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 isonebularine (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 the 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 was discovered by in silico screening of a virtual library against plant 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.

The solid-phase synthesis of 3-aryl-7-amino imidazotriazines 5 via palladium-­catalyzed direct arylation was achieved. Thus, 7-amino imidazotriazines 4 were prepared by reductive amination of resin support 1 with alkyl amines followed by coupling with 3. The arylation of triazines 4 with aryl bromides in the presence of Pd(OAc)2, Ph3P, and AcOK in DMA afforded the resin-supported 3-aryl-7-amino imidazotriazines which were subject to the resin cleavage to give 5 in 16-91% overall yield (20 examples).