Synthesis, Anticancer Screening, and Virtual Analysis of 5-S-Substituted Derivatives of 1,3-Oxazol-4-ylphosphonates and 1,3-Oxazole-4-carbonitriles

Abstract Ten 5-(arylsulfanyl), 5-(arylsulfinyl), and 5-(arylsulfonyl) derivatives of 1,3-oxazol-4-ylphosphonates and 1,3-oxazole-4-carbonitriles were synthesized and characterized using IR, 1H NMR, 13C NMR, 31P NMR spectroscopy, elemental analysis, and mass spectrometry. Their anticancer activity was assessed against NCI-60 human tumor cell lines using a single-dose assay. Diethyl [2-phenyl-5-(phenylsulfonyl)-1,3-oxazol-4-yl]phosphonate, diethyl [5-(4-chlorophenylsulfonyl)-2-(4-methylphenyl)-1,3-oxazol-4-yl]phosphonate, and 5-(4-methylphenylsulfonyl)-2-phenyl-1,3-oxazole-4-carbonitrile, which demonstrated the highest anticancer activity, were selected for five-dose screening. The two phosphonates showed selectivity (SIr > 3 by TGI and LC50) against most leukemia lines, while the 1,3-oxazole-4-carbonitrile derivative was selective against renal (63%), colon (57%), and breast cancer (50%). One compound demonstrated selectivity against the entire leukemia subpanel. A comparison analysis revealed that no standard drug exhibited a high degree of similarity to compounds across all potency vectors. This suggests that the molecular mechanisms may be unique. Possible targets such as cannabinoid receptor 2, adenosine A3 receptor, and cyclin-dependent kinase 2 have been proposed based on in silico studies. The parameters of druglikeness predicted by the ADMET analysis were within the rational range for all compounds. The two phosphonates are expected to be preferable for the development of antileukemia agents, while 5-(4-methylphenylsulfonyl)-2-phenyl-1,3-oxazole-4-carbonitrile is considered promising for agents targeting renal, colon, and breast cancers.