RESUMEN
A series of 25 amides (15 new) derived from (3aR)-(+)-sclareolide were prepared and subjected to Ellman's assay to determine their efficacies as inhibitors for AChE or BuChE. Five amides (9, 13, 14, 15 and 17) caused inhibition of one of the enzymes greater than 60%; thereby those that inhibited BuChE were more active than positive control galantamine, and they showed better Ki values (1.07 to 8.49). In general, it was found that molecules holding a meta-substituted phenyl group showed a higher percentage of enzymatic inhibition. Molecular modelling calculations indicated the putative interactions of compounds with the amino acids residues of both enzymes AChE and BuChE. The cytotoxicity of compounds 9, 13, 14, 15 and 17 was evaluated against a non-malignant murine embryonic fibroblast cell line (NIH 3T3). Of special note is compound 15, as it presented the second-best Ki value for BuChE (1.71), was not cytotoxic (EC50 > 30 µM). Compound 15 also does not violate Lipinski rules, and showed permeability in the blood brain barrier, indicating that it can be considered a lead for the development of new drugs to treat Alzheimer's disease.
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Acetilcolinesterasa , Inhibidores de la Colinesterasa , Ratones , Animales , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/química , Acetilcolinesterasa/metabolismo , Amidas/farmacología , Simulación del Acoplamiento MolecularRESUMEN
Bacterial quorum sensing (QS) and biofilm formation are promising targets for developing new therapies to treat chronic infections. Herein, we report the stereoselective synthesis of 18 new analogs of natural cadiolides. Among the new compounds, substances 8b, 8f, 8i, 9a, 9b and 9e completely inhibited the biofilm formation of Escherichia coli RP347 in vitro. In addition, compound 8b interfered acyl-homoserine lactone (AHL) mediated QS, while 9e interrupted the QS via autoinducer-2 (AI-2). Biological assays also revealed that synthetic intermediates alkynones are potent inhibitors of AI-2 and AHL-mediated QS. These results indicate that cadiolides and alkynones are good candidates for further structural modification for a new generation of more potent antimicrobial agents.
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4-Butirolactona/farmacología , Antibacterianos/farmacología , Biopelículas/efectos de los fármacos , Percepción de Quorum/efectos de los fármacos , 4-Butirolactona/síntesis química , Antibacterianos/síntesis química , Escherichia coli/efectos de los fármacos , Escherichia coli/fisiología , Pruebas de Sensibilidad Microbiana , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/fisiología , EstereoisomerismoRESUMEN
Butenolides and tetronic acids occupy a prominent position in synthetic chemistry due to their ubiquitous distribution in nature. This has stimulated investigations firstly in the synthesis of such systems and, laterly, the interest has turned to the understanding of the quantum structure of such systems, allowing a deeper understanding of the mechanism and reactivity of this cyclic scaffold. In contrast, tetronamides, which consist of compounds bearing a 4-aminofuran-2(5H)-one backbone, are relatively rare in nature and synthetic routes to such compounds are poorly explored. This review highlights both the importance of the tetronamide scaffold in medicinal chemistry and the most relevant recondite synthetic strategies for obtaining compounds of this class.
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Agroquímicos , Química FarmacéuticaRESUMEN
Leishmaniasis is a neglected disease, caused by a parasite of Leishmania genus and widespread in the tropical and subtropical areas of the world. Currents drugs are limited due to their toxicity and parasite resistance. Therefore, the discovery of new treatment, more effective and less toxic, is urgent. In this study, we report the synthesis of six gem-dihydroperoxides (2a-2f), with yields ranging from 10 % to 90 %, utilizing a new methodology. The dihydroperoxides were converted into ten tetroxanes (3a-3j), among which six (3b, 3c, 3d, 3g, 3h and 3j) showed activity against intracellular amastigotes of Leishmania amazonensis. The cytotoxicity of all compounds was also evaluated against canine macrophages (DH82), human hepatoma (HepG2) and monkey renal cells (BGM). Most compounds were more active and less toxic than potassium antimonyl tartrate trihydrate, used as positive control. Amongst all tetroxanes, 3b (IC50 =0.64â µm) was the most active, being more selective than positive control in relation to DH82, HepG2 and BGM cells. In summary, the results revealed a hit compound for the development of new drugs to treat leishmaniasis.
