Abstract Because of the great pharmacological potential of the pyrimidine motif, novel C-5 substituted N -3 acyclic and O -4 acyclic pyrimidine derivatives were prepared as an interesting class of compounds for biological evaluation. Introduction of the 2,3-dihydroxypropyl (DHP) and penciclovir (PCV)-like side chains to 2-methoxypyrimidin-4-one ( 2 ) afforded a mixture of N - and O -acyclic pyrimidine nucleosides in the ratio of 54: 29 ( 3 : 4 ) and 57:21 ( 5 : 6 ) with N -3 isomer being dominant. Distinction between N - and O -alkylated pyrimidine moiety was deduced from extensive experimental FT-IR, HPLC-MS and 1D ( 1 H, 13 C) and 2D (COSY, HMQC and HMBC) NMR analyses. The N -, O -regioisomers were also examined by computational method at density functional theory (DFT) RB3LYP/6-31G(d), 6-31G ∗∗ and 6-31+G ∗ levels. DFT global chemical reactivity descriptors (total energy, chemical hardness, electronic chemical potential and electrophilicity) were calculated for the isomers and used to predict and describe their relative stability and reactivity. The chemical reactivity indices were related to the C 2 N 3 C 4 bond angle. Theoretical predictions can be used to compare chemical reactivity and stability with future biological evaluation and behaviour of these compounds.

For some synthesized coumarin derivatives, 1H and 13C NMR isotropic chemical shifts and some other molecular properties were calculated using density functional theory. The calculations yield reliable results, that are in good correlation with experimental data. This is a good basis for the collaboration between experimentalists and quantum chemists.

The efficient syntheses of 5-(2-hydroxyethyl)- and 5-(3-hydroxypropyl)-substituted pyrimidine derivatives bearing 2,3-dihydroxypropyl, acyclovir-, ganciclovir- and penciclovir-like side chains are reported. A synthetic approach that included the alkylation of an N-anionic-5-substituted pyrimidine intermediate (method A) provided the target acyclonucleosides in significantly higher overall yields in comparison to those obtained by method B using sylilation reaction. The phosphorylation assays of novel compounds as potential substrates for thymidine kinase of herpes simplex virus type 1 (HSV-1 TK) showed that solely pyrimidine 5-substituted acyclonucleosides with a penciclovir-like side chain acted as a fraudulent substrates of HSV-1 TK. Moreover, the uracil derivative with penciclovir-like side chain with less bulky 2-hydroxyethyl substituent at C-5 proved to be a better substrate than the corresponding one with a 3-hydroxypropyl substituent. Therefore, this acyclonucleoside was selected as a lead compound for the development of a positron emission tomography HSV-1 TK activity imaging agent.