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Keywords:

  • Medicinal chemistry;
  • Antitumor agents;
  • Antiproliferation;
  • Nitrogen heterocycles;
  • Reaction mechanisms;
  • Tautomerism

Abstract

One-pot synthesis of new pentasubstituted triguanides 1ae starting from the corresponding monosubstituted guanidine derivatives and diisopropylcarbodiimide is described and a mechanism for formation of the products observed is proposed. The structures of 1ad were elucidated by spectroscopic analyses of their acetate salts. The structure of compound 1e was also confirmed by X-ray crystallography using its sulfate salt. The X-ray structure provided strong evidence of extensive electron delocalization within the triguanide core despite its non-planar structure. In addition, the effect of tautomerism on the course of the reaction, with emphasis on possible reaction paths leading to the side products, is discussed in some detail. Finally, antiproliferative effects of the acetate salts of the newly prepared compounds on five cancer lines in vitro were evaluated. It was found that acetates of 1ac exhibit strong cytostatic and cytotoxic activity, with the strongest effect observed for the acetate of benzyl derivative 1c.