It has recently been shown that the binding site of SAHase, an enzyme critical in the replication mechanism of viruses, is quite flexible and exhibits a large difference between the "open" and "closed" conformations, thus presenting an obstacle towards design efforts. As a possible solution to this dilemma, we have strategically designed and synthesized a series of structurally innovative nucleosides possessing a heteroaromatic purine ring split into its two components (for example, an imidazole and pyrimidine ring), thereby conferring additional degrees of conformational freedom and torsional flexibility to the ligand. As a result, these molecular "chameleons" can adapt to the environment of the flexible binding site in order to maximize and complement structural interactions, without losing the integrity of the crucial contacts involved in the enzyme's mechanism of action. The synthesis of several proximal analogues is presented herein.