Background: Ticagrelor is a widely administered orally active antiplatelet drug belonging to 1,2,3-triazolo[4,5-d]pyrimidines, which acts by reversibly inhibiting the platelet P2Y12 receptor. Importantly, we recently discovered that ticagrelor and AR-C124910, its main metabolite, exert bactericidal and anti-biofilm activity against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA).

Aims: The present work aimed at establishing structure-activity relationships of ticagrelor molecule derivatives represented by the general formula (I) in order to identify structural determinants of antiplatelet and antibacterial activity and to assess the possibility of dissociating the two properties.

[General formula for pyrimidine derivatives]

Methods: A series of pyrimidine derivatives, comprising 22 triazolopyrimidines (X₁ and X₂=N), including five ticagrelor metabolites, 23 purines (X₁=C and X₂=N) and 6 pyrazolopyrimidines (X₁=N and X₂=C) were synthetized. Molecule purity was assessed by NMR spectroscopy and elemental analysis. The antiplatelet activity of the test molecules was analysed by light transmission aggregometry upon platelet stimulation with ADP in citrated human platelet-rich-plasma using doses equal to ticagrelor IC₅₀. The antibacterial activity against MRSA (ATCC BAA-1556) was determined by the broth microdilution method as recommended by EUCAST guidelines, as well as in citrated whole blood.

Results: Among triazolopyrimidines, several molecules showed antiplatelet activity, but only ticagrelor and its metabolite AR-C124910 had both antiplatelet and antibacterial properties. In whole blood, antibacterial dosage of ticagrelor (20 µg/mL) significantly reduced bacteria survival by about 35% while antiplatelet-only molecules were inactive against bacteria. Importantly, we discovered new pyrazolopyrimidine and purine molecules that were able to kill bacteria as potently as ticagrelor, while they lacked antiplatelet effect, e.g., N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-6-(ethylthio)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride and N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-9-methyl-2-(propylthio)-9H-purin-6-amine.

Conclusions: Ticagrelor exerts direct in vitro antibacterial activity in whole blood. Antibacterial and antiplatelet activities could be dissociated by chemical structure modifications, which may lead to the discovery of a new class of antibiotics.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/from-the-antiplatelet-drug-ticagrelor-to-new-antibiotics/