Liliya F. Saifina

Background: Infectious diseases caused by resistant microbes and oncological ailments pose a serious threat to human health. However, an effective and safe drug against them has not yet been found. Therefore, pyrimidine derivatives may be of interest as dual-acting drugs due to their potent antimicrobial and cytotoxic properties. The relevance of our research is confirmed by several recent patents dedicated to the antimicrobial and anticancer activity of pyrimidine-based molecules. Objective: The purpose of this study was to evaluate the antimicrobial and cytotoxic activity of some 6-methyluracil derivatives of an amphiphilic nature in vitro. Methods: Antimicrobial activity was studied by serial dilution. Cytotoxicity was tested using the MTT test. The mechanisms of antimicrobial and cytotoxic activity were analyzed using the methods of colorimetry, flow cytometry, and enzyme-linked immunosorbent assay. Results: The tested compounds have high antibacterial activity against resistant strains of Staphylococcus aureus and some bacteria from the group of ESKAPE pathogens. Outstanding results were obtained for the lead compounds in the human duodenal adenocarcinoma cell line (HuTu-80), for which cytotoxicity was shown at the level of 5-fluorouracil with a high selectivity index (SI = 8.0–10.0). The mechanism of antibacterial action is associated with the permeabilization of the bacterial membrane. The cytotoxic effect is due to the arrest of the cell cycle in the G1 phase and the induction of mitochondrial apoptosis. The introduction of the hexynyl group into the C5 position of the pyrimidine ring leads to increased antibacterial and cytotoxic activity. Conclusion: The conducted studies allow us to consider the tested compounds as a promising basis for the creation of new effective antibacterial and сytotoxic agents.

A series of bisuracils, in which uracil and 3,6-dimethyluracil moieties were bridged with a polymethylene spacer, and the uracil moiety contained a pentamethylene radical with ionic and non-ionic aminobenzyl groups, were synthesised. These bisuracils have been identified as cholinesterase inhibitors with exceptional selectivity for acetylcholinesterase (AChE) over butyrylcholinesterase (BuChE). These bisuracils, which have been identified as highly effective AChE inhibitors, demonstrated activity at nano- and sub-nanomolar concentrations, with exceptional selectivity for AChE over BuChE. In kinetic studies of lead bisuracils 2b and 3c, both compounds exhibited mixed-type inhibition against AChE and BuChE. Additionally, molecular dynamic simulations demonstrated robust and stable interactions of 2b and 3c with the binding sites of their target. Bisuracil 2b showed significant potential for protection of AChE from irreversible inhibition by paraoxon; the most effective dose of 0.01 mg/kg was shown to reduce mortality in paraoxon-poisoned mice. Bisuracil 3c effectively inhibited brain AChE activity, reversing scopolamine-induced amnesia in mice at a dose of 5 mg/kg, which indicates its potential for cognitive enhancement. These findings position ionic bisuracils as promising prophylactics against organophosphate poisoning and non-ionic bisuracils as viable candidates for Alzheimer’s disease therapeutics.

By covalent binding of 1,2,3-triazolyl nucleoside analogues by a polymethylene chain at the N³ atoms, a series of homodimers was synthesized, in which nucleic bases are replaced by quinazoline-2,4-dione moieties connected to the β-D-ribofuranose residues by 1,2,3-triazolylbutyl linkers. Screening of in vitro antiviral activity against influenza A (H1N1) and Coxsackie B3 viruses revealed a lead compound that showed high antiviral activity (IC₅₀ = 11.6 μM) against influenza A/Puerto Rico/8/34 (H1N1) virus and a lead compound that exhibited high antiviral activity (IC₅₀ = 12.2 μM) against enterovirus Coxsackie B3.

A series of new dimers of pyrimidine nucleoside analogues have been synthesized. The dimers are composed of two uracil or thymine fragments linked at N³ through a polymethylene bridge and bearing a β-D-ribofuranose residue linked to N¹ of the nucleobase through a 1,2,3-triazolylalkyl spacer. Biological screening revealed that some of the synthesized dimers are active against influenza A (H1N1) virus and coxsackievirus B3 with IC₅₀ values of 13 and 4.5 μM, respectively.

