Design of a Small-Molecule Entry Inhibitor with Activity against Primary Measles Virus Strains (original) (raw)
Related papers
Doklady. Biochemistry and biophysics
Currently, designing antiviral drugs remains a topical problem because of a wide distribution of HIV infection, viral hepatites, and appearance of new viral infections (including those induced by coronaviruses). The special attention of researchers is attracted by the fluorine-containing heterocyclic compounds, which exhibit a unique set of proportions, because the presence of the fluorine atom increases their solubility in lipids and ability to penetrate across cell membranes . The compounds of the benzimidazole series occupy a key position among the known drugs. For example, the spasmolytic dibazol, neuroleptics pimozide and droperidol, antihistamine drug astemizol, and highly effective antiulcerogenic drug omeprazol are widely used in medicine . Benzimidazole derivatives (including fluorine-containing compounds) that exhibit antiviral activity against herpes virus were found .
Journal of Medicinal Chemistry, 2014
Venezuelan equine encephalitis virus (VEEV) is an emerging pathogenic alphavirus that can cause significant disease in humans. Given the absence of therapeutic options available and the significance of VEEV as a weaponized agent, an optimization effort was initiated around a quinazolinone screening hit 1 with promising cellular antiviral activity (EC 50 = 0.8 μM), limited cytotoxic liability (CC 50 > 50 μM), and modest in vitro efficacy in reducing viral progeny (63-fold at 5 μM). Scaffold optimization revealed a novel rearrangement affording amidines, specifically compound 45, which was found to potently inhibit several VEEV strains in the low nanomolar range without cytotoxicity (EC 50 = 0.02−0.04 μM, CC 50 > 50 μM) while limiting in vitro viral replication (EC 90 = 0.17 μM). Brain exposure was observed in mice with 45. Significant protection was observed in VEEV-infected mice at 5 mg kg −1 day −1 and viral replication appeared to be inhibited through interference of viral nonstructural proteins.
Journal of Medicinal Chemistry, 1987
2-Amino-6-[ [3-(trifluoromethyl)phenyl]thio]-4(3H)quinazolinone (2b). In 320 mL of bis(2-methoxyethyl) ether, 20.0 g (0.0594 mol) of 6-[[3-(trifluoromethyl)phenyl]thio]-2,4quinazolinediamine and 200 mL of 2 N hydrochloric acid were heated under reflux for 6 h. The chilled mixture was made basic by addition of 5 N ammonium hydroxide. The white solid precipitate was collected, washed with water, and dried in a vacuum oven a t 50 "C to give 18.7 g (92.7%) of the desired product. 2-Amino-6-[ [3-(trifluoromethyl)phenyl]thio]-4quinazolinethiol (3b). A mixture of 18.7 g (0.0555 mol) of 2-amino-6-[ [ 3-(trifluoromethyl)phenyl]thio]-4(3H)-quinazolinone and 50.0 g (0.225 mol) of phosphorus pentasulfide in 200 mL of pyridine was heated a t 80 "C for 22 h. The two-phase mixture (dark solution and yellow solid) was poured into 2500 mL of stirred hot water. After being boiled for 2 h, the mixture was filtered hot to collect 18.5 g of yellow-brown solid. This crude product was dissolved in about 500 mL of hot anhydrous ethanol, and water was added to the cloud point. The chilled dark mixture was filtered through several thicknesses of paper to remove a gummy brown precipitate. Water was again added to the warmed filtrate to the cloud point, and a reddish-orange precipitate was removed. The yellow filtrate was poured into 1800 mL of water, and the bright yellow precipitate was collected and dried, yielding 13.7 g of the desired thiol compound. 4-(Methylthio)-6-[ [3-(trifluoromethyl)phenyl]thio]-2quinazolinamine (4b). A mixture of 11.0 g (0.0312 mol) of 2-amino-6-[ [3-(trifluoromethyl)phenyl] thio]-4-quinazolinethiol and 3.4 mL (5.2 g, 0.0367 mol) of iodomethane in 50 mL of N,N-dimethylformamide was stirred at room temperature for 1 h. The resulting amber solution was poured into 600 mL of ice water. The suspension was made weakly acidic (pH 6.5-7.0) by addition of 10% sodium hydroxide. After the mixture was allowed to stand for 1 h, the yellow precipitate was collected and recrystallized from anhydrous ethanol to give 6.1 g of the desired product as tan crystals, which darken slowly with exposure to light. 