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.

Effect of Aryl-Cyclohexanones and their Derivatives on Macrophage Polarization In Vitro.

Macrophages are critical in both tissue homeostasis and inflammation, and shifts in their polarization have been indicated as pivotal for the resolution of inflammatory processes. Inflammation is a complex and necessary component of the immune response to stimuli that are harmful to host homeostasis and is regulated by cellular and molecular events that remain a source of ongoing investigation. Among the compounds studied that have potential against autoimmune and inflammatory diseases, cannabinoids are currently highlighted. In this work, nineteen aryl-cyclohexanones diesters and their derivatives were synthesized based on the aryl-cyclohexane skeleton of phytocannabinoids, such as cannabidiol (CBD), and were evaluated for their anti-inflammatory and macrophage polarization potential. The results showed that Compound 4 inhibited the production of nitric oxide in RAW 264.7 macrophages. Furthermore, it reduced the levels of pro-inflammatory cytokines IL-12p70, TNF-α, IFN-γ, MCP-1, and IL-6 while, at the same time, was able to increase the production of anti-inflammatory cytokines IL-4, IL-10, and IL-13. Compound 4 also reduced macrophage apoptosis, increased the expression of the CD206 (mannose receptor) and at the same time, decreased the expression of CD284 (TLR-4 receptor) on the surface of these cells. Finally, it increased the phagocytic capacity and inhibited the phosphorylation of the p65 of NF-kß. In conclusion, Compound 4, identified as diethyl-4-hydroxy-2-(4-methoxyphenyl)-4-methyl-6-oxocyclohexane-1-3-dicarboxylate, showed significant anti-inflammatory effect, while demonstrating the ability to transform phenotypically macrophages from the M1 phenotype (pro-inflammatory) to the M2 phenotype (anti-inflammatory). This led us to hypothesize that the main mechanism of anti-inflammatory effect of this molecule is linked to its immune modulation capacity.

Search for Antimicrobial Activity Among Fifty-Two Natural and Synthetic Compounds Identifies Anthraquinone and Polyacetylene Classes That Inhibit Mycobacterium tuberculosis.

Drug-resistant tuberculosis threatens to undermine global control programs by limiting treatment options. New antimicrobial drugs are required, derived from new chemical classes. Natural products offer extensive chemical diversity and inspiration for synthetic chemistry. Here, we isolate, synthesize and test a library of 52 natural and synthetic compounds for activity against Mycobacterium tuberculosis. We identify seven compounds as antimycobacterial, including the natural products isobavachalcone and isoneorautenol, and a synthetic chromene. The plant-derived secondary metabolite damnacanthal was the most active compound with the lowest minimum inhibitory concentration of 13.07 µg/mL and a favorable selectivity index value. Three synthetic polyacetylene compounds demonstrated antimycobacterial activity, with the lowest MIC of 17.88 µg/mL. These results suggest new avenues for drug discovery, expanding antimicrobial compound chemistries to novel anthraquinone and polyacetylene scaffolds in the search for new drugs to treat drug-resistant bacterial diseases.

A new polyacetylene glucoside from Vernonia scorpioides and its potential antihyperglycemic effect.

Natural polyacetylene compounds have been found mainly in seven botanical families and remain underexplored and understudied, despite its inherent chemical and biological reactivity, due to the presence of conjugated triple bonds. Some polyacetylene glucosides have been found to stimulate glucose uptake in C5BL/ks-db/db obese diabetic mice, and since polyacetylene glucosides previously found in Vernonia scorpioides showed little to none cytotoxicity, in this study the antihyperglycemic potential of a new V. scorpioides polyacetylene glucoside has been accessed in order to shine a new light on the biological activity of this unique scaffold. For the isolation of this new compound an optimized method of Centrifugal Partition Chromatography (CPC) is for the first time described together with its X-ray data. The results demonstrate that 3,4-dihydrovernoniyne-4-O-ß-glucoside has significant effect on glycaemia at low dose 0.5 mg/kg, and pointing that the anti-hyperglycemic effect may be due in part to the inhibition of intestinal disaccharidases.

Synthesis and in vitro evaluation of Ca2+ channel blockers 1,4-dihydropyridines analogues against Trypanosoma cruzi and Leishmania amazonensis: SAR analysis.

