BMS Derivatives C7‐Linked to β‐Cyclodextrin and Hyperbranched Polyglycerol Retain Activity against R5‐HIV‐1NLAD8 Isolates and Can Be Deemed Potential Microbicides

Amides from indole‐3‐glyoxylic acid and 4‐benzoyl‐2‐methylpiperazine, which are related to entry inhibitors developed by Bristol‐Myers Squibb (BMS), have been synthesized with aliphatic chains located at the C7 position of the indole ring. These spacers contain an azido group suitable for the well‐known Cu(I)‐catalyzed (3+2)‐cycloaddition or an activated triple bond for the nucleophilic addition of thiols under physiological conditions. Reaction with polyols (β‐cyclodextrin and hyperbranched polyglycerol) decorated with complementary click partners has afforded polyol‐BMS‐like conjugates that are not cytotoxic (TZM.bl cells) and retain the activity against R5‐HIV‐1NLAD8 isolates. Thus, potential vaginal microbicides based on entry inhibitors, which can be called of 4th generation, are reported here for the first time. Making mighty microbicides: Entry inhibitors similar to those reported by Bristol‐Myers Squibb have been linked, through the C7 position of their indole ring, to β‐cyclodextrin or hyperbranched polyglycerols by means of click reactions. They are not cytotoxic at all at 50–100 μM and two of them maintain anti‐HIV‐1 activity in vitro, against R5‐HIV‐1NLAD8 Isolates, in the low μM range. This paves the way for the development of a new generation of vaginal microbicides.