Chlorogenic Compounds from Coffee Beans Exert Activity against Respiratory Viruses

Chlorogenic acids are secondary metabolites in diverse plants. Some chlorogenic acids extracted from traditional medicinal plants are known for their healing properties, e.g., against viral infections. Also, green coffee beans are a rich source of chlorogenic acids, with 5-O-caffeoylquinic acid being the most abundant chlorogenic acid in coffee. We previously reported the synthesis of the regioisomers of lactones, bearing different substituents on the quinidic core. Here, 3,4-O-dicaffeoyl-1,5-\u3b3-quinide and three dimethoxycinnamoyl-\u3b3-quinides were investigated for in vitro antiviral activities against a panel of 14 human viruses. Whereas the dimethoxycinnamoyl-\u3b3-quinides did not show any antiviral potency in cytopathogenic effect reduction assays, 3,4-O-dicaffeoyl-1,5-\u3b3-quinide exerted mild antiviral activity against herpes simplex viruses, adenovirus, and influenza virus. Interestingly, when the compounds were evaluated against respiratory syncytial virus, a potent antiviral effect of 3,4-O-dicaffeoyl-1,5-\u3b3-quinide was observed against both subtypes of respiratory syncytial virus, with EC50 values in the submicromolar range. Time-of-addition experiments revealed that this compound acts on an intracellular post-entry replication step. Our data show that 3,4-O-dicaffeoyl-1,5-\u3b3-quinide is a relevant candidate for lead optimization and further mechanistic studies, and warrants clinical development as a potential anti-respiratory syncytial virus drug

Synthesis, Computational Analysis, and Antiproliferative Activity of Novel Benzimidazole Acrylonitriles as Tubulin Polymerization Inhibitors: Part 2

We used classical linear and microwave-assisted synthesis methods to prepare novel Nsubstituted, benzimidazole-derived acrylonitriles with antiproliferative activity against several cancer cells in vitro. The most potent systems showed pronounced activity against all tested hematological cancer cell lines, with favorable selectivity towards normal cells. The selection of lead compounds was also tested in vitro for tubulin polymerization inhibition as a possible mechanism of biological action. A combination of docking and molecular dynamics simulations confirmed the suitability of the employed organic skeleton for the design of antitumor drugs and demonstrated that their biological activity relies on binding to the colchicine binding site in tubulin. In addition, it also underlined that higher tubulin affinities are linked with (i) bulkier alkyl and aryl moieties on the benzimidazole nitrogen and (ii) electron-donating substituents on the phenyl group that allow deeper entrance into the hydrophobic pocket within the tubulin’s -subunit, consisting of Leu255, Leu248, Met259, Ala354, and Ile378 residues

Synthesis, biological evaluation and molecular modeling of a novel series of fused 1,2,3-triazoles as potential anti-coronavirus agents

Synthesis and biological evaluation of a novel library of fused 1,2,3-triazole derivatives are described. The in-house developed multicomponent reaction based on commercially available starting materials was applied and broad biological screening against various viruses was performed, showing promising antiviral properties for compounds 14d, 14n, 14q, 18f and 18i against human coronavirus 229E. Further in silico studies identified the key molecular interactions between those compounds and the 3-chymotrypsin-like protease, which is essential to the intracellular replication of the virus, supporting the hypothesis that the protease is the target molecule of the potential antiviral derivatives.publishedVersionFil: Karypidou, Konstantina. Katholikie Universiteit Leuven; Bélgica.Fil: Ribone, Sergio Roman. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas; Argentina.Fil: Ribone, Sergio Roman. Consejo Nacional de Investigaciones Científicas y Técnicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentina.Fil: Quevedo, Mario Alfredo. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas; Argentina.Fil: Quevedo, Mario Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentina.Fil: Persoons, Leentje. Katholikie Universiteit Leuven; Bélgica.Fil: Pannecouque, Christophe. Katholikie Universiteit Leuven; Bélgica.Fil: Helsen, Christine. Katholikie Universiteit Leuven; Bélgica.Fil: Claessens, Frank. Katholikie Universiteit Leuven; BélgicaFil: Dehaen, Wim. Katholikie Universiteit Leuven; Bélgic

Asymmetric Primaquine and Halogenaniline Fumardiamides as Novel Biologically Active Michael Acceptors

