Quantum description of polar and non-polar solvent influence on the properties of various anticancer drugs: A DFT study

[Display omitted] •Quantum chemical description of 5-Fluorouracil, Nitrosourea, and Hydroxyurea using DFT, and TD-DFT calculation.•Dipole moments increase with solvent polarity, reflecting high reactivity of the anticancer molecules in polar environments.•Electrostatic maps, DOS, and Fukui functions identify the most reactive sites in the studied anticancer molecules.•PDOS and Fukui function analysis shows carbon atoms are key to 5-Fluorouracil reactivity. This study investigated the effect of polar and non-polar solvents on the properties of 5-fluorouracil (5-FU), nitrosourea (NU), and hydroxyurea (HU) anticancer drugs using Density Functional Theory (DFT) and Time-Dependent DFT (TD-DFT) calculations. The drugs show high structural stability in gas and solvent phases, with variations in bond lengths ≤ 0.03 Å, and angles ≤ 1.25°. Polar environments reduce the molecular energy, with thelowest total energies obtained in water. The energy gaps of 5-FU and NU remained constant across solvents, while that of HU showed significant variation, exceeding 0.77 eV from gas to water. Dipole moment increased with solvent polarity, reflecting a high drug reactivity in polar environments, corroborated by molecular electrostatic potential analysis. The descriptor parameters, calculated using both Koopmans and the adiabatic approaches, showed an enhanced electrophilicity and electronic flexibility of these drugs in polar environments. Density of states analysis revealed a significant contribution of carbon atoms to the frontier orbitals of 5-FU, indicating this atom’s key role in molecular reactivity. Nitrogen and oxygen atoms dominate in NU and HU frontier orbitals. The key reactive sites such as nitrogen and oxygen atoms are identified through theFukui function studies. Natural bond orbitals and localized orbital locator showed that the drugs’ stability is primarily driven by the interactions of lone pair (LP) on N4 and N5 atoms with antibonding orbital (π*) of O3-C7 in 5-FU, LP on N3 atom with π* O2-N5 and π* O1-C6 bonds in NU, and LP on N3 atom with π* O2-C5 in HU. Weak interactions were investigated using the non-covalent interaction analysis. Finally, TD-DFT calculations showed that the absorption of all drugs wasobtained in theUV region. This study provides atomic-level insight thatcould enhance drug design and the development of nano-delivery systems.