RESUMO
The onset of the 2019 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic necessitated the identification of approved drugs to treat the disease, before the development, approval and widespread administration of suitable vaccines. To identify such a drug, we used a visual analytics workflow where computational tools applied over an AI-enhanced biomedical knowledge graph were combined with human expertise. The workflow comprised rapid augmentation of knowledge graph information from recent literature using machine learning (ML) based extraction, with human-guided iterative queries of the graph. Using this workflow, we identified the rheumatoid arthritis drug baricitinib as both an antiviral and anti-inflammatory therapy. The effectiveness of baricitinib was substantiated by the recent publication of the data from the ACTT-2 randomised Phase 3 trial, followed by emergency approval for use by the FDA, and a report from the CoV-BARRIER trial confirming significant reductions in mortality with baricitinib compared to standard of care. Such methods that iteratively combine computational tools with human expertise hold promise for the identification of treatments for rare and neglected diseases and, beyond drug repurposing, in areas of biological research where relevant data may be lacking or hidden in the mass of available biomedical literature.
RESUMO
In order to address the current downturn in the drug discovery pipeline, initiatives are being undertaken to synthesise screening libraries of sp3-rich, low molecular weight compounds. As part of the European Lead Factory initiative, the synthesis and derivatisation of a simple hexahydrooxazolo[5,4-c]pyridin-2(1H)-one bicyclic carbamate has been achieved. The synthetic route employed involved a telescoped hetero-Diels-Alder/[2,3]-sigmatropic rearrangement/cyclisation sequence to deliver the desired core scaffold containing two points for further diversification. When applied, this synthesis was found to be robust and scalable which allowed the production of a 155 compound library.
Assuntos
Oxazolidinonas/síntese química , Bibliotecas de Moléculas Pequenas/síntese química , Cristalografia por Raios X , Modelos Moleculares , Estrutura Molecular , Oxazolidinonas/química , Bibliotecas de Moléculas Pequenas/químicaRESUMO
Malonoyl peroxide 1, prepared in a single step from the commercially available diacid, is an effective reagent for the anti-dihydroxylation of alkenes. Reaction of 1 with an alkene in the presence of acetic acid at 40 °C followed by alkaline hydrolysis leads to the corresponding diol (35-92%) with up to 13:1 anti-selectivity. A mechanism consistent with experimental findings is proposed that accounts for the selectivity observed.
Assuntos
Alcenos/química , Malonatos/química , Peróxidos/química , Álcoois/química , Produtos Biológicos/química , Indicadores e Reagentes , Estrutura MolecularRESUMO
The application of a tandem condensation/cyclisation/[3+2]-cycloaddition/elimination reaction gives an sp(3)-rich tricyclic pyrazoline scaffold with two ethyl esters in a single step from a simple linear starting material. The successive hydrolysis and cyclisation (with Boc anhydride) of these 3-dimensional architectures, generates unprecedented 16-membered macrocyclic bisanhydrides (characterised by XRD). Selective amidations could then be achieved by ring opening with a primary amine followed by HATU-promoted amide coupling to yield an sp(3)-rich natural product-like library.
Assuntos
Produtos Biológicos/síntese química , Descoberta de Drogas , Compostos Macrocíclicos/síntese química , Bibliotecas de Moléculas Pequenas/síntese química , Aminas/química , Catálise , Ciclização , Reação de Cicloadição , Estrutura MolecularRESUMO
Reactions employing inexpensive reagents from sustainable sources and with low toxicity are becoming increasingly desirable from an academic and industrial perspective. A fascinating example of a synthetic transformation that requires development of alternative procedures is the osmium catalysed dihydroxylation. Recently there has been considerable interest in achieving this reaction through metal-free procedures. This review describes the methods available for metal-free syn-dioxygenation of alkenes.
Assuntos
Álcoois/síntese química , Alcenos/química , Oxigênio/química , Álcoois/química , Metais , Estrutura MolecularRESUMO
Cyclopropyl malonoyl peroxide (1), which can be prepared in a single step from the commercially available diacid, is an effective reagent for the dihydroxylation of alkenes. Reaction of 1 with an alkene in the presence of 1 equiv of water at 40 °C followed by alkaline hydrolysis leads to the corresponding diol (40-93%). With 1,2-disubstituted alkenes, the reaction proceeds with syn selectivity (3:1 to >50:1). A mechanism consistent with the experimental findings that is supported by oxygen-labeling studies is proposed.