Effects of Bisphosphonates on the Growth of Entamoeba histolytica and Plasmodium Species in Vitro and in Vivo

Abstract

The effects of a series of 102 bisphosphonates on the inhibition of growth of Entamoeba histolytica and Plasmodium falciparum in vitro have been determined, and selected compounds were further investigated for their in vivo activity. Forty-seven compounds tested were active (IC 50 < 200 µM) versus E. histolytica growth in vitro. The most active compounds (IC 50 ∼ 4-9 µM) were nitrogen-containing bisphosphonates with relatively large aromatic side chains. Simple n-alkyl-1-hydroxy-1,1-bisphosphonates, known inhibitors of the enzyme farnesylpyrophosphate (FPP) synthase, were also active, with optimal activity being found with C9-C10 side chains. However, numerous other nitrogen-containing bisphosphonates known to be potent FPP synthase inhibitors, such as risedronate or pamidronate, had little or no activity. Several pyridine-derived bisphosphonates were quite active (IC 50 ∼ 10-20 µM), and this activity was shown to correlate with the basicity of the aromatic group, with activity decreasing with increasing pK a values. The activities of all compounds were tested versus a human nasopharyngeal carcinoma (KB) cell line to enable an estimate of the therapeutic index (TI). Five bisphosphonates were selected and then screened for their ability to delay the development of amebic liver abscess formation in an E. histolytica infected hamster model. Two compounds were found to decrease liver abscess formation at 10 mg/kg ip with little or no effect on normal liver mass. With P. falciparum, 35 compounds had IC 50 values <200 µM in an in vitro assay. The most active compounds were also simple n-alkyl-1-hydroxy-1,1-bisphosphonates, having IC 50 values around 1 µM. Five compounds were again selected for in vivo investigation in a Plasmodium berghei ANKA BALB/c mouse suppressive test. The most active compound, a C9 n-alkyl side chain containing bisphosphonate, caused an 80% reduction in parasitemia with no overt toxicity. Taken together, these results show that bisphosphonates appear to be useful lead compounds for the development of novel antiamebic and antimalarial drugs.

A Quantitative Structure−Activity Relationship and Pharmacophore Modeling Investigation of Aryl-X and Heterocyclic Bisphosphonates as Bone Resorption Agents

“…The syntheses of the bisphosphonates investigated (3-51, 53-67; Figures 1 and 2) used methods which are described in more detail elsewhere. 25,26,[35][36][37][38][39][40][41][42] 52 was prepared using the following route: 31 and 49 were from Gador S.A. (Buenos Aires) and were a gift from Teresita Bellido at the University of Arkansas for Medical Sciences. Most compounds investigated were available from previous work.…”

Lipophilic analogs of zoledronate and risedronate inhibit Plasmodium geranylgeranyl diphosphate synthase (GGPPS) and exhibit potent antimalarial activity

“…In earlier work, we and others found that the bisphosphonate class of drugs (3) used to treat bonerelated diseases-osteoporosis, Paget disease, and hypercalcemia due to malignancy-also inhibited the growth of a range of parasitic protozoa, including Trypanosoma cruzi (4,5), Trypanosoma brucei (4, 6), Leishmania spp. (4,7,8), Toxoplasma gondii (4, 9), Cryptosporidium parvum (10,11), Entamoeba histolytica (4,12,13), and Plasmodium spp. (4,(13)(14)(15).…”

“…(4,7,8), Toxoplasma gondii (4, 9), Cryptosporidium parvum (10,11), Entamoeba histolytica (4,12,13), and Plasmodium spp. (4,(13)(14)(15). In the case of Plasmodium spp., the most potent inhibitors were not, however, the nitrogencontaining bisphosphonates such as zoledronate or risedronate (Scheme 1) used to treat bone diseases, but more lipophilic n-alkyl bisphosphonates (13).…”

“…(4,(13)(14)(15). In the case of Plasmodium spp., the most potent inhibitors were not, however, the nitrogencontaining bisphosphonates such as zoledronate or risedronate (Scheme 1) used to treat bone diseases, but more lipophilic n-alkyl bisphosphonates (13). Their target in Plasmodium falciparum was not determined.…”

Synthetic Procedures Leading towards Aminobisphosphonates

“…Because this compound was previously prepared by acid hydrolysis of N-benzhydrylaminomethylenebisphosphonic acid [83,100], it may be that it is formed upon hydrolysis of N-aryl derivatives. The three-component reaction was applied to synthesize a large series of physiologically active compounds, in some cases of very complex chemical structures, including bone antiresorptive drug candidates [75][76][77][78][79][80][81][82]; bone imaging [83,84], antiprotozoal [85][86][87][88], antibacterial [72,[89][90][91][92], anti-HIV [93] and anti-inflammatory [94] agents; herbicides [95][96][97]; and complex ones for various metals [10,98].…”