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Novel 6-methyluracil derivatives with ω-(substituted benzylethylamino)alkyl chains at the nitrogen atoms of the pyrimidine ring were designed and synthesized. The numbers of methylene groups in the alkyl chains were varied along with the electron-withdrawing substituents on the benzyl rings. The compounds are mixed-type reversible inhibitors of cholinesterases, and some of them show remarkable selectivity for human acetylcholinesterase (hAChE), with inhibitory potency in the nanomolar range, more than 10,000-fold higher than that for human butyrylcholinesterase (hBuChE). Molecular modeling studies indicate that these compounds are bifunctional AChE inhibitors, spanning the enzyme active site gorge and binding to its peripheral anionic site (PAS). In vivo experiments show that the 6-methyluracil derivatives are able to penetrate the blood-brain barrier (BBB), inhibiting brain-tissue AChE. The most potent AChE inhibitor, 3 d (1,3-bis[5-(o-nitrobenzylethylamino)pentyl]-6-methyluracil), was found to improve working memory in scopolamine and transgenic APP/PS1 murine models of Alzheimer's disease, and to significantly decrease the number and area of β-amyloid peptide plaques in the brain.

The ability of simple uracils to afford bis(uracil-5-yl)methanes upon reaction with paraformaldehyde is well documented. This reaction has been used in the preparation of pyrimidinophanes. The extension of the scope of this reaction to the synthesis of multipyrimidinophanes has been reported. Starting with isomeric pyrimidinophane containing 6-methyluracil and 5-methyluracil (thymine) moieties, linearly arranged multimacrocycles were prepared. A completely unexpected result was that the reactions of isomeric pyrimidinophanes containing 6-methyluracil moieties with paraformaldehyde produced only cyclic-arranged macrocycles, in particular, cryptand-like pyrimidinophanes and multipyrimidinophanes with a cyclic topology.

A series of acyclic compounds with two 3,6-dimethyluracil or 3-methyluracil units attached to a a thymine or isocyanurate fragment by polymethylene or xylylene spacers are investigated. Ring-closure reactions with paraformaldehyde in aqueous HCl in the presence of copper(I) chloride afforded pyrimidinophanes which can be considered macrocyclic counterparts of the acyclic triuracils. By X-ray diffraction data the structures of the macrocycles in the solid state are characterised by a close arrangement of the uracil units, but there are no π-π contacts between them. On the contrary, significant hypochromism of the macrocyclic triuracils compared with their acyclic counterparts indicates stacking between the thymine and 3,6-dimethyluracil units in chloroform and H2O solutions. The conformational behaviour of the acyclic and macrocyclic compounds in solution has been determined by NMR, UV and computational methods. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

The cyclization of 1,3-bis(ω-bromoalkyl)uracils with sodium sulfide led to pyrimidinophanes, containing one uracil unit and an S atom in the spacer, macrocyclic structure was confirmed by X-ray data; the S atom in bridge can be oxidized into sulfoxide or sulfone or converted into sulfonium ion.

New pyrimidinophanes containing four uracil units connected with methylene bridges through the N(1) and C(5) atoms of pyrimidine rings were obtained by treatment of 1,4-bis(3,6-dimethyluracil-1-yl)butane with paraform.

Reactions of 1,3-bis(ω-bromoalkyl)-substituted uracils, quinazoline-2,4-dione, and 5-methyl-1,3,5-triazine-2,4,6-trione and 1,3-bis(m-bromomethylbenzyl)-5-bromouracil with amines (aliphatic amines, benzylamines, naphthylmethanamine, and anisidine) gave a series of macrocyclic compounds having one pyrimidine or triazine fragment and an azapolymethylene bridge connecting the N1 and N3 atoms of the heteroring. The bridging nitrogen atom in some macrocyclic compounds was subjected to quaternization with methyl p-toluenesulfonate.

The reactions of 1,3-bis(alpha,omega-bromoalkyl)-6-methyluracils with 1,3-bis(alpha,omega-ethylaminoalkyl)-6-methyluracils or 1,3-bis(bromopentyl)thymine with butylamine afforded pyrimidinophanes containing one or two uracil units and nitrogen atoms in bridging polymethylene chains. In some cases individual geometric isomers of pyrimidinophanes differing in the mutual arrangement of the carbonyl and methyl groups at different pyrimidine rings were isolated. Quaternization of the bridging nitrogen atom with o-nitrobenzyl bromide, benzyl bromide, n-decyl bromide gave rise to water-soluble pyrimidinophanes which were evaluated for their antibacterial and antifungal activity. The arrangement of the carbonyl groups in macrocycles doesn't affect the activity. Antibacterial and antifungal activity of pyrimidinophanes increases with the increase of polymethylene N(pyr)-N-chain length and dramatically increases upon the introduction of n-decyl substituent at nitrogen atoms in spacers. Pyrimidinophanes with 5 and 6 methylene groups in N(pyr)-N-chain and n-decyl substituent showed significant bacteriostatic, fungistatic, bactericidal, fungicidal activity which comparable with standard antibacterial and antifungal drugs. Acyclic counterpart demonstrated the highest activity against fungi. Toxicity of more effective pyrimidinophanes was determined for mice and Daphnia magna Straus.

The reactions of disodium salts of N,N"-bis(2-mercapto-6-methylpyrimidin-4-yl)alkylenediamines with 1,3-bis(ω-bromoalkyl)-6-methyluracils afforded a series of macrocyclic compounds containing three pyrimidine fragments with different numbers of methylene groups in linking bridges.