicidal activity. This research supports the traditional use of H. velutina as an alternative insecticide for the control of A. aegypti, which is a vector for severe arboviruses, such as dengue and chikungunya.

Antileishmanial activity of new thiophene-indole hybrids: Design, synthesis, biological and cytotoxic evaluation, and chemometric studies.

In the present work, thirty-two hybrid compounds containing cycloalka[b]thiophene and indole moieties (TN5, TN5 1-7, TN6, TN6 1-7, TN7, TN7 1-7, TN8, TN8 1-7) were designed, synthesized and evaluated for their cytotoxic and antileishmanial activity against Leishmania amazonensis promastigotes. More than half of the compounds (18 compounds) exhibited significant antileishmanial activity (IC50 lower than 10.0µg/L), showing better performance than the reference drugs (tri- and penta-valent antimonials). The most active compounds were TN8-7, TN6-1 and TN7 with respective IC50 values of 2.1, 2.3 and 3.2µg/mL. Demonstrating that all of the compounds were less toxic than the reference drugs, even at the highest evaluated concentration (400µg/mL), no compound tested presented human erythrocyte cytotoxicity. Compound TN8-7's effectiveness against a trivalent antimony-resistant culture was demonstrated. It was observed that TN8-7's antileishmanial activity is associated with DNA fragmentation of L. amazonensis promastigotes. Chemometric studies (CPCA, PCA, and PLS) highlight intrinsic solubility/lipophilicity, and compound size and shape as closely related to activity. Our results suggest that hybrid cycloalka[b]thiophene-indole derivatives may be considered as lead compounds for further development of new drugs for the treatment of leishmaniasis.

Quantitative structure-sorption relationships of pesticides used in the sugarcane industry in the northern coastal area of Paraíba State, Brazil.

Sorption coefficients (K(oc)) are useful in the prediction of whether a pesticide will remain dissolved in solution or will become adsorbed onto soil particles after its application. Measuring this process experimentally is difficult, expensive and time-consuming. Hence, much effort has been directed toward estimating K(oc) through statistical modelling. In this study, we investigated the physicochemical properties of pesticides employed by a local sugarcane company, in the northern coastal plain of Paraíba state in Brazil, by using several molecular descriptors, among them, GRid INdependent Descriptors (GRIND). Quantitative assessment of the structure-property relationship (QSPR) model indicated that size, shape, octanol-water coefficient, solubility and the balance between hydrophilic and lipophilic regions, are all relevant to K(oc) values.

A benzoic acid derivative and flavokawains from Piper species as schistosomiasis vector controls.

The search of alternative compounds to control tropical diseases such as schistosomiasis has pointed to secondary metabolites derived from natural sources. Piper species are candidates in strategies to control the transmission of schistosomiasis due to their production of molluscicidal compounds. A new benzoic acid derivative and three flavokawains from Piper diospyrifolium, P. cumanense and P. gaudichaudianum displayed significant activities against Biomphalaria glabrata snails. Additionally, "in silico" studies were performed using docking assays and Molecular Interaction Fields to evaluate the physical-chemical differences among the compounds in order to characterize the observed activities of the test compounds against Biomphalaria glabrata snails.

Antiparasitic activity of natural and semi-synthetic tirucallane triterpenoids from Schinus terebinthifolius (Anacardiaceae): structure/activity relationships.

Leishmaniasis and Chagas are diseases caused by parasitic protozoans that affect the poorest population in the World, causing a high mortality and morbidity. As a result of highly toxic and long-term treatments, the discovery of novel, safe and more efficacious drugs is essential. In this work, the in vitro antiparasitic activity and mammalian cytotoxicity of three natural tirucallane triterpenoids, isolated from leaves of Schinus terebinthifolius (Anacardiaceae), and nine semi-synthetic derivatives were investigated against Leishmania (L.) infantum and Trypanosoma cruzi. Trypomastigotes of T. cruzi were the most susceptible parasites and seven compounds demonstrated a trypanocidal activity with IC50 values in the range between 15 and 58 µg/mL. Four compounds demonstrated selectivity towards the intracellular amastigotes of Leishmania, with IC50 values in the range between 28 and 97 µg/mL. The complete characterization of triterpenoids was afforded after thorough analysis of nuclear magnetic resonance (NMR) data as well as electrospray ionization mass spectrometry (ESI-MS). Additionally, structure-activity relationships were performed using Decision Trees.

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

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

Anticonvulsant activity of Tetrahydrolinalool: behavioral, electrophysiological, and molecular docking approaches.

