The structure-activity relationships of the antiviral chemotherapeutic activity of isatin beta-thiosemicarbazone

Abstract

As part of an investigation devoted to the development of new antiviral agents a compound of established antiviral activity has been subjected to systematic structural modification. The structure-activity data so obtained have been used in the design of new compounds, some of which are described. The compound chosen was isatin beta-thiosemicarbazone, which has high activity against neurovaccinia infection in mice, and a 4-point parallel-line assay of in vivo chemotherapeutic activity has been developed, which has enabled the activity of the derivatives to be determined against isatin beta-thiosemicarbazone as a standard. The overall dimensions of the isatin beta-thiosemicarbazone molecule appear to be nearly maximal for the retention of high activity, as all substituents in the aromatic ring decrease the activity irrespective of their nature or position. The projection of the -CS.NH(2) group in relation to the ring nitrogen was found to be critical, as the alpha-thiosemicarbazone was inactive. A number of modifications of the side-chain were investigated:all led to reduction or loss of antiviral activity. The antiviral activity showed a positive correlation with chloroform solubility over a considerable range. The most active compound encountered was 1-ethylisatin beta-thiosemicarbazone, with an activity of 286 (isatin beta-thiosemicarbazone identical with100). Isatin beta-thiosemicarbazone showed no activity against 15 other viruses, and 20 related compounds showed on activity against ectromelia.