Prediction of pharmacokinetics and molecular docking of new 1,2,3,4-tetrahydropyrimidine derivatives linked to carbohydrazide by aromatic and heteroaromatic linkers

Abstract

Purpose: To predict pharmacokinetic parameters and molecular docking of a new series of 1,2,3,4-tetrahydropyrimidine derivatives linked to a carbohydrazide moiety through different aromatic and heteroaromatic linkers (Compounds I-X)Methods: The pharmacokinetic parameters (absorption, distribution, metabolism, excretion) were predicted using in silico studies. The binding complementarity, pose, and affinity to the active site of HDAC8 were investigated using molecular docking, which showed the effect of different linkers on the active site of the enzyme and the potential activity of the compounds.Results: The ADME analysis revealed that the compounds may be beneficial for targeting colon diseases such as colon cancer without significant systemic or central side effects, along with a lower incidence of multidrug resistance. Furthermore, compounds III, IV, VI, VII, and IX demonstrated acceptable properties according to Ghose parameter and compounds (I-X) have acceptable medicinal chemistry characteristics according to PAINS parameters. All designed compounds (I-X) show comparable interaction with amino acid residues in the active site of HDAC8 enzyme with the reference ligand (SAHA), along with higher binding energies than SAHA (-5.54 kcal/mol).Conclusion: This study demonstrates the potential of 1,2,3,4-tetrahydropyrimidine–carbohydrazide hybrids as promising scaffolds for the design of selective HDAC8 inhibitors and provides valuable insights for further structural optimization and synthesis.