RESUMO
Over the past decades, both 4'-modified nucleoside and carbocyclic nucleoside analogs have been under the spotlight as several compounds from either family showed anti-HIV, HCV, RSV or SARS-CoV-2 activity. Herein, we designed compounds combining these two features and report the synthesis of a series of novel 4'-substituted carbocyclic uracil derivatives along with their corresponding monophosphate prodrugs. These compounds were successfully prepared in 19 to 22 steps from the commercially available (-)-Vince lactam and were evaluated against a panel of RNA viruses including SARS-CoV-2, influenza A/B viruses and norovirus.
Assuntos
COVID-19 , Vírus da Influenza A , Pró-Fármacos , Humanos , Antivirais/farmacologia , Anticorpos Anti-Hepatite C , Vírus da Influenza B , Nucleosídeos , Pró-Fármacos/farmacologia , SARS-CoV-2 , UracilaRESUMO
Exploration of the chemical space of known influenza polymerase PB2 inhibitor Pimodivir, was performed by our group. We synthesized and identified compounds 16a and 16b, two novel thienopyrimidine derivatives displaying anti-influenza A activity in the single digit nanomolar range in cell culture. Binding of these unique compounds in the influenza polymerase PB2 pocket was also determined using molecular modeling.
Assuntos
Antivirais/química , Vírus da Influenza A/efeitos dos fármacos , Influenza Humana/tratamento farmacológico , Piridinas/química , Pirimidinas/química , Pirróis/química , RNA Polimerase Dependente de RNA/metabolismo , Proteínas Virais/metabolismo , Células A549 , Sequência de Aminoácidos , Animais , Antivirais/farmacologia , Descoberta de Drogas , Humanos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Piridinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
Yellow fever virus (YFV) is a human Flavivirus reemerging in parts of the world. While a vaccine is available, large outbreaks have recently occurred in Brazil and certain African countries. Development of an effective antiviral against YFV is crucial, as there is no available effective drug against YFV. We have identified several novel nucleoside analogs with potent antiviral activity against YFV with 50% effective concentration (EC50) values between 0.25 and 1 µM with selectivity indices over 100 in culture.
Assuntos
Antivirais/uso terapêutico , Nucleosídeos/análogos & derivados , Nucleosídeos/uso terapêutico , Febre Amarela/tratamento farmacológico , Vírus da Febre Amarela/efeitos dos fármacos , Vírus da Febre Amarela/patogenicidade , África , Animais , Brasil , Linhagem Celular Tumoral , Chlorocebus aethiops , Humanos , Estrutura Molecular , Células Vero , Febre Amarela/virologiaRESUMO
Based on the anti-hepatitis C activity of 2'-C-methyl-adenosine and 2'-C-methyl-guanosine, a series of new modified purine 2'-C-methyl nucleosides was prepared as potential anti-hepatitis C virus agents. Herein, we report the synthesis of both 6-modified and 2-modified purine 2'-C-methyl-nucleosides along with their anti-HCV replication activity and cytotoxicity in different cells.
