RESUMO
The total synthesis of four novel mono-methoxy and hydroxyl substituted ring-A dihydronarciclasine derivatives enabled identification of the 7-hydroxyl derivative as a potent and selective antiviral agent targeting SARSCoV-2 and HSV-1. The concentration of this small molecule that inhibited HSV-1 infection by 50% (IC50), determined by using induced pluripotent stem cells (iPCS)-derived brain organ organoids generated from two iPCS lines, was estimated to be 0.504 µM and 0.209 µM. No significant reduction in organoid viability was observed at concentrations up to 50 mM. Genomic expression analyses revealed a significant effect on host-cell innate immunity, revealing activation of the integrated stress response via PERK kinase upregulation, phosphorylation of eukaryotic initiation factor 2α (eIF2α) and type I IFN, as factors potentiating multiple host-defense mechanisms against viral infection. Following infection of mouse eyes with HSV-1, treatment with the compound dramatically reduced HSV-1 shedding in vivo.
Assuntos
Alcaloides de Amaryllidaceae , Antineoplásicos , Herpesvirus Humano 1 , Interferon Tipo I , Camundongos , Animais , Antivirais/farmacologia , Alcaloides de Amaryllidaceae/farmacologia , FosforilaçãoRESUMO
The synthesis of a lead anti-viral cyclopropyl carboxy acyl hydrazone 4F17 (5) and three sequential arrays of structural analogues along with the initial assessment and optimization of the antiviral pharmacophore against the herpes simplex virus type 1 (HSV-1) are reported.
Assuntos
Antivirais/química , Antivirais/farmacologia , Herpesvirus Humano 1/efeitos dos fármacos , Hidrazonas/química , Hidrazonas/farmacologia , Antivirais/síntese química , Linhagem Celular , Técnicas de Química Sintética , Herpes Simples/tratamento farmacológico , Humanos , Hidrazonas/síntese química , Relação Estrutura-AtividadeRESUMO
A new metabolite 1 has been isolated from the marine soft coral Sarcophyton ehrenbergi along with two known diterpenoids 2 and 3 and cholesterol 4. The structure of 1 was determined by means of detailed spectroscopic analysis and unambiguously confirmed to have the S configuration by the synthesis of both enantiomers using 4-benzyl-2-oxazolidinone auxiliaries. (S)- and (R)-1, 3 and some of the synthetic intermediates were evaluated for cytotoxic activity against human lung cancer (A549), prostate cancer (DU145), cervical cancer (HeLa) and breast cancer (MCF-7) cell lines in an in vitro bioassay.