Drugs containing the1,4-dihydropyridine (DHP) core have recently attracted attention concerning their antiparasitic effect against various species of Leishmania and Trypanosoma. This approach named drugs repositioning led to interesting results, which have prompted us to prepare 21 DHP's analogues. The 1,4-DHP scaffold was decorated with different function groups at tree points including the nitrogen atom (NH and N-phenyl), the aryl group attached to C-4 (various substituted aryl residues) and the carbon atoms 2 and 6 (bearing Ph or Me groups). Moreover, the products were evaluated for their cytotoxicity on three cancer and a non-tumoral cell lines. Only 6 of them were antiproliferative and their weak effect (CC50 comprised between 27 and 98µM) suggested these DHPs as good candidates against the intracellular amastigote forms of L. amazonensis and T. cruzi. L. amazonensis was sensitive to DHPs 5, 11 and 15 (IC50 values at 15.11, 45.70 and 53.13µM, respectively) while 12 of them displayed significant to moderate trypanocidal activities against T. cruzi. The best trypanocidal activities were obtained with compounds 2, 18 and 21 showing IC50 values at 4.95, 5.44, and 6.64µM, respectively. A part of the N-phenylated DHPs showed a better selectivity than their NH analogues towards THP-1 cells. 4-Chlorophenyl, 4-nitrophenyl and 3-nitrophenyl residues attached to the carbon atom 4 turned to be important sub-structures for the antitrypanosomal activity.

ESI-MS2 and Anti-inflammatory Studies of Cyclopropanic Triterpenes. UPLC-ESI-MS and MS2 Search of Related Metabolites from Donella ubanguiensis.

INTRODUCTION: Triterpenes are one of the largest secondary metabolites groups spread in the plant kingdom with various skeletons. These metabolites have showed various bioactivities including anti-inflammatory activity. OBJECTIVE: The study aims to explore the mass spectrometry fragmentation of donellanic acids A-C (DA A-C), three compounds identified from Donella ubanguiensis; in addition, the fragmentation behaviour of these metabolites will serve as a fingerprint to search and characterise triterpenes congeners in fruits, bark and wood crude extracts of D. ubanguiensis. This work was prompted by the anti-inflammatory activity on leukocyte migration, exudate concentrations and myeloperoxidase activity obtained for DA A-B. METHODOLOGY: The bioactivity was performed on mouse model of pleurisy induced by carrageenan and the parameters were analysed by veterinarian automated cell counter and colorimetric assays. While the tandem mass analyses of DA A-C were carried out by a direct infusion ESI-QTOF-MS/MS, the extracts were studied by UPLC-ESI-QTOF-MS and UPLC-ESI-QTOF-MS/MS. RESULTS: DA A displayed interesting anti-inflammatory activity by inhibiting leukocyte migration, exudate concentrations and myeloperoxidase activity (p < 0.05) while DA B was weakly active (p > 0.05). Moreover, the diagnostic of the MS2 behaviour of DA A-C in conjunction with the chromatograms and the obtained MS2 data of the crude extract led to the characterisation of three cyclopropane triterpenes (T1-T3) and six saponins (T4-T9) from the fruits, the bark, and the wood extracts. CONCLUSIONS: Donella species deserve more investigation since metabolites related to the anti-inflammatory compound (DA A) could be identified. Copyright © 2016 John Wiley & Sons, Ltd.

Synthesis and Evaluation of Quinazolines as Inhibitors of the Bacterial Cell Division Protein FtsZ.

The bacterial cell division protein FtsZ is one of many potential targets for the development of novel antibiotics. Recently, zantrin Z3 was shown to be a cross-species inhibitor of FtsZ; however, its specific interactions with the protein are still unknown. Herein we report the synthesis of analogues that contain a more tractable core structure and an analogue with single-digit micromolar inhibition of FtsZ's GTPase activity, which represents the most potent inhibitor of Escherichia coli FtsZ reported to date. In addition, the zantrin Z3 core has been converted to two potential photo-cross-linking reagents for proteomic studies that could shed light on the molecular interactions between FtsZ and molecules related to zantrin Z3.

Polyacetylenes from the leaves of Vernonia scorpioides (Asteraceae) and their antiproliferative and antiherpetic activities.

Polyacetylenes constitute an underexplored and unstable class of compounds that are found mainly in the Apiaceae, Araliaceae and Asteraceae families. Vernonia scorpioides (Lam.) Pers., Asteraceae is a lianous neotropical herb that usually grows in soils that have been deforested and are of poor quality. It is used in folk medicine for the treatment of several skin conditions. This study addresses the characterisation of eight polyacetylenes isolated from the leaves of V. scorpioides. Their structures were established on the basis of 1D and 2D NMR spectroscopy and MS analysis. Ab initio calculations including solvent effects were employed to aid the elucidation of the absolute configurations of the compounds. The in vitro antiproliferative and anti-herpetic activities of the polyacetylenes were determined. The isolated compounds presented no inhibitory effect against a human cell line of non-small cell lung cancer, but presented a mild non-selective in vitro antiviral activity, although their corresponding glycosides were inactive.