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Antiprotozoarios/farmacología , Leishmania/efectos de los fármacos , Tetraoxanos/química , Animales , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Perros , Haplorrinos , Humanos , Macrófagos/citología , Macrófagos/metabolismo , Tetraoxanos/síntesis química , Tetraoxanos/farmacologíaRESUMEN
INTRODUCTION: Essential oils of Cymbopogon nardus and C. winterianus have fungicidal, bactericidal, and insect repellent activities. In addition, they are components of fragrances, cosmetics, and household products. The growing demand for essential oils has intensified adulteration practices of such products. OBJECTIVES: To evaluate the authenticity and quality of citronella commercial essential oils based on chemical composition [by gas chromatography mass spectrometry (GC-MS)] and the contents of its major constituents [by 1 H-NMR, and gas chromatography with a flame ionisation detector using internal standardisation (GC-IS)]. MATERIALS AND METHODS: The chemical composition of essential oil was determined by GC-MS. Major components were quantified by 1 H-NMR and the results compared to those obtained by GC-IS. RESULTS: The adulteration of oils was verified by GC and 1 H-NMR. In the pure oils, the results obtained by 1 H-NMR were similar to those obtained by GC-IS for most of the oils. However, in adulterated oils, signal overlap prevented the quantification of citronellol and geraniol by NMR. Importantly, due to dilution with dipropylene glycol it was not possible to quantify citronellal using 1 H-NMR. However, for both pure and adulterated oils, GC-IS method proved successful in quantifying notable constituents. CONCLUSION: All the methods used proved efficient in detecting adulteration. However, whilst GC-IS provided quantification of constituents of interest, both in pure and adulterated oils, their quantification by NMR was only possible in non-adulterated samples. None of the oils evaluated presented a composition within the threshold established by British Pharmacopoeia quality standards.
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Cymbopogon , Aceites Volátiles , Cromatografía de Gases y Espectrometría de Masas , Espectroscopía de Resonancia Magnética , Aceites de PlantasRESUMEN
A series of 2,5-bis(alkyl/arylamino)-1,4-benzoquinones (1-12) were investigated inâ vitro for their potential to inhibit the activity of jack bean urease. Compounds 1-6, 8, 9, 11 and 12 effectively inhibited the jack bean urease activity by 90.8 % when tested at 5â µm, whereas 7 and 10 had relatively little effect. The IC50 for most compounds was in the nanomolar range (31.4â nm and 36.0â nm for 2 and 8, respectively). The mechanism of enzyme inhibition shown by 2 and 8 is typical of mixed-type inhibitors, whose affinity for the active site is over 6- and 2-fold higher (Ki =30.0 and 22.8â nm, for 2 and 8, respectively) than that of an allosteric site. Molecular docking studies revealed that both 2 and 8 establish hydrogen bonds with the amino acids residues Asp494, Met588, His593 and Ala636 in the active site of jack bean urease. These results indicate that such aminoquinones are useful leads for the development of more efficient urease inhibitors of wider utility.
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Benzoquinonas/química , Inhibidores Enzimáticos/química , Ureasa/antagonistas & inhibidores , Sitio Alostérico , Benzoquinonas/metabolismo , Benzoquinonas/farmacología , Canavalia/enzimología , Dominio Catalítico , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Cinética , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Ureasa/metabolismoRESUMEN
This study evaluated the inhibitory effects of lactams on Streptococcus mutans, Enterococcus faecalis, and Candida glabrata multispecies biofilm formation. γ-Alkylidene-γ-lactams 1, 2, and 3 [solubilized in 3.5% dimethyl sulfoxide (DMSO)] were tested. Glass coverslips were conditioned with either the lactams or 3.5% DMSO (control) for 1 h, inoculated with microbial cultures, and incubated for 48 h. To assess the effect of the lactams on biofilm formation, the following parameters were determined: the biofilm biomass (by both crystal violet staining and protein determination); the amount of insoluble polysaccharides of the extracellular matrix; and the number of viable and total cells [by both colony-forming unit counting and quantitative real-time PCR (qPCR)]. Data were analysed using one-way anova and post-hoc Tukey tests. Lactams 1, 2, and 3 promoted a statistically significant reduction in the amount of biofilm biomass, but only lactam 3 resulted in a statistically significant reduction in the number of attached viable E. faecalis. Both total protein content and the amount of extracellular polysaccharides decreased significantly. The effects of γ-alkylidene-γ-lactams 1, 2, and 3 on the inhibition of multispecies biofilm formation were evident by their ability to reduce the amount of protein and extracellular polysaccharides.
