Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.

Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.

Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.

Efficacy and Safety of Teriflunomide in Chinese Patients with Relapsing Forms of Multiple Sclerosis: A Subgroup Analysis of the Phase 3 TOWER Study / 中华医学杂志(英文版)

Background@#Disease-modifying therapy is the standard treatment for patients with multiple sclerosis (MS) in remission. The primary objective of the current analysis was to assess the efficacy and safety of two teriflunomide doses (7 mg and 14 mg) in the subgroup of Chinese patients with relapsing MS included in the TOWER study.@*Methods@#TOWER was a multicenter, multinational, randomized, double-blind, parallel-group (three groups), placebo-controlled study. This subgroup analysis includes 148 Chinese patients randomized to receive either teriflunomide 7 mg (n = 51), teriflunomide 14 mg (n = 43), or placebo (n = 54).@*Results@#Of the 148 patients in the intent-to-treat population, adjusted annualized relapse rates were 0.63 (95% confidence interval [CI]: 0.44, 0.92) in the placebo group, 0.48 (95% CI: 0.33, 0.70) in the teriflunomide 7 mg group, and 0.18 (95% CI: 0.09, 0.36) in the teriflunomide 14 mg group; this corresponded to a significant relative risk reduction in the teriflunomide 14 mg group versus placebo (-71.2%, P = 0.0012). Teriflunomide 14 mg also tended to reduce 12-week confirmed disability worsening by 68.1% compared with placebo (hazard ratio: 0.319, P = 0.1194). There were no differences across all treatment groups in the proportion of patients with treatment-emergent adverse events (TEAEs; 72.2% in the placebo group, 74.5% in the teriflunomide 7 mg group, and 69.8% in the teriflunomide 14 mg group); corresponding proportions for serious adverse events were 11.1%, 3.9%, and 11.6%, respectively. The most frequently reported TEAEs with teriflunomide versus placebo were neutropenia, increased alanine aminotransferase, and hair thinning.@*Conclusions@#Teriflunomide was as effective and safe in the Chinese subpopulation as it was in the overall population of patients in the TOWER trial. Teriflunomide has the potential to meet unmet medical needs for MS patients in China.@*Trial Registration@#ClinicalTrials.gov, NCT00751881; https://clinicaltrials.gov/ct2/show/NCT00751881?term=NCT00751881&rank=1.

Special metabolites isolated from Urochloa humidicola (Poaceae)

ABSTRACT This study aims to identify special metabolites in polar extracts from Urochloa humidicola (synonym Brachiaria humidicola) that have allelopathic effects and induce secondary photosensitization in ruminants. The compounds were isolated and identified via chromatographic and spectroscopic techniques. The compounds 4-hydroxy-3-methoxy-benzoic acid, trans-4-hydroxycinnamic acid, and p-hydroxy-benzoic acid; the flavonols isorhamnetin-3-O-β-d-glucopyranoside and methyl quercetin-3-O-β-d-glucuronate; and kaempferitrin, quercetin-3-O-α-l-rhamnopyranoside, and tricin were identified in the extract from the leaves of Urochloa humidicola. Two furostanic saponins, namely, dioscin and 3-O-α-l-rhamnopyranosyl-(1-4)-[α-l-rhamnopyranosyl-(1-2)]-β-d-glucopyranosyl-penogenin, as well as catechin-7-O-β-d-glucopyranoside were identified in the methanolic extract obtained from the roots of this plant. This species features a range of metabolites that may be toxic for animals if used in food and may interfere with the growth medium, thereby inhibiting the development of other species.

The chemical constituents of Ligularia pleurocaulis / 药学学报

<p><b>AIM</b>To study the chemical constituents of the underground part of Ligularia pleurocaulis (Franch.) Hand-Mazz.</p><p><b>METHODS</b>The dried roots and rhizomes of L. pleurocaulis were extracted with methanol. Isolation and purification were performed by silica gel column chromatography and recrystallization etc. Structures of the pure compounds were established on basis of spectral analysis.</p><p><b>RESULTS</b>Twelve compounds were obtained from L. pleurocaulis, they were 6-angeloyloxy-furanoligularenone (1), 2-oxo-3-hydroxy-eremophila-1(10),3,7(11),8-tetraen-8,12-olide (2), tiglic acid (3), oleanolic acid (4), lupeol (5), beta-sitosterol (6), daucosterol (7), caffeic acid (8), emodin (9), 7-methoxy-coumarin (10), ferulic acid (11) and 4-hydroxy-2,5-dimethoxy-benzaldehyde (12).</p><p><b>CONCLUSION</b>Compound 1 is a new eremophilane and compound 2 is a new natural compound. All above compounds were obtained for the first time from L. pleurocaulis.</p>

Isolation and structure identification of chemical constituents from Anabasis brevifolia / 药学学报

