Synthesis of new oxazole hybridized with pyrazole and/or thiazole compounds: Molecular modeling and cytotoxic activity

Two series of oxazole-pyrazole hybrids 6a-c and oxazole-thiazole hybrids 7-8 were prepared and characterized by compatible results of spectroscopic analyses (infrared-IR, nuclear magnetic resonance-NMR, and mass spectrometry-MS). The density functional theory (DFT)/B3LYP optimization of the built hybrids 3-5 released a planar configuration, whereas the others 6-8 displayed varied spatial structures. The FMO’s shapes of the considered analogs indicated that the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) of pyrazolyl hybrids 6a-c was centered on the oxazolylphenyl carboxamide and chlorophenylpyrazole portions, respectively. Conversely, the benzylidene conjugates 8a-b have displayed alternative configurations, mainly on the phenyl thiazolidinylidene cyanoacetamide segment. Cytotoxic assay was performed using three different human malignant cell lines and a normal lung fibroblast. Analog 8a exhibited the strongest anticancer effectiveness against HT-29 and MCF-7 cells, IC 50 = 13.22±0.16 and 6.41±0.47 μM, respectively. However, furthermost analogs showed higher selectivity toward cancer cells compared to the normal WI-38 cells against the drug reference (dasatinib). Moreover, the synthesized hybrids revealed significant variations in inhibitory effectiveness against CA IX and CA XII. Derivative 6c emerged as the most active CA IX inhibitor (IC₅₀ = 0.011±0.015 μM), while analog 7 was the most effective against CA XII (IC₅₀ = 0.119±0.043 μM), showing the capability of these analogs as selective CA isoform levelling in anticancer therapy. Molecular docking was utilized to assign their binding affinity towards the human carbonic anhydrase II enzyme (PDB ID: 1V9E), where the conjugates 8b and 8a showed significant binding profiles, S = -7.0940 and -6.5463 kcal/mol, respectively. In addition, the SwissADME pharmacokinetic and drug-likeness showed that most analogs were within the acceptable drug-likeness range, with no breaches of Lipinski’s rule.