Synthesis, anticancer screening, and virtual analysis of 5-S-substituted derivatives of 1,3-oxazol-4-ylphosphonates and 1,3-oxazol-4-carbonitriles

Ten 5-arylthio derivatives of 1,3-oxazol-4-ylphosphonates and 1,3-oxazol-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 the NCI-60 human tumour cell lines using a single-dose assay. Diethyl [2-phenyl-5-(phenylsulfonyl)-1,3-oxazol-4-yl]phosphonate, diethyl {2-(4-methylphenyl)-5-[(4-chlorophenyl)sulfonyl]-1,3-oxazol-4-yl}phosphonate and 5-[(4-methylphenyl)sulfonyl]-2-phenyl-1,3-oxazole-4-carbonitrile, which demonstrated the highest anticancer activity among the tested 5-arylthio derivatives of 1,3-oxazol-4-ylphosphonates and 1,3-oxazol-4-carbonitriles, were selected for five-dose screening. Two phosphonates showed selectivity (SIr > 3 by TGI and LC50) against most leukaemia lines, while 4-cyano-1,3-oxazole derivative was selective against renal (63%), colon (57%), and breast cancer (50%). One compound demonstrated selectivity against the entire leukaemia 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. Two phosphonates are expected to be preferable for the development of antileukemia agents, while 5-[(4-methylphenyl)sulfonyl]-2-phenyl-1,3-oxazole-4-carbonitrile is considered promising for agents targeting renal, colon, and breast cancers.

Publication History

Received: 01 September 2025

Accepted after revision: 07 November 2025

Accepted Manuscript online:
07 November 2025