4-Hydrazino-6-[ [3-(trifluoromethyl)phenyl]thio]-2quinazolinamine (5b). To a solution of 2.0 g (0.0057 mol) of 2-amino-6-[ [ 3-(trifluoromethyl)phenyl] thio]-4-quinazolinethiol in 40 mL of pyridine was added 1.6 mL (0.05 mol) of anhydrous hydrazine. The mixture was stirred at room temperature overnight and poured into 300 mL of iced water. The precipitate that formed was collected and recrystallized from acetonitrile to afford 1.45 g of product. N4-Hydroxy-6-[ [3-(trifluoromethyl)phenyl]thio]-2,4quinazolinediamine (6d). A mixture of 2.0 g (0.00525 mol) of 4-(methylthio)-6-[ [ 3-(trifluoromethyl)phenyl] thiol-2-quinazolinamine and 0.37 g (0.005 32 mol) of hydroxylamine hydrochloride
Antitumor, antiviral, and antimicrobial evaluations were performed on a novel series of acrylamide incorporated benzo[d]thiazole compounds. The structures of these compounds were confirmed by different spectral tools. Most of these compounds except compounds 6 and 7 have high to moderate antimicrobial activity through binding to sterol components of cells or alteration in cell permeability and cell death [1]. Concerning the antitumor activity, the two molecules 5 and 6 exhibit strong cytotoxic effects against human breast cancer (MCF7), human liver carcinoma (HEPG2), and prostate cancer (PC3). It is believed that the cytotoxic effect of these compounds was attributed to different cellular pathways including tyrosine kinase inhibition [2], tubulin polymerization inhibition, and cell death via apoptosis. On the other hand, they have showed less toxic effect against the normal HBF4 (normal melanocytes) cells. Antiviral assay was shown for all synthesized compounds. Compounds 4, 5, and 8 exhibit a promising antiviral activity against vesicular stomatitis virus (VSV), while our lead compound 3 show the less viral inhibition in this series.
RSC medicinal chemistry, 2019
I. Compound Synthesis and Characterisation All starting materials and solvents were obtained either from commercial sources or prepared according to the literature citation. Unless otherwise stated all reactions were stirred. Organic solutions were routinely dried over anhydrous magnesium sulfate. Hydrogenations were performed on a Thales H-cube flow reactor under the conditions stated or under pressure in a gas autoclave (bomb). Column chromatography was performed on pre-packed silica cartridges (230-400 mesh, 40-63 µm) containing the amount indicated. The cation exchange resin, SCX, was purchased from Supelco and treated with 1M hydrochloric acid prior to use. Unless stated otherwise the reaction mixture to be purified by solid supported exchange was first diluted with MeOH and made acidic with a few drops of glacial AcOH. The resulting solution was loaded onto the SCX bed, the resin washed with MeOH and the desired material then recovered by elution with 0.7 M NH 3 in MeOH. Preparative Chiral High Performance Liquid Chromatography Method 1: Chiralpak® IA (Daicel Ltd.) column (2 x 25 cm), flow rate 13.5 mL min-1 eluting with a mixture of ethanol:DCM:isohexane (10🔞72) containing 0.2% Et 2 NH, using UV detection at 254 nm. Samples were loaded onto the column via an at-column dilution pump, pumping chloroform (1.5 mL min-1) for the duration of the run, giving a combined flow rate of 15 mL min-1. Analytical Methods Reverse Phase HPLC Conditions for the LCMS Analytical Methods Methods 1a and 1b: Waters Xselect CSH C18 XP column, 2.5 µm (4.6 x 30 mm) at 40 °C; flow rate 2.5-4.5 mL min-1 eluting with a H 2 O-MeCN gradient containing either 0.1% v/v formic acid (Method 1a) or 10 mM NH 4 HCO 3 in water (Method 1b) over 4 min employing UV S6 ClCO 2 Et LDA, THF Me S Me S OTBS OTBS Br Br CO 2 Et To a solution of diisopropylamine (1.87 mL, 13.1 mmol) in THF (10 mL) at-78 °C was added n-butyllithium (2.5 M in hexanes, 4.77 mL, 11.9 mmol) and the mixture maintained at this temperature for 10 min. To this solution was added (2-(2-bromothien-3-yl)propoxy)(tertbutyl)dimethylsilane (4.00 g, 11.9 mmol) in THF (10 mL) and the mixture maintained at-78 °C for 1 h. Ethyl chloroformate (1.15 mL, 11.9 mmol) was added and the mixture was allowed to warm to-40 °C, then quenched by the addition of sat aq NH 4 Cl (20 mL) and then diluted with EtOAc (100 mL). The organic phase was separated, washed with water (2 x 40 mL) and then dried (Na 2 SO 4) and evaporated in vacuo. The residue thus obtained was purified by flash column chromatography (SiO 2 , 330 g, 0-10% Et 2 O in isohexanes, gradient elution) to afford the title compound as a yellow oil (2.10 g, 90% pure by 1 H NMR, 39% yield); 1 H NMR
