New insights into molecular recognition of 1,1-bisphosphonic acids by farnesyl diphosphate synthase

Abstract

As part of our project pointed at the search of new antiparasitic agents against American trypanosomiasis (Chagas disease) and toxoplasmosis a series of 2-alkylaminoethyl-1-hydroxy-1,1-bisphosphonic acids has been designed, synthesized and biologically evaluated against the etiologic agents of these parasitic diseases, Trypanosoma cruzi and Toxoplasma gondii, respectively, and also towards their target enzymes, T. cruzi and T. gondii farnesyl pyrophosphate synthase (FPPS), respectively. Surprisingly, while most pharmacologically active bisphosphonates have a hydroxyl group at the C-1 position, the additional presence of an amino group at C-3 resulted in decreased activity towards either T. cruzi cells or TcFPPS. Density functional theory calculations justify this unexpected behavior. Although these compounds were devoid of activity against T. cruzi cells and TcFPPS, they were efficient growth inhibitors of tachyzoites of T. gondii. This activity was associated with a potent inhibition of the enzymatic activity of TgFPPS. Compound 28 arises as a main example of this family of compounds exhibiting an ED₅₀ value of 4.7 μM against tachyzoites of T. gondii and an IC₅₀ of 0.051 μM against TgFPPS.

Keywords: Antiparasitic agents; Bisphosphonates; Farnesyl pyrophosphate synthase; Toxoplasma gondii; Trypanosoma cruzi.

Figure 1

Chemical structures of representative FDA-approved bisphosphonates clinically employed for different bone disorders.

Figure 2

Chemical structures of representative members of bisphosphonic acids derived from fatty acids.

Figure 3

Simplified models of 12–14 (12a) and 27–31 (27a) to carry out molecular modeling studies.

Figure 4

Most stable geometries of simple models 12a (a) and 27a (b). Hydrogen bonds were labelled as strong (s) when d_Acceptor-H < 2 Å and θ_{donor-H-Acceptor} > 145°, or as weak (w) if they do not meet both of these criteria.

Figure 5

Chemical structures of compound 32, exhibiting a typical six-membered hydrogen bond (see ref. 56), and its isosteric analogue 33.

Scheme 1

Isoprenoid biosynthesis in trypanosomatids.

Scheme 2

Isoprenoid biosynthesis in Apicomplexan parasites.

Scheme 3

Synthetic approach for the preparation of modified alkylaminoethyl bisphosphonates.