Further Polycyclic Quinones of Micromonospora sp.

The crude acetone extract of a marine Micromonospora sp. strain associated with Eudistoma vannnamei was fractioned with hexane and ethyl acetate. The crude extract and both soluble fractions were assayed against several bacteria strains. The new polycyclic quinones 12-hydroxy-9-propyltetracene-6,1-dione (1), 5,12-dihydroxy-4-methoxy-9-propyltetracene-5,12-dione (2), and 4,6-dihydroxy-3-methoxycarbonyl- methyl-6a-(oxobutyl)-5,12-anthraquinone (3), along with the known 4,6-dihydroxy-3-methoxycarbonyl-methyl-6a-(oxo-3-methyl-butyl)-5,12-anthraquinone (4) and 4,6-dihydroxy-3-methoxycarbonyl-methyl-6a-(oxopentyl)-5,12-anthraquinone (5) were isolated from the hexane-soluble fraction, while from the active ethyl acetate fraction were isolated the known 4,6,11-trihydroxy-9-propyltetracene-5,12-dione (6), 4-methoxy-9-propyltetracene-6,11-dione (7), 7,8,9,10-tetrahydro-9-hydroxy-4-methoxy-9-propyltetracene-6,11-dione (8), and 10ß-carbomethoxy-7,8,9,10-tetrahydro-4,6,7α,9α,11-pentahydroxy-9-propyltetracene-5,12-dione (9). The structures of the new compounds were established by interpretation of HRMS and NMR techniques. A study of molecular docking was performed with the compounds from the active ethyl acetate fraction to correlate tentatively with the antimicrobial activity. Molecular docking, RMSD, RMSF, and MM-GBSA evaluations were performed to investigate the inhibitory activity of 6-8 against the protein PDB-codex 1MWT, being considered a promising target for studying drug development responsible for inhibiting replication of Staphylococcus aureus. Penicillin G was used as the standard inhibitory. Anthracyclinones 6-8 were the best hydrolase inhibitor with affinity energy -8.1 to -7.9 kcal/mol compared to penicillin G, which presented -6.9 kcal/mol. Both 8 and 7 present potent inhibitory effects against hydrolase through molecular dynamics simulation and exhibit favorable drug-like properties, promising new hydrolase blockers to fight bacterial infections from Staphylococcus aureus.

Anxiolytic effects of N-(4,5-dihydro-5-oxo-1,2-dithiolo-[4,3,b]-pyrrole-6-yl)-N-methylformamide, a pyrroloformamide isolated from a marine Streptomyces sp., in adult zebrafish by the 5-HT system.

General anxiety disorders are among the most prevalent mental health problems worldwide. The emergence and development of anxiety disorders can be due to genetic (30-50%) or non-genetic (50-70%) factors. Despite medical progress, available pharmacotherapies are sometimes ineffective or can cause undesirable side effects. Thus, it becomes necessary to discover new safe and effective drugs against anxiety. This study evaluated the anxiolytic effect in adult zebrafish (Danio rerio) of a natural pyrroloformamide (PFD), N-(4,5-dihydro-5-oxo-1,2-dithiolo-[4,3,b]-pyrrole-6-yl)-N-methylformamide, isolated from a Streptomyces sp. bacterium strain recovered from the ascidian Eudistoma vannamei. The complete structure of PFD was determined by a detailed NMR analysis, including 1H-13C and 1H-15N-HBMC data. In addition, conformational and DFT computational studies also were performed. A group of fishes (n = 6) was treated orally with PFD (0.1, 0.5 and 1.0 mg/mL; 20 µL) and subjected to locomotor activity and light/dark tests, as well as, acute toxicity 96 h. The involvement of the GABAergic and serotonergic (5-HT) systems was investigated using flumazenil (a silent modulator of GABA receptor) and 5-HT1, 5-HT2A/2C and 5-HTR3A/3B receptors antagonists, known as pizotifen, granisetron and cyproheptadine, respectively. PFD was nontoxic, reduced locomotor activity and promoted the anxiolytic effect in zebrafish. Flumazenil did not inhibit the anxiolytic effect of the PFD via the GABAergic system. This effect was reduced by a pretreatment with pizotifen and granisetron, and was not reversed after treatment with cyproheptadine. Molecular docking and dynamics studies confirmed the interaction of PFD with the 5-HT receptor.Communicated by Ramaswamy H. Sarma.