International Journal of Pharmacy and Pharmaceutical Sciences, 2015
Objective: Marek's disease (MD) is a widespread, herpesvirus-induced neoplastic disease in the domestic chicken that is caused by Marek's disease virus (MDV). Marek's disease virus (MDV) belongs to the alphaherpesvirus family such as Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2). Recently Bag and co-workers 2014 reported that, 7-methoxy-1-methyl-4, 9-dihydro-3H-pyrido [3, 4-b]indole (Harmaline) showed potent anti-HSV-1 activity against both wild type and clinical isolates of HSV-1. The present work aimed to synthesize some new heterocyclic systems incorporated to indole moiety starting from ethyl 2-(3-acetyl-1H-indol-1-yl)acetate (1) in order to evaluate their antiviral activity in a trail to explore potential antiviral agents against MDV to limit the disease course and losses. Methods: Reaction of ethyl 2-(3-acetyl-1H-indol-1-yl) acetate (1) with semicarbazide hydrochloride yielded semicarbazone derivative 2. The oxidative cyclization of 2 using thionyl chloride and selenium dioxide afforded 1, 2, 3-thia and 1, 2, 3-selenadiazole derivatives 3 and 4, respectively. On the other hand, reaction of 1 with 4-chloro and 4-nitrobenzaldehydes under Claisen-Schmidt conditions gave α, β-unsaturated keto derivatives 5a, b. Cyclization of 5a, b using hydrazine hydrate, phenyl hydrazine, urea, thiourea or guanidine led to the formation of pyrazoles 6a, b, 7a, b, and pyrimidines derivatives 8a, b-10a, b; respectively. Condensation of 1 with phenyl hydrazine followed by Vilsmeier Haack formylation gave pyrazole-4-carboxaldehyde derivative 12. Reaction of aldehydic function group of 12 with different reagents led to the formation of pyrazol-5-ones 14-16, thiazolidinone 18, aziditine 19, 1, 6-diaminopyridine 21, triazolo(1, 5-a)pyridine 22 and pyrano(2, 3-c) pyrazole derivatives 23. The in vitro antiviral activity of the selected compounds 6a, b 7a, b 8a, b 9a, b and 10a, b was studied against Marek's disease virus (MDV). Results: Chicken embryo experiment showed that compounds 7b, 8b, 9b and 10a possessed significant antiviral activity with IC50 ranged between 5 and 6 µg/ml and substantial therapeutic indices (TI) of 80 and 83 were recorded. Cytotoxicity assay indicated that CC50 of 7b, 8b, 9b and 10 were greater than 400 and 500 mg/ml. Conclusion: Compounds 7b, 8b, 9b and 10a showed promising effect as anti-MDV infectivity application.
Synthesis and Antiviral Activity of Novel Ethyl 2-(3-HETEROCYCLE-1H-INDOL-1-YL) Acetate Derivatives
International Journal of Pharmacy and Pharmaceutical Sciences, 2015
Objective: Marek's disease (MD) is a widespread, herpesvirus-induced neoplastic disease in the domestic chicken that is caused by Marek's disease virus (MDV). Marek's disease virus (MDV) belongs to the alphaherpesvirus family such as Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2). Recently Bag and co-workers 2014 reported that, 7-methoxy-1-methyl-4, 9-dihydro-3H-pyrido [3, 4-b]indole (Harmaline) showed potent anti-HSV-1 activity against both wild type and clinical isolates of HSV-1. The present work aimed to synthesize some new heterocyclic systems incorporated to indole moiety starting from ethyl 2-(3-acetyl-1H-indol-1-yl)acetate (1) in order to evaluate their antiviral activity in a trail to explore potential antiviral agents against MDV to limit the disease course and losses. Methods: Reaction of ethyl 2-(3-acetyl-1H-indol-1-yl) acetate (1) with semicarbazide hydrochloride yielded semicarbazone derivative 2. The oxidative cyclization of 2 using thionyl chloride and selenium