4"-Benzoylureido-TSAO derivatives as potent and selective non-nucleoside HCMV inhibitors. Structure-activity relationship and mechanism of antiviral action

Journal of Medicinal Chemistry
Sonia de CastroMaría-José Camarasa

Abstract

Analogues of the 4"-benzoyl-ureido-TSAO derivative (1) modified at different positions have been prepared and evaluated against wild-type strains of HCMV and murine cytomegalovirus (MCMV) in cell culture. In addition, the activity of the most active derivatives against several drug-resistant HCMV mutants has been determined. A stringent structure-antiviral activity relationship was observed for the 4"-benzoylureido- TSAO derivatives for which the concomitant presence of a highly lipophilic substituent at both 2'- and 5'-positions was required to fully preserve the antihuman cytomegalovirus efficacy. Time-of-addition studies and HCMV immediately early and early gene expression studies revealed a target at the time of viral DNA synthesis, although direct inhibition of HCMV-encoded DNA polymerase could not be observed in cell-free assays. Lack of cross-resistance against a broad variety of mutant HCMV strains points to an antiviral target that is different from those drugs that are currently approved for clinical use.

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Citations

Jun 30, 2012·Chemical Reviews·Shovan Mondal
Jun 22, 2016·The Journal of Organic Chemistry·Thomas RawnerOliver Reiser
Mar 27, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Bi LiHaimin Lei
May 30, 2020·The Journal of Organic Chemistry·Shohei FuruyaShin-Ichi Fukuzawa

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