Novel primaquine (PQ) and halogenaniline asymmetric fumardiamides 4a–f, potential Michael acceptors, and their reduced analogues succindiamides 5a–f were prepared by simple three-step reactions: coupling reaction between PQ and mono-ethyl fumarate (1a) or mono-methyl succinate (1b), hydrolysis of PQ-dicarboxylic acid mono-ester conjugates 2a, b to corresponding acids 3a, b, and a coupling reaction with halogenanilines. 1- [bis(Dimethylamino)methylene]-1H-1, 2, 3- triazolo[4, 5-b]pyridinium 3-oxide hexafluorophosphate (HATU) was used as a coupling reagent along with Hünig′s base. Compounds 4 and 5 were evaluated against a panel of bacteria, several Mycobacterium strains, fungi, a set of viruses, and nine different human tumor cell lines. p-Chlorofumardiamide 4d showed significant activity against Staphylococcus aureus, Streptococcus pneumoniae and Acinetobacter baumannii, but also against Candida albicans (minimum inhibitory concentration (MIC) 6.1–12.5 µg/mL). Together with p-fluoro and p-CF3 fumardiamides 4b, f, compound 4d showed activity against Mycobacterium marinum and 4b, f against M. tuberculosis. In biofilm eradication assay, most of the bacteria, particularly S. aureus, showed susceptibility to fumardiamides. m-CF3 and m- chloroaniline fumardiamides 4e and 4c showed significant antiviral activity against reovirus- 1, sindbis virus and Punta Toro virus (EC50 = 3.1–5.5 µM), while 4e was active against coxsackie virus B4 (EC50 = 3.1 µM). m-Fluoro derivative 4a exerted significant cytostatic activity (IC50 = 5.7–31.2 μM). Acute lymphoblastic leukemia cells were highly susceptible towards m-substituted derivatives 4a, c, e (IC50 = 6.7–8.9 μM). Biological evaluations revealed that fumardiamides 4 were more active than succindiamides 5 indicating importance of Michael conjugated system

Drug repurposing: phosphate prodrugs of anticancer and antiviral FDA-approved nucleosides as novel antimicrobials

Objectives Following a drug repurposing approach, we aimed to investigate and compare the antibacterial and antibiofilm activities of different classes of phosphate prodrugs (HepDirect, cycloSal, SATE and mix SATE) of antiviral and anticancer FDA-approved nucleoside drugs [zidovudine (AZT), floxouridine (FUDR) and gemcitabine (GEM)] against a variety of pathogenic Gram-positive and -negative bacteria. Methods Ten prodrugs were synthesized and screened for antibacterial activity against seven Gram-negative and two Gram-positive isolates fully susceptible to traditional antibiotics, alongside six Gram-negative and five Gram-positive isolates with resistance mechanisms. Their ability to prevent and eradicate biofilms of different bacterial pathogens in relation to planktonic growth inhibition was also evaluated, together with their effect on proliferation, viability and apoptosis of different eukaryotic cells. Results The prodrugs showed decreased antibacterial activity compared with the parent nucleosides. cycloSal-GEM-monophosphate (MP) prodrugs 20a and 20b were the most active agents against Gram-positive bacteria (Enterococcus faecalis and Staphylococcus aureus) and retained their activity against antibiotic-resistant isolates. cycloSal-FUDR-MP 21a partially retained good activity against the Gram-positive bacteria E. faecalis, Enterococcus faecium and S. aureus. Most of the prodrugs tested displayed very potent preventive antibiofilm specific activity, but not curative. In terms of cytotoxicity, AZT prodrugs did not affect apoptosis or cell viability at the highest concentration tested, and only weak effects on apoptosis and/or cell viability were observed for GEM and FUDR prodrugs. Conclusions Among the different prodrug approaches, the cycloSal prodrugs appeared the most effective. In particular, cycloSal (17a) and mix SATE (26) AZT prodrugs combine the lowest cytotoxicity with high and broad antibacterial and antibiofilm activity against Gram-negative bacteria

Iron/Copper Co-Catalyzed Cross-Coupling Reaction for the Synthesis of 6-Substituted 7-Deazapurines and the Corresponding Nucleosides