Tetrahydrolinalool (THL) is an acyclic monoterpene alcohol, produced during linalol metabolism and also a constituent of essential oils. As described in the literature, many monoterpenes present anticonvulsant properties, and thus we became interested in evaluating the anticonvulsant activity of Tetrahydrolinalool using in mice model as well as in silico approaches. Our results demonstrated that THL increased latency to seizure onset and also reduced the mortality, in picrotoxin induced seizure tests. The results may be related to GABAergic regulation, which was also suggested in seizure testing induced by 3-mercapto-propionic acid. In the strychnine-induced seizure testing, none of the groups pretreated with THL modulated the parameters indicative of anticonvulsant effect. The electrophysiological results revealed that THL treatment reduces seizures induced by pentylenetetrazole. The in silico molecular docking studies showed that the interaction between THL and a GABAA receptor model formed a stable complex, in comparison to the crystaligraphic structure of diazepam, a structurally related ligand. In conclusion, all the evidences showed that THL presents effective anticonvulsant activity related to the GABAergic pathway, being a candidate for treatment of epileptic syndromes.

An In Silico Approach to Exploring the Antinociceptive Biological Activities of Linalool and its Metabolites.

Pain is characterized by the unpleasant sensory and emotional sensation associated with actual or potential tissue damage, whereas nociception refers to the mechanism by which noxious stimuli are transmitted from the periphery to the CNS. The main drugs used to treat pain are nonsteroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics, which have side effects that limit their use. Therefore, in the search for new drugs with potential antinociceptive effects, essential oils have been studied, whose constituents (monoterpenes) are emerging as a new therapeutic possibility. Among them, linalool and its metabolites stand out. The present study aims to investigate the antinociceptive potential of linalool and its metabolites through a screening using an in silico approach. Molecular docking was used to evaluate possible interactions with important targets involved in antinociceptive activity, such as α2-adrenergic, GABAergic, muscarinic, opioid, adenosinergic, transient potential, and glutamatergic receptors. The compounds in the investigated series obtained negative energies for all enzymes, representing satisfactory interactions with the targets and highlighting the multi-target potential of the L4 metabolite. Linalool and its metabolites have a high likelihood of modulatory activity against the targets involved in nociception and are potential candidates for future drugs.

Synthesis, structure-activity relationships (SAR) and in silico studies of coumarin derivatives with antifungal activity.

The increased incidence of opportunistic fungal infections, associated with greater resistance to the antifungal drugs currently in use has highlighted the need for new solutions. In this study twenty four coumarin derivatives were screened in vitro for antifungal activity against strains of Aspergillus. Some of the compounds exhibited significant antifungal activity with MICs values ranging between 16 and 32 µg/mL. The structure-activity relationships (SAR) study demonstrated that O-substitutions are essential for antifungal activity. It also showed that the presence of a short aliphatic chain and/or electron withdrawing groups (NO(2) and/or acetate) favor activity. These findings were confirmed using density functional theory (DFT), when calculating the LUMO density. In Principal Component Analysis (PCA), two significant principal components (PCs) explained more than 60% of the total variance. The best Partial Least Squares Regression (PLS) model showed an r2 of 0.86 and q2(cv) of 0.64 corroborating the SAR observations as well as demonstrating a greater probe N1 interaction for active compounds. Descriptors generated by TIP correlogram demonstrated the importance of the molecular shape for antifungal activity.

Praemonitus praemunitus: can we forecast and prepare for future viral disease outbreaks?

Understanding the origins of past and present viral epidemics is critical in preparing for future outbreaks. Many viruses, including SARS-CoV-2, have led to significant consequences not only due to their virulence, but also because we were unprepared for their emergence. We need to learn from large amounts of data accumulated from well-studied, past pandemics and employ modern informatics and therapeutic development technologies to forecast future pandemics and help minimize their potential impacts. While acknowledging the complexity and difficulties associated with establishing reliable outbreak predictions, herein we provide a perspective on the regions of the world that are most likely to be impacted by future outbreaks. We specifically focus on viruses with epidemic potential, namely SARS-CoV-2, MERS-CoV, DENV, ZIKV, MAYV, LASV, noroviruses, influenza, Nipah virus, hantaviruses, Oropouche virus, MARV, and Ebola virus, which all require attention from both the public and scientific community to avoid societal catastrophes like COVID-19. Based on our literature review, data analysis, and outbreak simulations, we posit that these future viral epidemics are unavoidable, but that their societal impacts can be minimized by strategic investment into basic virology research, epidemiological studies of neglected viral diseases, and antiviral drug discovery.