Synthesis of New Thiazole-Pyrazole Analogues: Molecular Modelling, Antiproliferative/Antiviral Activities, and ADME Studies

Twelve thiazole-pyrazole analogues 4, 6, and 8 were synthesized by introducing various pyrazole systems into the core, 2-((4-acetylphenyl)amino)-4-methylthiazole (2), through many synthetic approaches. The density functional theory (DFT) study of the synthesized analogues revealed coincided configurations of their highest occupied and lowest unoccupied molecular orbitals (HOMO and LUMO), except for the nitro derivatives, in which the intramolecular charge-transfer (CT) may be denoted as π → π* and n → π*. In addition, the in vitro antiproliferative efficacy towards some cancer cell lines was examined (Panc-1, HT-29, MCF-7) and the non-cancerous (WI-38), using Dasatinib (Reference). The analogues 4c and 4d demonstrated the most potent anticancer effect, particularly against Panc-1 and MCF-7 cells. Moreover, the antiviral activity against H5N1, using a plaque reduction assay, showed that analogue 6a exhibited the most potent antiviral activity (100% inhibition and TC₅₀ = 61 μg/μL), comparable to the reference drug amantadine (TC₅₀ = 72 μg/μL, 100% inhibition). Furthermore, the molecular docking disclosed that the analogues exhibited a range of interactions, such as H-bonding and π-π stacking, with binding affinities between −4.8558 and − 8.3673 kcal/mol. Additionally, the SwissADME predictions indicated that the synthesized analogues possess promising drug-like characteristics, but analogues 4a–d and 8c demonstrated inadequate solubility and bioavailability, which restricts their use as viable oral medications.