Pyrroloformamide (PFD), isolated from the marine Streptomyces sp. associated ascidian Eudistoma vannamei, showed no toxicity in adult zebrafish but reduced its locomotor activity.The structural elucidation of PFD was determined by the analysis of 1D and 2D NMR and HRESIMS data.The density functional theory (DFT) study confirmed the existence of two conformers as determined by NMR spectra.The serotonergic system modulated the anxiolytic effect of PFD via the 5-HT receptor in adult zebrafish.Molecular docking and dynamics studies confirmed the interaction of PFD with the 5-HT receptor.

Synthesis and anxiolytic effect of europium metallic complex containing lapachol [Eu(DBM)3. LAP] in adult zebrafish through serotonergic neurotransmission: in vivo and in silico approach.

Anxiety-related mental health problems are estimated at 3.6% globally, benzodiazepines (BZDs) are the class of drugs indicated for the treatment of anxiety, including lorazepam and diazepam. However, concerns have been raised about the short- and long-term risks associated with BZDs. Therefore, despite anxiolytic and antidepressant drugs, there is a need to develop more effective pharmacotherapies with fewer side effects than existing drugs. The present work reported the synthesis, anxiolytic activity, mechanism of action in Adult Zebrafish (Danio rerio) and in silico study of a europium metallic complex with Lapachol, [Eu(DBM)3. LAP]. Each animal (n = 6/group) was treated intraperitoneally (i.p.; 20 µL) with the synthesized complex (4, 20 and 40 mg/Kg) and with the vehicle (DMSO 3%; 20 µL), being submitted to the tests of locomotor activity and 96h acute toxicity. The light/dark test was also performed, and the serotonergic mechanism (5-HT) was evaluated through the antagonists of the 5-HTR1, 5-HTR2A/2C and 5-HTR3A/3B receptors. The complex was characterized using spectrometric techniques, and the anxiolytic effect of complex may be involved the neuromodulation of receptors 5-HT3A/3B, since the pre-treatment with pizotifen and cyproheptadine did not block the anxiolytic effect of [Eu(DBM)3. LAP], unlike fluoxetine had its anxiolytic effect reversed. In addition, molecular docking showed interaction between the [Eu(DBM)3. LAP] and 5HT3A receptor with binding energy -7.8 kcal/mol and the ADMET study showed that complex has low toxic risk. It is expected that the beginning of this study will allow the application of the new anxiolytic drugs, given the pharmacological potential of the lapachol complex.Communicated by Ramaswamy H. Sarma.

Synthesis, structural, characterization, antibacterial and antibiotic modifying activity, ADMET study, molecular docking and dynamics of chalcone (E)-1-(4-aminophenyl)-3-(4-nitrophenyl)prop-2-en-1-one in strains of Staphylococcus aureus carrying NorA and MepA efflux pumps.

Chalcones have an open chain flavonoid structure that can be obtained from natural sources or by synthesis and are widely distributed in fruits, vegetables, and tea. They have a simple and easy to handle structure due to the α-ß-unsaturated bridge responsible for most biological activities. The facility to synthesize chalcones combined with its efficient in combating serious bacterial infections make these compounds important agents in the fight against microorganisms. In this work, the chalcone (E)-1-(4-aminophenyl)-3-(4-nitrophenyl)prop-2-en-1-one (HDZPNB) was characterized by spectroscopy and electronic methods. In addition, microbiological tests were performed to investigate the modulator potential and efflux pump inhibition on S. aureus multi-resistant strains. The modulating effect of HDZPNB chalcone in association with the antibiotic norfloxacin, on the resistance of the S. aureus 1199 strain, resulted in increase the MIC. In addition, when HDZPNB was associated with ethidium bromide (EB), it caused an increase in the MIC value, thus not inhibiting the efflux pump. For the strain of S. aureus 1199B, carrying the NorA pump, the HDZPNB associated with norfloxacin showed no modulatory, and when the chalcone was used in association with EB, it had no inhibitory effect on the efflux pump. For the tested strain of S. aureus K2068, which carries the MepA pump, it can be observed that the chalcone together the antibiotic resulted in an increase the MIC. On the other hand, when chalcone was used in association with EB, it caused a decrease in bromide MIC, equal to the reduction caused by standard inhibitors. Thus, these results indicate that the HDZPNB could also act as an inhibitor of the S. aureus gene overexpressing pump MepA. The molecular docking reveals that chalcone has a good binding energies -7.9 for HDZPNB/MepA complexes, molecular dynamics simulations showed that Chalcone/MetA complexes showed good stability of the structure in an aqueous solution, and ADMET study showed that the chalcone has a good oral bioavailability, high passive permeability, low risk of efflux, low clearance rate and low toxic risk by ingestion. The microbiological tests show that the chalcone can be used as a possible inhibitor of the Mep A efflux pump.Communicated by Ramaswamy H. Sarma.

