Purine nucleosides as selective inhibitors of butyrylcholinesterase – a multidisciplinary study

Abstract

The computational study of the most relevant interactions of the nanomolar purine nucleoside BuChE selective inhibitor has shown that the benzyl group at position 2 and the purine acetamido group are required for activity. In addition, the synthesis of a 6-iodinated radiolabelled analogue and the study of in vivo bioavailability have shown a low percentage of uptake by the brain after 1 hour. These results encouraged the synthesis of a small library of new compounds, focussing on deoxygenation at other positions aiming to access active and more bioavailable structures. Deoxygenation at positions 4 and 3,4 afforded new nucleosides that displayed low inhibition of both cholinesterases, while deoxygenation at position 6 and the lyxopyranosyl group afforded the two most active compounds (IC₅₀ ranging from 3.7 to 7.8 μM); one of them was not cytotoxic at the bioactive concentration, while the other one showed a slight cytotoxicity. Interestingly, these structures exhibited the same anomeric stereochemistry and were purine N⁷-linked, similar to the lead compound 3 (IC₅₀ = 50 nM), thus confirming the importance of the αDN⁷ purine nucleoside structure. Thus, optimization of the purine nucleoside synthetic procedure was carried out by changing the reaction temperature, the anomeric leaving group or the Lewis acid. The most satisfactory reaction yields and regioselectivity were obtained by using the original N-glycosylation conditions at 25 °C, which afforded the highest yield of 25% when compared to the 8% of the αDN⁷ purine nucleoside, and an increase in N⁷ regioselectivity, with the total N⁷ nucleoside yield increasing from 36% to 52%.