Design, Synthesis, and Antipicornavirus Activity of 1-[5-(4-Arylphenoxy)alkyl]-3-pyridin-4-ylimidazolidin-2-one Derivatives

Abstract

A series of pyridylimidazolidinone derivatives was synthesized and tested in vitro against enterovirus 71 (EV71). On the basis of compound 33 (DBPR103), introduction of a methyl group at the 2- or 3-position of the linker between the imidazolidinone and the biphenyl resulted in markedly improved antiviral activity toward EV71 with IC(50) values of 5.0 nM (24b) and 9.3 nM (14a), respectively. Increasing the branched chain to propyl resulted in a progressive decrease in activity, while inserting different heteroatoms entirely rendered the compound only weakly active. The introduction of a bulky group (cyclohexyl, phenyl, or benzyl) led to loss of activity against EV71. The 4-chlorophenyl moiety in 14a was replaced with bioisosteric groups such as oxadiazole (28a-d) or tetrazole (32a,b), dramatically improving anti-EV71 activity and selectivity indices. Compounds 14a, 24b, 28b, 28d, and 32a exhibited a strong activity against lethal EV71, and no apparent cellular toxicity was observed. Three of the more potent imidazolidinone compounds, 14a, 28b, and 32b, were subjected to a large group of picornaviruses to determine their spectrum of antiviral activity.

Selective inhibitors of picornavirus replication

“…7) of the linker spacer between the imidazolidinone and biphenyl substantially improved the activity against EV71. 126 The (S)-(þ) enantiomer (EC 50 ¼ 3 nM) was 10-fold more potent against EV71 than the (R)-(À) enantiomer. 128 Furthermore, replacement of the chlorophenyl ring in this molecule (compound 14a) with the oxadiazole ring or the tetrazole ring resulted in dramatically improved inhibitory activity.…”

Structure of human enterovirus 71 in complex with a capsid-binding inhibitor

“…The inhibitors bind into the hydrophobic pocket within VP1 with high affinity and therefore cannot be dislodged upon receptor binding. Several putative capsidbinding inhibitors of EV71 were synthesized and shown to be effective (34,35), but molecular details of their interactions with the capsid proteins were not known.…”

Antiviral activity of pyridyl imidazolidinones against enterovirus 71 variants

“…Although the V192M mutant exhibited poorer susceptibility to these three compounds in comparison with wild type and the other mutant EV71 viruses, it could be inhibited to 50% with 5.5 lM BPROZ-101 and 10.679 lM BPROZ-161, respectively. Antiviral activity of pyridyl imidazolidinones with different substitutions at the central position of the hydrophobic linker From our previous work, we found that the introduction of a methyl group at the central position of the linker between the imidazolidinone and the biphenyl groups (BPROZ-033) resulted in markedly improved antiviral activity [6]. The methyl group may contribute to the hydrophobic interactions between the compound and the VP1 protein.…”

“…Data was analyzed by using GraphPad Prism 4.0 software Chemical compounds Eleven modified pyridyl imidazolidinones were synthesized and used as chemical probes for antiviral assays. The synthesis methods for theses compounds have been described previously [6,7,9,33]. The chemical names for these compounds follow.…”

“…However, it cannot neutralize EV71-induced cytopathic effects in vitro assay [33]. Therefore, using WIN compounds as a template for computational drug design, we synthesized a novel class of potent and selective EV71 inhibitors, pyridyl imidazolidinones [6,7,9,33]. From our previous genetic approach, we have found consistent mutations at six positions in the VP1 of resistant viruses in comparison with that of drug-sensitive wild-type EV71 [35].…”