124351-86-6Relevant articles and documents
Effects of Bisphosphonates on the Growth of Entamoeba histolytica and Plasmodium Species in Vitro and in Vivo
Ghosh, Subhash,Chan, Julian M. W.,Lea, Christopher R.,Meints, Gary A.,Lewis, Jared C.,Tovian, Zev S.,Flessner, Ryan M.,Loftus, Timothy C.,Bruchhaus, Iris,Kendrick, Howard,Croft, Simon L.,Kemp, Robert G.,Kobayashi, Seike,Nozaki, Tomoyoshi,Oldfield, Eric
, p. 175 - 187 (2007/10/03)
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 (IC50 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 (IC50 ～ 10-20 μM), and this activity was shown to correlate with the basicity of the aromatic group, with activity decreasing with increasing pKa 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 IC50 values 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.
Studies on novel bone resorption inhibitors. I. Synthesis and pharmacological activities of aminomethylenebisphosphonate derivatives
Takeuchi,Sakamoto,Yoshida,Abe,Isomura
, p. 688 - 693 (2007/10/02)
A series of aminomethylenebisphosphonate derivatives was synthesized and evaluated for their antiresorptive activities using a parathyroid hormone (PTH)-induced hypercalcemia model in rats (PIH model). Among these compounds, (cycloheptylamino)methylenebis(phosphonic acid) (3j) was finally selected for further investigation, proving 10-fold as potent as pamidronate in the PIH model and an immobilization bone atrophy model in rats (DA model). The structure-activity relationships of this series of bisphosphonates are discussed.
