Table 3.

The in silico predicted toxicological properties of compounds 9 and 16 and their interaction with major toxicity targets in silico. The interactions were calculated using ProTox-II software with default parameters.

Toxicity Target	Compound 9		Compound 16		DOX
	Result	Probability	Result	Probability	Result	Probability
Hepatotoxicity	Active	0.59	Active	0.58	Inactive	0.86
Carcinogenicity	Active	0.58	Inactive	0.51	Inactive	0.9
Immunotoxicity	Inactive	0.96	Active	0.66	Active	0.99
Mutagenicity	Inactive	0.52	Inactive	0.53	Active	0.98
Cytotoxicity	Inactive	0.72	Inactive	0.64	Active	0.94
Aryl hydrocarbon Receptor (AhR)	Active	0.58	Active	0.56	Inactive	0.92
Androgen Receptor (AR)	Inactive	0.92	Inactive	0.97	Inactive	0.99
Androgen Receptor Ligand Binding Domain (AR-LBD)	Inactive	0.98	Inactive	0.97	Inactive	0.55
Aromatase	Inactive	0.84	Inactive	0.86	Active	0.52
Estrogen Receptor Alpha (ER)	Inactive	0.88	Inactive	0.8	Inactive	0.73
Estrogen Receptor Ligand Binding Domain (ER-LBD)	Inactive	0.98	Inactive	0.97	Inactive	0.74
Peroxisome Proliferator Activated Receptor Gamma (PPAR-Gamma)	Inactive	0.97	Inactive	0.83	Inactive	0.97
Nuclear factor (erythroid-derived 2)-like 2/antioxidant responsive element (nrf2/ARE)	Inactive	0.96	Inactive	0.87	Inactive	0.98
Heat shock factor response element (HSE)	Inactive	0.96	Inactive	0.87	Inactive	0.98
Mitochondrial Membrane Potential (MMP)	Active	0.52	Active	0.6	Inactive	0.56
Phosphoprotein (Tumor Suppressor) p53	Inactive	0.8	Inactive	0.71	Active	0.52
ATPase family AAA domain-containing protein 5 (ATAD5)	Inactive	0.76	Inactive	0.91	Inactive	0.63

Overall, these data show that both compounds 9 and 16 display favorable predicted ADME properties. The low predicted toxicity of compound 16 and exceptional in vitro potency in cell culture models make it an attractive lead for further pre-clinical validation and optimization.