<p><b>AIM</b>To study the chemical consitituents of the n-butanol-extracts of Anabasis salsa and Various chromatographic techniques were used to the chloroform-extract of Anabasis brevifolia.</p><p><b>METHODS</b>separate and purify the constituents. Their physico-chemical properties and spectral data were used to elucidate their structures.</p><p><b>RESULTS</b>Five compounds were isolated and identified as 2-O-beta-D-glucopyranosyloxy-4,6-dimethoxy phenylenthanone (1), 2-O-(2)-beta-D-glucopyranosyloxy-4, 6-dimethoxy phenylenthanone (2), 3-methyl-but-2-enoic acid-[2-(4-methoxy phenyl)-ethyl]-amide (3), 5,6,7,2'-tetramethoxy isoflavonoid (4), 2'-hydroxy-5,6,7-trimethoxyisoflavonoid (5).</p><p><b>CONCLUSION</b>Compounds 2, 3, and 5 are new compounds. And the others were isolated from Anabasis L. for the first time.</p>

Chemical components of essential oils from the herb of Ligularia virgaurea / 中国中药杂志

<p><b>OBJECTIVE</b>To provide the foundation for reasonable utilization by analyzing the essential oils of Ligularia virgaurea.</p><p><b>METHOD</b>The essential oils were extracted by using steam distillation and separated with GC capillary columns. The components were quantitatively determined with normalization method, and were identified with GC-MS.</p><p><b>RESULT</b>41 components were identified, which took up 72.73% of the essential oils.</p><p><b>CONCLUSION</b>The main components of essential oils were 4-methyl-1-(1-methylethyl)-3-cyclohexen-1-ol(14.369%), crotonic acid, 2,2-dimethyl-butanoic acid, 1-methyl-3-(1-methylethyl)-benzene, (1s-endo)-1,7,7-trimethyl-bicyclo[2,2,1]heptan-2-ol, trans-1-methyl-4-(1-methylethyl)-2-cyclohexen-1-ol, alpha-cadinol and alpha,alpha,4-trimethyl-3-cyclohexene-1-methanol.</p>

Bulk copolymerization of acrylamide and crotonic acid

Bulk copolymerization of acrylamide and crotonic acid has been carried out. The results indicate that both monomers form copolymer in all monomeric ratios. The induction period is 40 minutes. The increasing concentration of acrylamide and benzoyl peroxide and increase in temperature and time enhance the rate of formation of copolymer. Monomer reactivity ratios of acrylamide and crotonic acid are determined experimentally using the rearranged form of copolymer composition equation. Molecular weight of the copolymer samples show that the copolymer of low molecular weight may be prepared at high temperature. All copolymer samples are white crystalline substances that become light brown at 200-210°C and burn when temperature reaches to 270°C

Synthesis and characterization of noncrosslinked and crosslinked poly [vinyl alcohol-co-crotonc acid] hydrogels

The aim of this work was to investigate the possibility of combining hydrophilic [VAL] monomer with crotonic acid [CA] monomer and to explore their potential for drug delivery. Six noncrosslinked poly[vinyl acetate-co-crotonic acid] [VAC/CA] samples 50:50 to 95:05 mole% were prepared. The monomer feed ratio affects the molecular weight and the polymerization hindered by increasing the CA traction in the monomer mixture. This is most probably due to differences in reactivity ratios. All the samples were hydrolysed in methanolic KOH solution. Salt form was converted into acid form by adding acetic acid. In poly[vinyl alcohol-co-crotonic acid] [VAL/CA] polymers, the OH and the COOH groups seem to be partially involved in a lactonized form. By increasing the COOH groups, the amount of OH groups reduced through lactone ring formation. The COOH groups are few in numbers and might be at scattered positions in the chain, making the gels unable to show pH-sensitivity. One sample of VAL/CA containing monomeric composition [VAC/CA 90: 10] was crosslinked with glutaraldehyde, with various crosslinking ratios. A remarkable effect of crosslinking ratio was observed on swelling and phenazone release

Preparation of slow release coprecipitates of soluble drugs using polyvinyl acetate crotonic acid copolymer

Coprecipitates of soluble drugs; namely, diphenhydramine HCI and tripelennamine HCI with polyvinyl acetate crotonic acid copolymer were prepared with different drug to polymer ratios. Comparative dissolution rate studies of the coprecipitates and physical mixture showed that the coprecipitates slowed the release rate of the drug. The decrease in release rate was more pronounced for compressed disks prepared from coprecipitates. As the polymer concentration increased, the retardation effect increased

Ketoacids and lactones: part 3-synthesis of 2,4-disubstituted-2-hydroxybutyrolactones and 2-butenonic acids

Several 4-aryl-2-hydroxy-2-[p-substituted] phenacylbutanoic acids III have been prepared from the corresponding aralkyl pyruvic acids I. Their corresponding 2,4-dinitrophenylhydrazones IV were prepared. They were readily dehydrated to give 4-aryl-2-[p-substituted] phenacyl-2-butenoic acids V. Their reduction gave 4-aryl-2-[2-arylethyl]-2-hydroxybutyrolactones VIII

Reactivity of some butenolides towards intramolecular alkylation reactions

A furfurylidene -gamma- aryl delta- beta, Nu- butenolides Ib react with anhydrous aluminium chloride in the presence of toluene or anisole to give the same products obtained when benzene was used as a solvent, 4-arylbenzofuran-6-carboxylic acids III. The preferred intramolecular alkylation in case of Ib compared with the fluorenylidene analogues la, which under the same conditions undergo inter-molecular alkylation, is explained in terms of HMO calculations