Ticagrelor is an orally active antiplatelet drug belonging to 1,2,3-triazolo[4,5-d]pyrimidines, which acts by reversibly inhibiting the platelet P2Y12 receptor for ADP. Although ticagrelor does not need to be metabolized to be active in vivo, it is extensively metabolized to form a main metabolite known as AR-C124910, equally potent to inhibit P2Y12 receptors. Importantly, we recently discovered that ticagrelor and AR-C124910 exert bactericidal and anti-biofilm activity against gram-positive bacteria.

The present work aimed at establishing structure-activity relationships of a series of 1,2,3-triazolo[4,5-d]pyrimidines in order to identify structural determinants of antiplatelet and antibacterial activity.

Ticagrelor, five main metabolites and eighteen 1,2,3-triazolo[4,5-d]pyrimidines lacking different chemical groups or bearing atom substitutions were synthetized. The antiplatelet activity of the test molecules was analysed by light transmission aggregometry upon platelet stimulation with ADP in citrated platelet-rich-plasma. The antibacterial activity against Staphylococcus aureus strains was determined by the broth microdilution method.

Only ticagrelor and AR-C124910 showed antibacterial activity. We found out that molecules lacking either the difluorphenylcyclopropyl group or the hydroxyethoxy cyclopentane-1,2-diol were all inactive against bacteria. Interestingly, such restriction did not apply to the antiplatelet activity. Indeed, seven of these molecules, devoid of antibacterial activity, still inhibited the ADP-induced platelet aggregation.

We identified molecules that preserved potent antiplatelet activity while being inactive against S. aureus. These molecules might help demonstrating ticagrelor antibacterial activity in vivo, independently of or in addition to its antiplatelet activity.