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Biopelículas/efectos de los fármacos , Lactamas/farmacología , Biopelículas/crecimiento & desarrollo , Candida glabrata/efectos de los fármacos , Candida glabrata/crecimiento & desarrollo , Células Cultivadas , Dimetilsulfóxido/farmacología , Enterococcus faecalis/efectos de los fármacos , Enterococcus faecalis/crecimiento & desarrollo , Fibroblastos/efectos de los fármacos , Humanos , Lactamas/química , Pruebas de Sensibilidad Microbiana , Streptococcus mutans/efectos de los fármacos , Streptococcus mutans/crecimiento & desarrolloRESUMEN
In this study, we explore the cytotoxic activity of four natural abenquines (2a-d) and fourteen synthetic analogues (2e-j and 3a-h) against a panel of six human cancer cell lines using a SRB assay. It was found that most of the compounds revealed higher levels of cytotoxic activities than naturally occurring abenquines. The analogues carrying ethylpyrrolidinyl and ethylpyrimidinyl with either an acetyl group (2h-i) or a benzoyl group (3f-g), were the most potent against all human cancer cell lines and displayed EC50 between a range of 0.6-3.4µM. Notably, of the compounds tested, compound 2i proved the most cytotoxic against both ovarian (A2780) and breast (MCF7) cells, showing EC50=0.6 and 0.8µM respectively. Likewise, the analogues 2i, 3f and 3g showed strong activity against cell HT29 with EC50=0.9µM for these compounds.
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Antineoplásicos/farmacología , Quinonas/farmacología , Células 3T3 , Animales , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Quinonas/químicaRESUMEN
The first synthesis of enhygrolide A, a scarce γ-alkylidenebutenolide antibiotic of the obligate marine myxobacterium Enhygromyxa salina, was achieved in five steps and 54% overall yield from tetronic acid. Key steps include (i) organocatalytic reductive alkylation, (ii) iron-catalyzed sp2-sp3 cross-coupling, and (iii) vinylogous aldol condensation. Aside from its brevity and reliance on environmentally sustainable processes, the synthesis demonstrates the serviceability of butenolide pivalates in cross-coupling reactions.
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4-Butirolactona/análogos & derivados , Antibacterianos/síntesis química , Compuestos de Bencilideno/síntesis química , Myxococcales/química , 4-Butirolactona/síntesis química , 4-Butirolactona/química , 4-Butirolactona/farmacología , Aldehídos/química , Alquilación , Antibacterianos/química , Antibacterianos/farmacología , Compuestos de Bencilideno/química , Compuestos de Bencilideno/farmacología , Catálisis , Biología Marina , Estructura Molecular , EstereoisomerismoRESUMEN
The first synthesis of the tetronamide antibiotic basidalin was accomplished in five steps and 39% overall yield from readily available 4-bromo-2-triisopropylsilyloxyfuran and 2-formyl-1,3-dithiane. Highlights include: (i) regio- and stereocontrolled assemblage of a pivotal (Z)-γ-ylidene-ß-bromobutenolide intermediate by stereodirected vinylogous aldol condensation (SVAC), (ii) installation of the amino group via aza-Michael addition/elimination, and crucially (iii) facile access to basidalin by late-stage dithiane removal.
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Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/síntesis química , Policétidos/química , Aldehídos/química , Furanos/síntesis química , Furanos/química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Quinolizinas/química , Estereoisomerismo , Compuestos de Azufre/químicaRESUMEN
A stereoselective vinylogous aldol reaction of N-monosubstituted tetronamides with aldehydes is described. The procedure is simple and scalable, works well with both aromatic and aliphatic aldehydes, and affords mainly the corresponding syn-aldol adducts. In many cases, the latter are obtained essentially free of their anti-isomers (dr > 99 : 1) in high yields (70-90%). Experimental and computational studies suggest that the observed diastereoselectivity arises through anti-syn isomer interconversion, enabled by an iterative retro-aldol/aldol reaction.
