Design and in silico study of thiourea–pyrazolopyrimidine hybrids as dual PI3K/mTOR inhibitors for cancer therapy

Background : Cancer remains a major cause of mortality worldwide, with the PI3K/mTOR signaling pathway playing a crucial role in tumor progression, proliferation, and therapeutic resistance. Although several dual PI3K/mTOR inhibitors have been developed, their clinical outcomes remain limited due to poor bioavailability, significant toxicities, and rapid resistance. Molecular hybridization offers a rational strategy to address these limitations by integrating multiple pharmacophores into a single scaffold. Aim : This study aimed to design and evaluate thiourea–pyrazolopyrimidine hybrids as potential dual PI3K/mTOR inhibitors using in silico approaches, supported by the preliminary synthesis of precursor molecules. Materials and methods : Eighty hybrid compounds were generated using ChemDraw and MarvinSketch, optimized by energy minimization, and docked against PI3K (PDB ID: 3L54) and mTOR (PDB ID: 4JT6) using AutoDock 4.2. The best candidates were further validated through 30 ns molecular dynamics (MD) simulations using Desmond, while pharmacokinetic and toxicity properties were assessed using pkCSM. Results : Several derivatives, particularly 2-phenylbenzoate and 4-thiophen analogs, demonstrated stronger binding affinities than native ligands, supported by stable hydrogen bonding and hydrophobic interactions. MD simulations confirmed the stability of the complexes, with RMSD and RMSF values indicating consistent conformations throughout the trajectory. ADMET predictions suggested favorable absorption, low CYP450 inhibition, and reduced mutagenic potential, especially for CF 3 and lipophilic substituents. Conclusion : In conclusion, thiourea–pyrazolopyrimidine hybrids exhibit promising dual PI3K/mTOR inhibitory potential with enhanced pharmacokinetic and safety profiles compared to lead compounds. These results establish a solid foundation for further synthesis, characterization, and biological evaluation as novel anticancer candidates.