Synthesis of New Imidazopyridine Nucleoside Derivatives Designed as Maribavir Analogues.

Georgios Papadakis,Panagiotis Marakos,Robert Snoeck,Nikolaos Lougiakis,Graciela Andrei,Nicole Pouli,Maria Gerasi

doi:10.3390/molecules25194531

Abstract

The strong inhibition of Human Cytomegalovirus (HCMV) replication by benzimidazole nucleosides, like Triciribine and Maribavir, has prompted us to expand the structure–activity relationships of the benzimidazole series, using as a central core the imidazo[4,5-b]pyridine scaffold. We have thus synthesized a number of novel amino substituted imidazopyridine nucleoside derivatives, which can be considered as 4-(or 7)-aza-d-isosters of Maribavir and have evaluated their potential antiviral activity. The target compounds were synthesized upon glycosylation of suitably substituted 2-aminoimidazopyridines, which were prepared in six steps starting from 2-amino-6-chloropyridine. Even if the new compounds possessed only a slight structural modification when compared to the original drug, they were not endowed with interesting antiviral activity. Even so, three derivatives showed promising cytotoxic potential.

Highlights

Human cytomegalovirus (HCMV) is a prevalent herpesvirus, with IgG antibodies indicating past infection found in approximately 60% of adults in developed countries and almost 100% in developing ones [1]
As a continuation of our previous involvement with the synthesis and evaluation of purine isosteric bioactive nucleosides [16,17,18,19], we designed and synthesized a number of novel nucleoside derivatives, which can be considered as 4-(or 7)-aza-d-isosters of Maribavir, having in mind that the d-enantiomer of Maribavir possesses interesting anti-Human Cytomegalovirus (HCMV) properties as well [20]
The diverse nature of the 2-amino groups in each of the final pair of isomeric nucleosides was at route the core our attempt to explore theaccess spatialtolimitations possible target enzymes

Summary

Introduction

Human cytomegalovirus (HCMV) is a prevalent herpesvirus, with IgG antibodies indicating past infection found in approximately 60% of adults in developed countries and almost 100% in developing ones [1]. Ganciclovir (GCV) and its orally bioavailable prodrug, Valganciclovir, have served as gold standards for pre-emptive therapy and prophylaxis against HCMV in solid organ transplant patients [6]. As well as for the treatment of CMV retinitis [7] for almost 30 years. Their myelosuppressive potential precludes their prophylactic use in stem cell transplant recipients, which has led to their administration, mostly upon engraftment [8]. Mutations mapping in the gene encoding for the UL97 kinase (responsible for the first phosphorylation of GCV towards its active triphosphate form) and in the UL54 gene encoding for the DNA polymerase (target of ganciclovir triphosphate), have led to the emergence of drug resistant strains [9].

Objectives

Methods

Results