RESUMEN
Although quinones present a large array of biological activities, a few studies on the herbicidal potential of 2,5-bis(alkyl/arylamino)-1,4-benzoquinones have been reported to date. In this work, starting from benzoquinone, 13 2,5-bis(alkyl/arylamino)-1,4-benzoquinones were prepared in 46 - 93% yield. The products were fully characterized by spectroscopic analyses and their phytotoxicity against Cucumis sativus and Sorghum bicolor seedlings was investigated. At 100 ppm, compounds caused 10 - 88% growth inhibition of the dicotyledonous species, whereas the monocotyledon was less affected. Most compounds exerted little inhibitory effect on a cyanobacterial model strain. However, at 100 µm, compounds 8 - 10 caused about 50% inhibition of algal growth, and compounds 1 and 2 reduced cell viability in the 1 - 10 µm range. The ability of benzoquinone derivatives to interfere with the light-driven ferricyanide reduction by isolated spinach chloroplasts was evaluated. Some substances showed a moderate effect as uncouplers, but no relationship was found between this property and their biological activity, indicating that the herbicidal effect is not associated with the inhibition of the photosynthetic electron transport chain. Phytotoxic compounds were not toxic to insects, strengthening the possibility that they may serve as lead for the development of eco-friendly herbicides.
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Aminas/química , Benzoquinonas/farmacología , Cucumis sativus/efectos de los fármacos , Herbicidas/farmacología , Sorghum/efectos de los fármacos , Animales , Benzoquinonas/síntesis química , Benzoquinonas/química , Cucumis sativus/crecimiento & desarrollo , Relación Dosis-Respuesta a Droga , Herbicidas/síntesis química , Herbicidas/química , Insectos/efectos de los fármacos , Estructura Molecular , Sorghum/crecimiento & desarrolloRESUMEN
Natural phytotoxins and their synthetic analogs are a potential source of new bioactive compounds for agriculture. Analogs of rubrolides, a class of γ-alkylidene-γ-lactones isolated from different ascidians, have been shown to interfere with the photosynthetic electron-transport chain, yet their activity needs to be improved. With this aim, ten 5-aryl-6-benzyl-4-bromopyridazin-3(2H)-ones were prepared in yields ranging from 44 to 88% by reaction of their correspondent γ-alkylidene-γ-lactones with NH2 NH2 . The structures of these rubrolide analogs were determined by (1) H- and (13) C-NMR, 2D-NMR (COSY and HETCOR), NOE difference, and MS techniques. These compounds were evaluated for their abilities of interfering with the light-driven reduction of ferricyanide by isolated spinach chloroplasts. Lactones with electron-withdrawing substituents in the para-position of the benzylidene ring were the most effective inhibitors. Characterization of the activity of 11b/11b' suggested a mechanism based on the interaction with the plastoquinone binding site of photosystem II. Addition of several compounds to the culture medium of a cyanobacterial model strain was found to inhibit algal growth. However, the relative effectiveness was not consistent with their activity in vitro, suggesting the occurrence of multiple targets and/or detoxyfication mechanisms. Indeed, the compounds showed differential effects on the heterotrophic growth of some crop species, Cucumis sativus and Sorghum bicolor. Pyridazin-3(2H)-ones 12e, 12i, and 12j, which have been found poorly active against the photosynthetic electron transport, were the most effective in inhibiting the growth of some weeds, Ipomoea grandifolia and Brachiaria decumbens, under greenhouse conditions.
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Compuestos Aza/farmacología , Lactonas/farmacología , Fotosíntesis/efectos de los fármacos , Compuestos Aza/química , Brachiaria/efectos de los fármacos , Brachiaria/crecimiento & desarrollo , Cucumis sativus/efectos de los fármacos , Cucumis sativus/crecimiento & desarrollo , Relación Dosis-Respuesta a Droga , Ipomoea/efectos de los fármacos , Ipomoea/crecimiento & desarrollo , Lactonas/química , Modelos Moleculares , Estructura Molecular , Sorghum/efectos de los fármacos , Sorghum/crecimiento & desarrolloRESUMEN
Several molecules have been discovered that interfere with formation of bacterial biofilms, opening a new strategy for the development of more efficient treatments in case of antibiotic resistant bacteria. Amongst the most active compounds are some natural brominated furanones from marine algae Delisea pulchra that have proven to be able to control pathogenic biofilms. We have recently reported that some rubrolide analogues are able to inhibit biofilm formation of Enterococcus faecalis. In the present Letter we describe results of the biological evaluation of a small library of 28 compounds including brominated furanones and the corresponding lactams against biofilm formation of Staphylococcus aureus, Pseudomonas aeruginosa, Staphylococcus epidermidis and Streptococcus mutans. Our results showed that in general these compounds were more active against biofilms of S. epidermidis and P. aeruginosa, with little or no inhibition of planktonic bacterial growth. In some cases they were able to prevent biofilm formation of P. aeruginosa at concentrations as low as 0.6 µg/mL (1.3 µM, compound 3d) and 0.7 µg/mL (1.3 µM, 3f). Results also indicate that, in general, lactams are more active against biofilms than their precursors, thus designating this class of molecules as good candidates for the development of a new generation of antimicrobial drugs targeted to biofilm inhibition.
