RESUMEN
The synthesis and anti-HIV evaluation of hitherto unknown 3'-fluoro-5'-norcarbocyclic nucleoside phosphonates bearing adenine with modifications at the 4' position (ethynyl, vinyl, ethyl, hydroxymethyl) is described. One of the synthesized compounds was found to be an inhibitor of HIV-1 replication, but with moderate efficiency relative to (R)-9-(2-phosphonylmethoxypropyl)adenine ((R)-PMPA, tenofovir), with no concomitant cytotoxicity.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Nucleósidos/síntesis química , Nucleósidos/farmacología , Organofosfonatos/química , Adenina/química , Células Sanguíneas , Supervivencia Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos/métodos , Humanos , Estructura Molecular , Relación Estructura-Actividad , Tenofovir/farmacología , Replicación Viral/efectos de los fármacosRESUMEN
Bis-thiazolium salts are able to inhibit phosphatidylcholine biosynthesis in Plasmodium and to block parasite proliferation in the low nanomolar range. However, due to their physicochemical properties (i.e., permanent cationic charges, the flexibility, and lipophilic character of the alkyl chain), the oral bioavailability of these compounds is low. New series of bis-thiazolium-based drugs have been designed to overcome this drawback. They feature linker rigidification via the introduction of aromatic rings and/or a decrease in the overall lipophilicity through the introduction of heteroatoms. On the basis of the structure-activity relationships, a few of the promising compounds (9, 10, and 11) were found to exhibit potent antimalarial in vitro and in vivo activities (EC(50) < 10 nM and ED(50) ip < 0.7 mg/kg).