Author:

Keywords:

SILVER - 260644;info:eu-repo/grantAgreement/EC/FP7/260644, Science & Technology, Life Sciences & Biomedicine, Chemistry, Medicinal, Pharmacology & Pharmacy, Flavivirus inhibitors, Dengue virus, Yellow fever virus, Bis-O-tritylated nucleosides, 3 ',5 '-di-O-Trityl-uridine, DENGUE VIRUS, 3′,5′-di-O-Trityl-uridine, MUGGLEKABKZTPD-KJQSMSQRSA-N, QJBAWUAFPJZOKV-HOCDMSHKSA-N, Antiviral Agents, Dose-Response Relationship, Drug, Flavivirus, Microbial Sensitivity Tests, Molecular Structure, Nucleosides, Structure-Activity Relationship, 0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 1115 Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry, 3214 Pharmacology and pharmaceutical sciences, 3404 Medicinal and biomolecular chemistry, 3405 Organic chemistry

Abstract:

Following up on a hit that was identified in a large scale cell-based antiviral screening effort, a series of triphenylmethyl alkylated nucleoside analogues were synthesized and evaluated for their in vitro antiviral activities against the dengue virus (DENV) and the yellow fever virus (YFV). Hereto, trityl moieties were attached at various positions of the sugar ring combined with subtle variations of the heterocyclic base. Several triphenylmethyl modified nucleosides were uncovered being endowed with submicromolar in vitro antiviral activity against the YFV. The most selective inhibitor in this series was 3',5'-bis-O-tritylated-5-chlorouridine (1b) affording a selectivity index of over 90, whereas the 3',5'-bis-O-tritylated inosine congener (5b) displayed the highest activity, but proved more toxic. The finding of these lipophilic structures being endowed with high antiviral activity for flaviviruses, should stimulate the interest for further structure-activity research.