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Antibacterianos/farmacología , Biopelículas/efectos de los fármacos , Furanos/farmacología , Lactonas/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Relación Dosis-Respuesta a Droga , Furanos/síntesis química , Furanos/química , Lactonas/síntesis química , Lactonas/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pseudomonas aeruginosa/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Staphylococcus aureus/efectos de los fármacos , Staphylococcus epidermidis/efectos de los fármacos , Streptococcus mutans/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
A series of 19 novel eugenol derivatives containing a 1,2,3-triazole moiety was synthesized via a two-step process, with the key step being a copper(I)-catalyzed azide-alkyne cycloaddition reaction. The compounds were assessed for their antifungal activities against Colletotrichum gloeosporioides, the causative agent of papaya anthracnose. Triazoles 2k, 2m, 2l, and 2n, at 100 ppm, were the most effective, reducing mycelial growth by 88.3, 85.5, 82.4, and 81.4%, respectively. Molecular docking calculations allowed us to elucidate the binding mode of these derivatives in the catalytic pocket of C. gloeosporioides CYP51. The best-docked compounds bind closely to the heme cofactor and within the channel access of the lanosterol (LAN) substrate, with crucial interactions involving residues Tyr102, Ile355, Met485, and Phe486. From such studies, the antifungal activity is likely attributed to the prevention of substrate LAN entry by the 1,2,3-triazole derivatives. The triazoles derived from natural eugenol represent a novel lead in the search for environmentally safe agents for controlling C. gloeosporioides.
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Carica , Colletotrichum , Eugenol , Fungicidas Industriales , Simulación del Acoplamiento Molecular , Enfermedades de las Plantas , Triazoles , Colletotrichum/efectos de los fármacos , Eugenol/farmacología , Eugenol/química , Carica/química , Fungicidas Industriales/farmacología , Fungicidas Industriales/química , Fungicidas Industriales/síntesis química , Triazoles/química , Triazoles/farmacología , Triazoles/síntesis química , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/prevención & control , Relación Estructura-Actividad , Diseño de Fármacos , Proteínas Fúngicas/química , Estructura MolecularRESUMEN
The total synthesis of (±)-streptonigrin, a potent tetracyclic aminoquinoline-5,8-dione antitumor antibiotic that reached phase II clinical trials in the 1970s, is described. Two routes to construct a key pentasubstituted pyridine fragment are depicted, both relying on ring-closing metathesis but differing in the substitution and complexity of the precursor to cyclization. Both routes are short and high yielding, with the second-generation approach ultimately furnishing (±)-streptonigrin in 14 linear steps and 11% overall yield from inexpensive ethyl glyoxalate. This synthesis will allow for the design and creation of druglike late-stage natural product analogues to address pharmacological limitations. Furthermore, assessment of a number of chiral ligands in a challenging asymmetric Suzuki-Miyaura cross-coupling reaction has enabled enantioenriched (up to 42% ee) synthetic streptonigrin intermediates to be prepared for the first time.
Asunto(s)
Antibióticos Antineoplásicos/síntesis química , Estreptonigrina/síntesis química , Antibióticos Antineoplásicos/química , Ciclización , Estructura Molecular , Estereoisomerismo , Estreptonigrina/químicaRESUMEN
Detrimental biofilms of bacterial pathogens cause chronic infections with a high-level tolerance to antibiotics. To identify new control agents, we synthesized and tested a total of 14 tetronamides (including 5 new compounds) and 6 denigrin intermediates on the model species Escherichia coli. At a concentration of 50 µg/mL, two tetronamides and two methylated denigrins exhibited significant inhibitory effects against biofilm formation of E. coli RP437, e.g., by 60 and 94%, respectively. Structural analysis of the tested compounds revealed that p-methoxybenzylidene and p-methoxyphenethyl moieties of denigrins are important for biofilm inhibition, while the former group is also essential to the activity against quorum sensing (QS) via AI-2. Specifically, tetramethyldenigrin B has strong inhibitory effects against both E. coli biofilm formation and AI-2-mediated QS and thus provides a promising lead structure for designing better control agents. Consistently, tetramethyldenigrin B also showed inhibitory activity against biofilm formation of uropathogenic E. coli. Together, these findings provide new insights for the rational design of novel biofilm and QS inhibitors.
