Towards anti-Toxoplasmosis agents: synthesis and biological evaluation of diosgenin ester derivatives

This study employed a fused hybrid strategy for the structural modification of diosgenin. Diosgenin-cinnamate hybrids (1-13) were synthesised via Steglich esterification and evaluated for anti-Toxoplasma gondii activity and IEC-6 cytotoxicity. Compounds 1-7 exhibited IC₅₀ values of 334-891 µM against the parasite and 261-979 µM against host cells, whereas 8-13 and diosgenin were inactive (IC₅₀ >1000 µM). Compared to spiramycin (SI = 0.97), compounds 1, 3, 5, 6 and 7 showed selectivity indices (SI) of 1.07-1.19, with the para-nitro derivative 5 having the highest SI (1.19) and the lowest host cytotoxicity. Para-nitro group increased SI versus ortho, while the meta-nitro analogue was inactive. For fluorine substitution, only the ortho derivative retained activity. Boc protection proved essential; free phenols (8, 9) were inactive. Saturation of the α,β-unsaturated ester reduced potency. This is the first report on anti-T. gondii activity of diosgenin-cinnamate hybrids. The near-unity SI values indicate a narrow therapeutic margin, warranting further optimisation.