RESUMEN
Novel 2-substituted-6-[(4-substituted-1-piperidyl)methyl]-1H-benzimidazoles were designed and synthesized as Ebola virus inhibitors. The proposed structures of the new prepared benzimidazole-piperidine hybrids were confirmed based on their spectral data and CHN analyses. The target compounds were screened in vitro for their anti-Ebola activity. Among tested molecules, compounds 26a (EC50=0.93 µM, SI = 10) and 25a (EC50=0.64 µM, SI = 20) were as potent as and more selective than Toremifene reference drug (EC50 = 0.38 µM, SI = 7) against cell line. Data suggests that the mechanism by which 25a and 26a block EBOV infection is through the inhibition of viral entry at the level of NPC1. Furthermore, a docking study revealed that several of the NPC1 amino acids that participate in binding to GP are involved in the binding of the most active compounds 25a and 26a. Finally, in silico ADME prediction indicates that 26a is an idealy drug-like candidate. Our results could enable the development of small molecule drug capable of inhibiting Ebola virus, especially at the viral entry step.
Asunto(s)
Antivirales/farmacología , Bencimidazoles/farmacología , Diseño de Fármacos , Fiebre Hemorrágica Ebola/tratamiento farmacológico , Antivirales/síntesis química , Antivirales/química , Bencimidazoles/síntesis química , Bencimidazoles/química , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células HeLa , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Several hitherto unknown (E)-but-2-enyl nucleoside phosphonoamidate analogs (ANPs) were prepared directed with nitrogen reagents by cross-metathesis in water-under ultrasound irradiation. Two diastereoisomers were formally identified by X-ray diffraction. These compounds were evaluated against a large spectrum of DNA and RNA viruses. Among them, the phosphonoamidate thymine analogue 19 emerged as the best prodrug against varicella-zoster virus (VZV) with EC50 values of 0.33 and 0.39⯵M for wild-type and thymidine kinase deficient strains, respectively, and a selectivity index ≥200⯵M. This breakthrough approach paves the way for new purine and pyrimidine (E)-but-2-enyl phosphonoamidate analogs.
Asunto(s)
Antivirales/farmacología , Coronavirus Humano 229E/efectos de los fármacos , Herpesvirus Humano 1/efectos de los fármacos , Herpesvirus Humano 2/efectos de los fármacos , Herpesvirus Humano 3/efectos de los fármacos , Nucleósidos/farmacología , Antivirales/síntesis química , Antivirales/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Nucleósidos/síntesis química , Nucleósidos/química , Relación Estructura-ActividadRESUMEN
Nucleoside analogs are extremely useful for the development of therapeutic agents to control viral diseases and cancer. Among the numerous modifications on the nucleoside skeleton, replacement of the oxygen of the furanose ring by a CH2 group resulted in increased flexibility and higher resistance to phosphorylases and led to carbocyclic nucleoside analogs (or carbanucleosides). The broad spectrum of biological activities of carbocyclic nucleosides led to tremendous research interest in their syntheses. The article documents recent strategies for the synthesis of active carbocyclic nucleosides by presenting individual case studies, such as the neplanocins, entecavir and selected fluorinated carbocyclic nucleosides. Furthermore, it provides new insights into new directions for more potent and active carbocyclic nucleoside analogs.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Nucleósidos/química , Nucleósidos/farmacología , Virosis/tratamiento farmacológico , Virus/efectos de los fármacos , Adenosina/análogos & derivados , Adenosina/síntesis química , Adenosina/química , Adenosina/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Antivirales/síntesis química , Descubrimiento de Drogas , Guanina/análogos & derivados , Guanina/síntesis química , Guanina/química , Guanina/farmacología , Halogenación , Humanos , Neoplasias/tratamiento farmacológico , Nucleósidos/síntesis químicaRESUMEN
The detailed synthetic protocol for the straightforward, efficient synthesis of various alkenyl acyclonucleosides, including challenging trisubstituted alkenyl acyclonucleoside phosphonates, is described. The key step of those syntheses is an olefin cross-metathesis reaction between two olefins selected based on their reactivity using well-defined ruthenium alkylidene catalysts.