dioxide afforded 1, 2, 3-thia and 1, 2, 3-selenadiazole derivatives 3 and 4, respectively. On the other hand, reaction of 1 with 4-chloro and 4-nitrobenzaldehydes under Claisen-Schmidt conditions gave α, β-unsaturated keto derivatives 5a, b. Cyclization of 5a, b using hydrazine hydrate, phenyl hydrazine, urea, thiourea or guanidine led to the formation of pyrazoles 6a, b, 7a, b, and pyrimidines derivatives 8a, b-10a, b; respectively. Condensation of 1 with phenyl hydrazine followed by Vilsmeier Haack formylation gave pyrazole-4-carboxaldehyde derivative 12. Reaction of aldehydic function group of 12 with different reagents led to the formation of pyrazol-5-ones 14-16, thiazolidinone 18, aziditine 19, 1, 6-diaminopyridine 21, triazolo(1, 5-a)pyridine 22 and pyrano(2, 3-c) pyrazole derivatives 23. The in vitro antiviral activity of the selected compounds 6a, b 7a, b 8a, b 9a, b and 10a, b was studied against Marek's disease virus (MDV). Results: Chicken embryo experiment showed that compounds 7b, 8b, 9b and 10a possessed significant antiviral activity with IC50 ranged between 5 and 6 µg/ml and substantial therapeutic indices (TI) of 80 and 83 were recorded. Cytotoxicity assay indicated that CC50 of 7b, 8b, 9b and 10 were greater than 400 and 500 mg/ml. Conclusion: Compounds 7b, 8b, 9b and 10a showed promising effect as anti-MDV infectivity application.
PHYSICOCHEMICAL PROPERTIES AND BIOLOGICAL ACTIVITY OF THE NEW ANTIVIRAL SUBSTANCE
International Journal of Applied Pharmaceutics, 2020
Objective: To develop a set of quality control procedures for the promising antiviral pharmaceutical substance L-histidyl-1-adamantylethylamine dihydrochloride monohydrate, a derivative of rimantadine. Methods: Substances and solvents: synthesized in laboratory L-histidyl-1-adamantylethylamine dihydrochloride monohydrate (H-His-Rim•2HCl•H2O), rimantadine hydrochloride (Rim•HCl), 99%, ethanol 96%, N, N-dimethylformamide (DMF) anhydrous, 99.8% and n-hexane anhydrous, 95%, deionized high-resistance water (18.2 MΩ•cm at 25 °C, Milli-Q system), silver nitrate. Infrared (IR) Spectroscopy–Cary 630 Fourier Transform IR Spectrometer, elemental analysis–elemental composition analyzer CHNS-O EuroEA3000, ultraviolet (UV) spectrometry–Cary-60 spectrophotometer, polarimetry–POL-1/2 polarimeter with an external Peltier module, granulometric analysis by optical microscopy (Altami BIO 2 microscope) and low-angle laser light scattering (LALLS)–Master Sizer 3600, measurement of potential for hydrogen–potentiometer PB-11, Spirotox method–the study of temperature dependences of Spirostomum ambiguum lifetime to characterize the biological activity of the studied compounds. Results: The substance H-His-Rim•2HCl•H2O is an amorphous yellowish powder, slightly soluble in water, soluble in ethanol, freely soluble in N, N-dimethylformamide, and practically insoluble in n-hexane. A study of the elemental composition has confirmed the authenticity of H-His-Rim•2HCl•H2O. Comparison of the spectral characteristics of H-His-Rim•2HCl•H2O and Rim•HCl by IR spectroscopy and UV spectrometry confirmed the authenticity of the substance. The racemic form of the substance Rim•HCl with an insignificant amount of impurity of the levorotatory enantiomer was proved polarimetrically: α =-0.0126±0.0003 (1% aqueous solution, 20±0.5 °С). The specific optical rotation of 1% aqueous solution H-His-Rim•2HCl•H2O . In 1% ethanol solution -10.32±0.12. Using the method of laser light diffraction for a substance H-His-Rim•2HCl•H2O, the dimensional spectra «fraction of particles, %-d, μm» were characterized, the maximum of which in hexane is in the region of 40–50 μm. Arrhenius’s kinetics on the Spirotox model established statistically significant differences in ligand-receptor interactions, which are characterized by values of observed apparent activation energy °bsEa, kJ/mol: 132.36±1.55 for H-His-Rim•2HCl•H2O and 176.15±0.48 for Rim•HCl. Conclusion: The developed set of methods for assessment of physical and chemical properties and biological activity of a new antiviral substance H-His-Rim•2HCl•H2O is the basis for establish of regulatory documentation.