Synthesis and Biological Evaluation of 1‐Amino‐1,1‐bisphosphonates Derived from Fatty Acids Against Trypanosoma cruzi Targeting Farnesyl Pyrophosphate Synthase.

Szajnman, Sergio H.; Ravaschino, Esteban L.; Docampo, Roberto; Rodríguez, Juan B.

doi:10.1002/chin.200605233

Cited by 7 publications

(11 citation statements)

References 40 publications

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“…We showed that these potent FPPS inhibitors can produce radical cures of both cutaneous 14 and visceral 15 leishmaniasis and also that they have significant activity against T. cruzi, both in vitro and in vivo, 10,24,25 and Bouzahzah et al 26 have reported similar findings in T. cruzi with risedronate (4) at doses comparable to those used in the treatment of Paget's disease in humans. 27 Interestingly, long alkyl-chain bisphosphonates also inhibit FPPS and T. cruzi growth, [28][29][30] the electrostatic interactions of the basic nitrogen atoms with the protein being replaced, presumably, by van der Waals attractive or dispersion forces in the case of the long alkyl-chain species. Bisphosphonates have also been shown to have activity in inhibiting the resistance of the human AIDS virus, HIV-1, to azidothymidine (AZT).…”

Section: Introductionmentioning

confidence: 99%

Inhibition ofTrypanosomacruziHexokinase by Bisphosphonates

et al. 2005

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Hexokinase is the first enzyme involved in glycolysis in most organisms, including the etiological agents of Chagas disease (Trypanosoma cruzi) and African sleeping sickness (Trypanosoma brucei). The T. cruzi enzyme is unusual since, unlike the human enzyme, it is inhibited by inorganic diphosphate (PPi). Here, we show that non-hydrolyzable analogues of PPi, bisphosphonates, are potent inhibitors of T. cruzi hexokinase (TcHK). We determined the activity of 42 bisphosphonates against TcHK, and the IC(50) values were used to construct pharmacophore and comparative molecular similarity indices analysis (CoMSIA) models for enzyme inhibition. Both models revealed the importance of electrostatic, hydrophobic, and steric interactions, and the IC(50) values for 17 active compounds were predicted with an average error of 2.4x by using the CoMSIA models. The compound most active against T. cruzi hexokinase was found to have a 2.2 microM IC(50) versus the clinically relevant intracellular amastigote form of T. cruzi, but only a approximately 1-2 mM IC(50) versus Dictyostelium discoideum and a human cell line, indicating selective activity versus T. cruzi.

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Section: Introductionmentioning

confidence: 99%

Inhibition ofTrypanosomacruziHexokinase by Bisphosphonates

et al. 2005

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“…Because of multiple side effects of statins, such as muscle pain, increased risk of diabetes mellitus, and abnormalities in liver enzyme tests, many other enzymes that are involved in cholesterol biosynthetic pathway beyond HMG-CoA reductase are also being considered as targets for developing cholesterollowering drugs. These drugs include bisphosphonates which inhibit farnesyl-diphosphate synthase [82] and lonafarnib (SCH66366) and tipifarnib (R115777) which inhibit farnesyltransferase [83]. YM-53601, RPR-107393, and TAK-475 (Lapaquistat) can inhibit squalene synthase [84][85][86], and Ro 48-8071, BIBB515, and terbinafine (Lamisil) are potent inhibitors of 2,3oxidosqualene cyclase or squalene epoxidase [87][88][89].…”

Section: Cholesterol-lowering Drugsmentioning

confidence: 99%

Cholesterol Lowering in Cancer Prevention and Therapy

Huang¹,

Freter²

2016

Cholesterol Lowering Therapies and Drugs

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The accumulation of cholesterol in cancer cells and tumor tissues promotes cell growth, proliferation, and migration as well as tumor progression. Cholesterol synthesis is catalyzed by a series of enzymatic reactions. Regulation of these key enzymes can control cholesterol synthesis and modulate cellular cholesterol levels in the cells. Meanwhile, controlling cholesterol transportation, absorption, and depletion could also significantly reduce cellular cholesterol levels. The current evidence supports that cholesterol lowering agents, beyond the expected cholesterol-lowering properties, also display an important anticancer activity in reducing cancer cell growth, proliferation and migration, and inducing apoptosis in a variety of cancer cells. Understanding the mechanisms of cholesterol metabolism and cholesterol lowering could potentially benefit cancer patients in cancer prevention and treatment.

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“…The treatment of human bone resorption disorders currently involves bisphosphonate-containing drugs which due to their potential innocuousness are good candidates to control tropical diseases. Some fatty acids-derived bisphosphonate compounds resulted potent inhibitors of the proliferation of T. cruzi intracellular amastigotes at low µM level, but none of them was effective against epimastigotes [140,141]. The drug accumulation in parasite acidocalcisomes seems to be responsible for the selective action displayed by bisphophonate compounds against T. cruzi [142].…”

Section: A-farnesylpyrophosphate Synthase (Fpps)mentioning

confidence: 99%

An Insight on Targets and Patented Drugs for Chemotherapy of Chagas Disease

Duschak¹,

Couto²

2007

PRI

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Chagas disease or American Trypanosomiasis, a parasitic infection typically spread by triatomine bugs, affects millions of people throughout Latin America. Current chemotherapy based on the nitroaromatic compounds, benznidazole and nifurtimox provides unsatisfactory results and suffers from considerable side effects and low efficacy. Therefore, there is an urgent need for new drugs to treat this neglected disease. Over the last two decades, new advances and understanding in the biology and the biochemistry of Trypanosoma cruzi has allowed the identification of multiple targets for Chagas disease chemotherapy. This review summarizes antichagasic agents obtained based on i) target metabolic biochemical pathways or parasite specific enzymes, ii) natural products and its derivatives, iii) design and synthesis of lead compounds. Related patents filed and issued from 2000 to early 2006 are also discussed. Most of them claimed inhibitors on specific parasite targets such as cysteine proteinase, sterol biosynthesis, protein farnesyltransferase, etc. Particularly, those related to cysteine proteinase inhibitors were the most represented. Natural products also displayed many anti-T cruzi lead compounds. In addition, a few patents claiming natural or synthetic compounds with antichagasic activity, disclosed no specific target. However, only a small proportion of all these patents displayed specific data of biological trypanocidal activity.

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Synthesis and Biological Evaluation of 1‐Amino‐1,1‐bisphosphonates Derived from Fatty Acids Against Trypanosoma cruzi Targeting Farnesyl Pyrophosphate Synthase.

Cited by 7 publications

References 40 publications

Inhibition ofTrypanosomacruziHexokinase by Bisphosphonates

Inhibition ofTrypanosomacruziHexokinase by Bisphosphonates

Cholesterol Lowering in Cancer Prevention and Therapy

An Insight on Targets and Patented Drugs for Chemotherapy of Chagas Disease

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