Compounds with the dioxopyrimidine cycle inhibit cholinesterases from different groups of animals

We firstly synthesized derivatives of 6-methyluracil, alloxazine, and xanthine, containing ω-tetraalkylammonium (TAA) groups at the N1 and N3 atoms in a pyrimidine cycle and assayed their anticholinesterase activities. Compounds with triethylpentylammoniumalkyl groups behaved as typical reversible inhibitors of acetylcholinesterase (AChE) (pI50 3.20–6.22) and butyrylcholinesterase (BuChE) (pI50 3.05–5.71). Compounds, containing two ethyl residues and a substituted benzyl fragment in the tetraalkylammonium group at N3 atoms or two similar TAA groups at N1 and N3 atoms, possessed very high anticholinesterase activity. Although these compounds displayed the activity of typical irreversible AChE inhibitors (a progressive AChE inactivation; ki 7.6 × 108 to 3.5 × 109 M−1 min−1), they were reversible inhibitors of BuChE (pI50 3.9–6.9). The efficiency of AChE inhibition by some of these compounds was more than 104 times higher than the efficiency of BuChE inhibition. Several synthesized TAA derivates of 6-methyluracil reversibly inhibited electric eel and cobra venom AChEs and horse serum BuChE. However, depending on their structure, the tested compounds possessed the time-progressing inhibition of mammalian erythrocyte AChE, typically of irreversible inhibitors. As shown upon dialysis and gel-filtration, the formed mammalian AChE–inhibitor complex was stable. Thus, a new class of highly active, selective, and irreversible inhibitors of mammalian AChE was described. In contrast to classical phosphorylating or carbamoylating AChE inhibitors, these compounds are devoid of acylating functions. Probably, these inhibitors interact with certain amino acid residues at the entrance to the active-site gorge.