RESUMEN
The chemical composition of the volatile oils from five Anacardiaceae species and their activities against Gram positive and negative bacteria were assessed. The peroxidative damage within bacterial cell membranes was determined through the breakdown product malondialdehyde (MDA). The major constituents in Anacardium humile leaves oil were (E)-caryophyllene (31.0%) and α-pinene (22.0%), and in Anacardium occidentale oil they were (E)-caryophyllene (15.4%) and germacrene-D (11.5%). Volatile oil from Astronium fraxinifolium leaves were dominated by (E)-ß-ocimene (44.1%) and α-terpinolene (15.2%), whilst the oil from Myracrodruon urundeuva contained an abundance of δ-3-carene (78.8%). However, Schinus terebinthifolius leaves oil collected in March and July presented different chemical compositions. The oils from all species, except the one from A. occidentale, exhibited varying levels of antibacterial activity against Staphylococcus aureus, Bacillus cereus and Escherichia coli. Oil extracted in July from S. terebinthifolius was more active against all bacterial strains than the corresponding oil extracted in March. The high antibacterial activity of the M. urundeuva oil could be ascribed to its high δ-3-carene content. The amounts of MDA generated within bacterial cells indicate that the volatile oils induce lipid peroxidation. The results suggest that one putative mechanism of antibacterial action of these volatile oils is pro-oxidant damage within bacterial cell membrane explaining in part their preservative properties.
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Anacardiaceae/química , Bacterias/efectos de los fármacos , Bacterias/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Aceites Volátiles/química , Aceites Volátiles/farmacología , Antibacterianos/química , Antibacterianos/farmacología , Pruebas de Sensibilidad Microbiana , Extractos Vegetales/química , Extractos Vegetales/farmacología , Aceites de Plantas/química , Aceites de Plantas/farmacologíaRESUMEN
Background: Nitazoxanide exerts antiviral activity in vitro and in vivo and anti-inflammatory effects, but its impact on patients hospitalized with COVID-19 pneumonia is uncertain. Methods: A multicentre, randomized, double-blind, placebo-controlled trial was conducted in 19 hospitals in Brazil. Hospitalized adult patients requiring supplemental oxygen, with COVID-19 symptoms and a chest computed tomography scan suggestive of viral pneumonia or positive RT-PCR test for COVID-19 were enrolled. Patients were randomized 1:1 to receive nitazoxanide (500 mg) or placebo, 3 times daily, for 5 days, and were followed for 14 days. The primary outcome was intensive care unit admission due to the need for invasive mechanical ventilation. Secondary outcomes included clinical improvement, hospital discharge, oxygen requirements, death, and adverse events within 14 days. Results: Of the 498 patients, 405 (202 in the nitazoxanide group and 203 in the placebo group) were included in the analyses. Admission to the intensive care unit did not differ between the groups (hazard ratio [95% confidence interval], 0.68 [0.38-1.20], p = 0.179); death rates also did not differ. Nitazoxanide improved the clinical outcome (2.75 [2.21-3.43], p < 0.0001), time to hospital discharge (1.37 [1.11-1.71], p = 0.005), and reduced oxygen requirements (0.77 [0.64-0.94], p = 0.011). C-reactive protein, D-dimer, and ferritin levels were lower in the nitazoxanide group than the placebo group on day 7. No serious adverse events were observed. Conclusions: Nitazoxanide, compared with placebo, did not prevent admission to the intensive care unit for patients hospitalized with COVID-19 pneumonia. Clinical Trial Registration: Brazilian Registry of Clinical Trials (REBEC) RBR88bs9x; ClinicalTrials.gov, NCT04561219.
RESUMEN
The synthesis of the potent antitumor agent (±)-streptonigrin has been achieved in 14 linear steps and 11% overall yield from ethyl glyoxalate. The synthesis features a challenging ring-closing metathesis reaction, followed by elimination and aromatization, to furnish a key pentasubstituted pyridine fragment.