An efficient access to 6-substituted 7-deazapurine and the corresponding nucleosides by coupling aryl or alkyl Grignard reagents and halogenated purine nucleosides in the presence of Fe(acac)3/CuI is described. A series of 6-substituted 7-deazapurines and the corresponding nucleosides were obtained in medium to good yields. For the synthesis of modified nucleosides that will be the subject of biological testing, we propose to use iron-catalyzed instead of palladium-catalyzed reaction. The synthesized compounds were tested for their antiproliferative activity. The cytotoxicity study of compounds 11a-q shows that by modifying the 6-position of 7-deazapurine ribonucleosides, the compounds may become selective for certain cancer cell lines.status: publishe

Interaction between mouse adenovirus type 1 and cell surface heparan sulfate proteoglycans

Application of human adenovirus type 5 (Ad5) derived vectors for cancer gene therapy has been limited by the poor cell surface expression, on some tumor cell types, of the primary Ad5 receptor, the coxsackie-adenovirus-receptor (CAR), as well as the accumulation of Ad5 in the liver following interaction with blood coagulation factor X (FX) and subsequent tethering of the FX-Ad5 complex to heparan sulfate proteoglycan (HSPG) on liver cells. As an alternative vector, mouse adenovirus type 1 (MAV-1) is particularly attractive, since this non-human adenovirus displays pronounced endothelial cell tropism and does not use CAR as a cellular attachment receptor. We here demonstrate that MAV-1 uses cell surface heparan sulfate proteoglycans (HSPGs) as primary cellular attachment receptor. Direct binding of MAV-1 to heparan sulfate-coated plates proved to be markedly more efficient compared to that of Ad5. Experiments with modified heparins revealed that the interaction of MAV-1 to HSPGs depends on their N-sulfation and, to a lesser extent, 6-O-sulfation rate. Whereas the interaction between Ad5 and HSPGs was enhanced by FX, this was not the case for MAV-1. A slot blot assay demonstrated the ability of MAV-1 to directly interact with FX, although the amount of FX complexed to MAV-1 was much lower than observed for Ad5. Analysis of the binding of MAV-1 and Ad5 to the NCI-60 panel of different human tumor cell lines revealed the preference of MAV-1 for ovarian carcinoma cells. Together, the data presented here enlarge our insight into the HSPG receptor usage of MAV-1 and support the development of an MAV-1-derived gene vector for human cancer therapy.status: publishe

Synthesis and Antitumor Activity of C-7-Alkynylated and Arylated Pyrrolotriazine C-Ribonucleosides

A number of biologically active nucleoside analogues contain the adenine isostere 4-amino-pyrrolo[2,1-f][1,2,4]triazine connected to various sugar moieties through a C-C anomeric linkage. We employed palladium-catalyzed cross-coupling chemistry to promptly functionalize the 7-position of such a heterocyclic scaffold with various alkynyl and aryl groups starting from a common 7-iodo-pyrrolotriazine C-ribonucleoside intermediate. Analogues bearing a 7-cyclopropyl-, 7-propyl-, and 7-butylacetylene moiety displayed potent cytotoxic activity, with the latest being the most selective of this series toward cancer cells. Further insights revealed that such C-nucleosides could exert their antiproliferative action by causing dose-dependent DNA damage.status: publishe

Synthesis and anti-herpetic activity of phosphoramidate ProTides

Among the many prodrug approaches aimed at delivering nucleoside monophosphates into cells, the phosphoramidate ProTide approach is one that has shown success, which has made it possible for some of the phosphoramidates to enter into clinical trials. Herein, we report the synthesis and antiviral activity of a series of phosphoramidate ProTides designed to bypass the thymidine kinase (TK) dependence of the parent nucleoside analogues. Phosphoramidate derivatives of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) that contain L-alanine or pivaloyloxymethyl iminodiacetate (IDA-POM) exhibit anti-HSV-1 and anti-VZV activity in cell cultures, but they largely lost antiviral potency against TK-deficient virus strains. Among deazapurine nucleosides and their phosphoramidate derivatives, the 7-deazaadenine containing nucleosides and their phosphoramidate triester derivatives showed weak antiviral activity against VZV. Apparently, intracellular nucleotide delivery with these phosphoramidates is partly successful. However, none of the compound prodrugs showed superior activity to their parent drugs.status: publishe