1. In Vitro and In Vivo Activity of Sulfur-Containing Linear Bisphosphonates against Apicomplexan Parasites [PublishAheadOfPrint]

We tested a series of sulfur-containing linear bisphosphonates against Toxoplasma gondii, the etiologic agent of toxoplasmosis. The most potent compound (22, 1-[(n-decylsulfonyl)ethyl]-1,1-biphosphonic acid) is a sulfone-containing compound, which had an EC₅₀ of 0.11 ± 0.02 μM against intracellular tachyzoites. The compound showed low toxicity when tested in tissue culture with a selectivity index of >2,000. 22 also showed high activity in vivo in a toxoplasmosis mouse model. The compound inhibited the Toxoplasma farnesyl diphosphate synthase (TgFPPS) but the concentration needed to inhibit 50% of the enzymatic activity (IC₅₀) was higher than the concentration that inhibited 50% of growth. We tested 22 against two other Apicomplexan parasites, Plasmodium falciparum (EC₅₀ of 0.6 ± 0.01 μM), the agent of malaria, and Cryptosporidium parvum (EC₅₀ of ~65 μM), the agent of cryptosporidiosis. Our results suggest that 22 is an excellent novel compound that could lead to the development of potent agents against Apicomplexan parasites.

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