In vitro and in vivo activity of sulfur-containing linear bisphosphonates against Apicomplexan parasites

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

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY

AMER SOC MICROBIOLOGY

Lugar: Washington; Año: 2016

0066-4804

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) with a higher IC50, suggesting that 22 may be inhibiting other enzymes of the isoprenoid pathway. We tested 22 against other Apicomplexan parasites like 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