title: 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 microM) versus E. histolytica growth in vitro. The most active compounds (IC(50) approximately 4-9 microM) 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) approximately 10-20 microM), 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 microM 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 microM. 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.
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
authors.forename: Subhash
authors.initials: S
authors.lastname: Ghosh
authors.forename: Julian M W
authors.initials: JM
authors.lastname: Chan
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Lea
authors.forename: Gary A
authors.initials: GA
authors.lastname: Meints
authors.forename: Jared C
authors.initials: JC
authors.lastname: Lewis
authors.forename: Zev S
authors.initials: ZS
authors.lastname: Tovian
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Flessner
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Loftus
authors.forename: Iris
authors.initials: I
authors.lastname: Bruchhaus
authors.forename: Howard
authors.initials: H
authors.lastname: Kendrick
authors.forename: Simon L
authors.initials: SL
authors.lastname: Croft
authors.forename: Robert G
authors.initials: RG
authors.lastname: Kemp
authors.forename: Seiki
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Nozaki
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D006224:Cricetinae; D004164:Diphosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004748:Entamoeba histolytica / Q000187:drug effects*; D004749:Entamoebiasis / Q000188:drug therapy; D006801:Humans; D066298:In Vitro Techniques; D008100:Liver Abscess / Q000188:drug therapy / Q000469:parasitology; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D010962:Plasmodium berghei / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D000981:Antiprotozoal Agents; D004164:Diphosphonates