Campesterol Semi-Synthetic Derivatives as Potential Antibacterial: in†vitro and in silico Evaluation.

In this study, twelve campesterol derivatives (2-13) were prepared by esterification reaction at the hydroxy group in C-3 and catalytic hydrogenation at the carbon-carbon double bond in C-5(6). All obtained compounds were characterized by IR, 1 H-NMR, 13 C-NMR, and MS spectra. Campesterol (1) and its derivatives (2-13) were evaluated in vitro against Staphylococcus aureus (ATCC 6538), Streptococcus mutans (ATCC 0046), Escherichia coli (ATCC 10536), Pseudomonas aeruginosa (ATCC 15442), and Klebsiella pneumoniae (ATCC 10031) using the microdilution method. Among tested compounds, 4, 6, 9, 11, 12, and 13 displayed the best antibacterial activity. Moreover, to support the antibacterial activity experiments, the investigation of molecular interactions of more active compounds, and also compound 1 and neomycin, used as starting material and positive control, respectively, at the binding site of the target proteins was performed using molecular docking simulations. Four compounds (7, 9, 10 and 11) are herein described for the first time.

Isolation, characterization and in silico study of propenamide alkaloids from Hymenoepmecis bicolor poison against active µ-opioid receptor.

Some insects produce venoms to defend against predators and directly interact with opioid receptors. In the present study, it was identified two alkaloids in the wasp venom species Hymenoepimecis bicolor. It was demonstrated that these could act as potential inhibitors of opioid receptors through their robust affinity to the receptors. The interaction profile was given to opioid receptors (µOR), with 60% of targets similar to alkaloid 1, with 0.25 probability, and 46.7% of targets similar to alkaloid 2, with a probability 0.17 of affinity as a target, which is considered signaling macromolecules and can mediate the most potent analgesic and addictive properties of opiate alkaloids. Notably, both alkaloids showed -7.6 kcal/mol affinity to the morphine agonies through six residues, Gly124, Asp147, Trp293, Ile296, Ile322, and Tyr326. These observations suggest further research on opioid receptors using in vitro studies of possible therapeutic applications.Communicated by Ramaswamy H. Sarma.

Synthesis and in silico study of chenodeoxycholic acid and its analogues as an alternative inhibitor of spike glycoprotein of SARS-CoV-2.

COVID-19, caused by SARS-CoV-2, is a viral infection that has generated one of the most significant health problems in the world. Spike glycoprotein is a crucial enzyme in viral replication and transcription mediation. There are reports in the literature on using bile acid in the fight against this virus through in vitro tests. This work presents the synthesis of nine chenodeoxycholic acid derivatives (1-9), which were prepared by oxidation, acetylation, formylation, and esterification reactions, and the analogs 6-9 have not yet been reported in the literature and the possibility of conducting an in silico study of bile acid derivatives as a therapeutic alternative to combat the virus using glycoprotein as a macromolecular target. As a result, five compounds (1, 6-9) possessed favorable competitive interactions with the lowest energies compared to the native ligand (BLA), and the highlighted compound 9 got the best scores. At the same time, analog 1 presented the best ADME filter result. Molecular dynamics also simulated these compounds to verify their stability within the active protein site to seek new therapeutic propositions to fight against the pandemic. Physical and spectroscopic data have fully characterized all the compounds.Communicated by Ramaswamy H. Sarma.