In Vitro and in Vivo activities of sulfur-containing linear bisphosphonates against apicomplexan parasites

SZAJNMAN, SERGIO H.; GALAKA, TAMILA; LI, ZHU-HONG; LI, CATHERINE; HOWELL, NATHAN M.; CHAO, MARÍA N.; STRIEPEN, BORIS; MURALIDHARAN, VASANT; MORENO, SILVIA N.J.; RODRIGUEZ, JUAN B.

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY

AMER SOC MICROBIOLOGY

Lugar: Washington; Año: 2017 vol. 61

0066-4804

We tested a series of sulfur-containing linear bisphosphonates against Toxoplasma gondii, the etiologic agent of toxoplasmosis. The most potent compound (compound 22; 1-[(n-decylsulfonyl)ethyl]-1,1-bisphosphonic acid) is a sulfonecontaining compound, which had a 50% effective concentration (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. Compound 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 compound 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 compound 22 is an excellent novel compound that could lead to the development of potent agents against apicomplexan parasites.