2-Alkylaminoethyl-1,1-Bisphosphonic Acids Are Potent Inhibitors of the Enzymatic Activity of Trypanosoma cruzi Squalene Synthase

Rodrígues-Poveda, Carlos A.; González-Pacanowska, Dolores; Szajnman, Sergio H.; Rodríguez, Juan B.

doi:10.1128/aac.00796-12

Cited by 16 publications

(18 citation statements)

References 40 publications

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“…Some linear amino 1,1‐bisphosphonates were also found to behave as very efficient inhibitors of T. cruzi SQS ( Tc SQS). For example, compound 71 , which had been originally designed to block Tc FPPS activity, became an extremely potent inhibitor of Tc SQS at very low nanomolar concentrations, as shown in Figure …”

Section: Bisphosphonatesmentioning

confidence: 99%

“…Squalenes ynthase (SQS) is another keye nzyme of isoprenoid biosynthesis that catalyzes the reductive dimerization of two molecules of farnesyl diphosphate to produce squalene. [97] This enzyme is very important not only as at arget for cholesterollowering agents, [98] but also for antiparasitic and antifungal compounds. [9,99] In trypanosomatids, SQS catalyzes the first committed step in isoprenoid biosynthesis, leadingt oe rgosterol insteado fc holesterol, as occurs in mammals.…”

Section: Bisphosphonates Targeting Squalene Synthasementioning

confidence: 99%

“…For example, compound 71,w hich had been originally designed to block TcFPPS activity,b ecamea ne xtremelyp otent inhibitor of TcSQS at very low nanomolar concentrations, as shown in Figure 17. [97] The a-phosphonosulfonate derivatives [100,101] are interesting compounds that possess as tereogenic center( compounds 92 and 93). In fact, the absolutes tereochemistry of carbon was found to have as trong influence on the inhibitory activity against SQS.…”

Section: Bisphosphonates Targeting Squalene Synthasementioning

confidence: 99%

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The Role of the Phosphorus Atom in Drug Design

2019

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Although the phosphorus atom is found in a variety of oxidation states, most of the phosphorus‐containing molecules of pharmacological importance possess phosphorus in the form of phosphonate or phosphinate functional groups, or in a major oxidation state as a phosphate group. The most common occurrence of phosphorus in drugs is either in prodrugs or in compounds for which the phosphorus atom plays a role in the biological activity, such as in modified nucleotides, in metabolically stable analogues of metabolites bearing phosphate groups, and as bioisosteric analogues of carboxyl groups.

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Section: Bisphosphonatesmentioning

confidence: 99%

Section: Bisphosphonates Targeting Squalene Synthasementioning

confidence: 99%

Section: Bisphosphonates Targeting Squalene Synthasementioning

confidence: 99%

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The Role of the Phosphorus Atom in Drug Design

2019

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“…Despite the fact that most SQS inhibitors tested in the parasite also block the mammalian host enzyme, this inhibition is tolerable in mammals. In addition, it has been possible to develop specific antiparasitic SQS inhibitors (Orenes Lorente et al 2005 ;Sealey-Cardona et al 2007 ), such as aryloxylethyl thiocyanates (WC-9) (Elhalem et al 2002 ; ) and 2-alkylaminoethyl-1,1-bisphosphonic acids (Rodrigues-Poveda et al 2012 ). Another enzyme in the parasitic sterol biosynthesis pathway is squalene epoxidase (EC1.4.99.7) that converts squalene to 2,3 oxidosqualene.…”

Section: Sterol Biosynthesismentioning

confidence: 99%

Selection of Molecular Targets for Drug Development Against Trypanosomatids

Smirlis

Soares

2013

Subcellular Biochemistry

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Trypanosomatid parasites are a group of flagellated protozoa that includes the genera Leishmania and Trypanosoma, which are the causative agents of diseases (leishmaniases, sleeping sickness and Chagas disease) that cause considerable morbidity and mortality, affecting more than 27 million people worldwide. Today no effective vaccines for the prevention of these diseases exist, whereas current chemotherapy is ineffective, mainly due to toxic side effects of current drugs and to the emergence of drug resistance and lack of cost effectiveness. For these reasons, rational drug design and the search of good candidate drug targets is of prime importance. The search for drug targets requires a multidisciplinary approach. To this end, the completion of the genome project of many trypanosomatid species gives a vast amount of new information that can be exploited for the identification of good drug candidates with a prediction of "druggability" and divergence from mammalian host proteins. In addition, an important aspect in the search for good drug targets is the "target identification" and evaluation in a biological pathway, as well as the essentiality of the gene in the mammalian stage of the parasite, which is provided by basic research and genetic and proteomic approaches. In this chapter we will discuss how these bioinformatic tools and experimental evaluations can be integrated for the selection of candidate drug targets, and give examples of metabolic and signaling pathways in the parasitic protozoa that can be exploited for rational drug design.

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“…Interestingly, Tc SQS activity is also inhibited by bisphosphonates . Bisphosphonates are the main modulators of FPPS, a key enzyme of isoprenoid biosynthesis .…”

Section: Rationalementioning

confidence: 99%

Activity of Fluorine‐Containing Analogues of WC‐9 and Structurally Related Analogues against Two Intracellular Parasites: Trypanosoma cruzi and Toxoplasma gondii

Chao

Storey

et al. 2016

ChemMedChem

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Two obligate intracellular parasites, Trypanosoma cruzi, agent of Chagas disease, and Toxoplasma gondii, agent of toxoplasmosis, upregulate the mevalonate pathway of their host cells upon infection, suggesting that this host pathway could be a potential drug target. In this work we designed, synthesized and evaluated the effect of a number of compounds structurally related to WC-9 (4-phenoxyphenoxyethyl thiocyanate), a known squalene synthase inhibitor, on T. cruzi and T. gondii growth in tissue culture cells. The fluorine-containing derivatives 3-(3-fluorophenoxy) and 3-(4-fluorophenoxy)phenoxyethyl thiocyanates exhibited EC50 values of 1.6 µM and 4.9 µM, respectively, against tachyzoites of T. gondii, while they showed similar potency as WC-9 against intracellular T. cruzi (EC50 values 5.4 µM and 5.7 µM, respectively). In addition, 2-[3-(phenoxy)phenoxyethylthio]ethyl-1,1-bisphosphonate, which is a hybrid inhibitor containing 3-phenoxyphenoxy and bisphosphonate groups, has activity on T. gondii proliferation at sub micromolar levels (EC50 = 0.7 µM), suggesting combined inhibitory effect of the two functional groups.

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2-Alkylaminoethyl-1,1-Bisphosphonic Acids Are Potent Inhibitors of the Enzymatic Activity of Trypanosoma cruzi Squalene Synthase

Cited by 16 publications

References 40 publications

The Role of the Phosphorus Atom in Drug Design

The Role of the Phosphorus Atom in Drug Design

Selection of Molecular Targets for Drug Development Against Trypanosomatids

Activity of Fluorine‐Containing Analogues of WC‐9 and Structurally Related Analogues against Two Intracellular Parasites: Trypanosoma cruzi and Toxoplasma gondii

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