4′′-Benzoylureido-TSAO Derivatives as Potent and Selective Non-Nucleoside HCMV Inhibitors. Structure−Activity Relationship and Mechanism of Antiviral Action

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.

Ring closing metathesis and metal-catalyzed cyclopropanation for the preparation of sultone derivatives

“…Ethenesulfonyl chloride (10) was prepared in-situ from the treatment of chloro ethyl sulfonyl chloride (9) with TEA under low temperature. The unsaturated sulfonate derivatives (11) were readily prepared by esterification of the secondary alcohols (8) with the in-situ generated ethenesulfonyl chloride (10) in the presence of TEA under low temperature (-40 o C). The structures of the formed sulfonates were confirmed by elemental analysis and spectral data.…”

“…New vinylic sultone constructed on benzene scaffold was obtained by RCM as presented in scheme 3. The first step was the preparation of the unsaturated sulfonate 16 that was readily obtained by esterification of the 2-allylphenol ( 15) with ethenesulfonyl chloride (10), in the presence of TEA under low temperature (0-40). The unsaturated sulfonate derivative ( 16) was formed with 78% yield and its structure was confirmed by elemental analysis and spectral data.…”

“…Additionally, several publications have reported several biological activities of the sultones that includes antitumor and antiviral (anti-HIV) activities. [9][10][11][12] On the other hand, a great deal of interest has been focused on the cyclopropanes as they have a wide contribution in the natural products and the biologically active synthetic compounds. [13][14][15][16] Furthermore, the ring strain of the ơ-bond in the cyclopropane ring make cyclopropane derivatives highly reactive in transition metal catalyzed reactions.…”

New Synthesis Method for Sultone Derivatives: Synthesis, Crystal Structure and Biological Evaluation of S-CA

“…The biological activities of sultones previously included toxicological, skin sensitization, antiviral (anti-HIV and HCMV) and antitumor activities [12][13][14]. Some compounds prepared by total synthesis had antitumor activities due to their sulphonic acid ester structures [15,16].…”

Synthesis of Uracil-, Coumarin- and Quinolone-Fused Benzosultams and Benzosultones

“…14 Sultones are also very biologically active compounds, and their biological activities are mainly related to toxicological, skin sensitization and antiviral activities. [15][16][17][18][19][20] On the other hand, coumarin, quinolone and pyrimidine derivatives are very well known for their biological activities and medicinal utilities. 21 Therefore, from our continuous efforts in sultam and sultone chemistry, 14a,22 we were interested to develop an efficient route for the synthesis of uracil-, coumarin-and quinolone-fused benzosultams and benzosultones.…”