We considered it timely to test the applicability of transferable multipole pseudo-atoms for restoring inner-crystal electronic force density fields. The procedure was carried out on the crystal of 1,3-bis(2-hydroxyethyl)-6-methyluracil, and some derived properties of the scalar potential and vector force fields were compared with those obtained from the experimental multipole model and from the aspherical pseudo-atom model with parameters fitted to the calculated structure factors. The procedure was shown to accurately replicate the general vector-field behavior, the peculiarities of the quantum potentials and the characteristics of the force-field pseudoatoms, such as charge, shape and volume, as well as to reproduce the relative arrangement of atomic and pseudoatomic zero-flux surfaces along internuclear regions. It was found that, in addition to the quantum-topological atoms, the force-field pseudoatoms are spatially reproduced within a single structural fragment and similar environment. In addition, the classical and nonclassical hydrogen bonds in the uracil derivative crystal, as well as the H...O, N...O and N...C interactions in the free π-stacked dimer of the uracil derivative molecules, were studied using the potential and force fields within the concepts of interatomic charge transfer and electron lone pair donation–acceptance. Remarkably, the nitrogen atoms in the N...O and N...C interactions behave rather like a Lewis base and an electron contributor. At the same time, the hydrogen atom in the H...O interaction, being a Lewis acid, also participates in the interatomic electron transfer by acting as a contributor. Thus, it has been argued that, when describing polar interatomic interactions within orbital-free considerations, it makes more physical sense to identify electronegative (electron occupier) and electropositive (electron contributor) atoms or subatomic fragments rather than nucleophilic and electrophilic sites.

The crystal and electronic structure of an isocyanuric acid derivative was studied by high-resolution single-crystal X-ray diffraction within the Hansen–Coppens multipole formalism. The observed deformation electron density shows signs of thermal smearing. The experimental picture meaningfully assigned to the consequences of unmodelled anharmonic atomic motion. Straightforward simultaneous refinement of all parameters, including Gram–Charlier coefficients, resulted in more significant distortion of apparent static electron density, even though the residual density became significantly flatter and more featureless. Further, the method of transferring multipole parameters from the model refined against theoretical structure factors as an initial guess was employed, followed by the subsequent block refinement of Gram–Charlier coefficients and the other parameters. This procedure allowed us to appropriately distinguish static electron density from the contaminant smearing effects of insufficiently accounted atomic motion. In particular, some covalent bonds and the weak π...π interaction between isocyanurate moieties were studied via the mutual penetration of atomic-like kinetic and electrostatic potential φ-basins with complementary atomic ρ-basins. Further, local electronic temperature was applied as an advanced descriptor for both covalent bonds and noncovalent interactions. Total probability density function (PDF) of nuclear displacement showed virtually no negative regions close to and around the atomic nuclei. The distribution of anharmonic PDF to a certain extent matched the residual electron density from the multipole model before anharmonic refinement. No signs of disordering of the sulfonyl group hidden in the modelled anharmonic motion were found in the PDF.

In this study, novel derivatives based on 6-methyluracil and condensed uracil were synthesized, namely, 2,4-quinazoline-2,4-dione with ω-(ortho-nitrilebenzylethylamino) alkyl chains at the N atoms of the pyrimidine ring. In this series of synthesized compounds, the polymethylene chains were varied from having tetra- to hexamethylene chains, and secondary NH, tertiary ethylamino, and quaternary ammonium groups were introduced into the chains. The molecular modeling of the compounds indicated that they could function as dual binding site acetylcholinesterase inhibitors, binding to both the peripheral anionic site and active site. The data from in vitro experiments show that the most active compounds exhibit affinity toward acetylcholinesterase within a nanomolar range, with selectivity for acetylcholinesterase over butyrylcholinesterase reaching four orders of magnitude. In vivo biological assays demonstrated the potency of these compounds in the treatment of memory impairment using an animal model of Alzheimer disease.