SAR studies on a novel series of human cytomegalovirus primase inhibitors

Human cytomegalovirus DNA replication: antiviral targets and drugs

“…To date, only a few inhibitors of HCMV UL70 primase have been reported [113][114][115]. A compound that belongs to the imidazolyl-pyrimidine chemical class ( Figure 6) was recently discovered during a HTS which employed a cell-based HCMV-luciferase replication assay.…”

“…It was suggested that a thiol group of UL70 acts as a nucleophile that attacks the inhibitor with displacement of the imidazole moiety, resulting in the formation of a covalent link between the compound and UL70 and leading to irreversible inhibition of the primase. A resistant virus was isolated carrying a single point mutation P571S next to the cysteine at position 570, which is the residue of UL70 that interacts with these compounds [115].…”

Diastereoselective Synthesis of Highly Substituted, Amino‐ and Pyrrolidino‐Tetrahydrofurans as Lead‐Like Molecular Scaffolds

“…7:1r atio of diastereomers after work-up) with preference for methylation trans to the aryl group. In both cases the major diastereomer was efficiently separated from the minor epimer by flash chromatography and all four compounds (15,16 and epi-15/16-epimeric at C-3) were fully characterised. The relative stereochemistry of THF 16 was determined at this stage by X-ray crystallography.…”

“…As part of our contributions to the European Lead Factory (ELF) drug discovery initiative, we were interested in the design and synthesis of new THF scaffolds bearing an amino substituent on the heterocycle backbone (i.e., at C‐3 or C‐4). In addition to serving as a convenient template for library synthesis, the biological activity of amino‐THFs is well precedented (e.g., compounds 1 – 3 , Figure ) . In the design of a lead‐like scaffold incorporating this structural feature that fulfilled the requirements of the ELF, we identified THF 4 as our principal target (Scheme ).…”

“…In addition to serving as ac onvenient template for library synthesis, the biological activity of amino-THFs is well precedented (e.g.,c ompounds 1-3,F igure 1). [15][16][17] In the design of al eadlike scaffold [18] incorporating this structural feature that fulfilled the requirements of the ELF, [14] we identified THF 4 as our principal target (Scheme 1). In addition to the key aminog roup at C-4, ac arboxylic acid or derived functionality (e.g.,a mide or hydroxymethyl) was proposed at C-3 as as econd major point for orthogonal diversification.…”