Mechanism and Structure Based Design of Inhibitors of AMP and Adenosine Deaminase

Inhibitors of the enzyme adenosine monophosphate deaminase (AMPD) show interesting levels of herbicidal activity. An enzyme mechanism-based approach has been used to design new inhibitors of AMPD starting from nebularine (6) and resulting in the synthesis of 2-deoxy iso-nebularine (16). This compound is a potent inhibitor of the related enzyme adenosine deaminase (ADA; IC₅₀ 16 nM), binding over 5000 times more strongly than nebularine. It is proposed that herbicidal activity of compound 16 is due to 5́-phosphorylation in planta to give an inhibitor of AMPD. Subsequently, an enzyme structure-based approach was used to design new non-ribosyl AMPD inhibitors. The initial lead structure were discovered through in silico screening a virtual library against AMPD. In a second step, binding to AMPD was further optimised via more detailed molecular modeling leading to 2-(benzyloxy)-5-(imidazo[2,1-f][1,2,4]triazin-7-yl)benzoic acid (36) (IC₅₀ 300 nM). This compound does not inhibit ADA and shows excellent selectivity for plant over human AMPD.