6-Benzylthioinosine analogues as subversive substrate of Toxoplasma gondii adenosine kinase: Activities and selective toxicities

Rais, Reem H.; Safarjalani, Omar N. Al; Yadav, Vikas; Guarcello, Vincenzo; Kirk, Marion; Chu, Chung K.; Naguib, Fardos N.M.; Kouni, Mahmoud H. el

doi:10.1016/j.bcp.2005.02.017

Cited by 31 publications

(92 citation statements)

References 14 publications

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“…The synthesis of the nucleoside 5prime;-monophosphates from the tested N 6 -benzyladenosine analogues was confirmed by HPLC and NMR analyses as previously described [20], indicating that these compounds are alternative substrates to T. gondii adenosine kinase. Since these compounds are alternate substrates of T. gondii adenosine kinase, their apparent K i values are equal to their apparent K m values [30] as presented in Table 1.…”

Section: Evaluation Of the N 6 -Benzyladenosine Analogues As Alternatsupporting

confidence: 59%

“…The adenosine kinase deficient mutant TgAK −3 was used as a control to verify that the promising drugs were metabolized by adenosine kinase in vivo as was the case in vitro. The effects of purine analogues as anti-toxoplasmosis agents in tissue culture was measured by their ability to inhibit the replication of intracellular T. gondii in tissue culture, using monolayers of human foreskin fibroblasts (CRL-1634, American Type Culture Collection), grown for no more than 20 passages in RPMI 1640 medium [20,31]. The viability of intracellular parasites was evaluated by the selective incorporation of radiolabeled uracil into nucleic acids of the parasites at least in triplicates as previously described [20,31].…”

Section: Evaluation Of N 6 -Benzyladenosine Analogues As Potential Anmentioning

confidence: 99%

“…The effects of purine analogues as anti-toxoplasmosis agents in tissue culture was measured by their ability to inhibit the replication of intracellular T. gondii in tissue culture, using monolayers of human foreskin fibroblasts (CRL-1634, American Type Culture Collection), grown for no more than 20 passages in RPMI 1640 medium [20,31]. The viability of intracellular parasites was evaluated by the selective incorporation of radiolabeled uracil into nucleic acids of the parasites at least in triplicates as previously described [20,31]. Briefly, confluent cells (4-5 day incubation) were cultured for 24 hrs in the 24-well flat bottom microtiter plates (∼5 x 10 5 /1 mL/well) and incubated at 37ºC in 5% CO 2 , 95% air to allow the cells to attach.…”

Section: Evaluation Of N 6 -Benzyladenosine Analogues As Potential Anmentioning

confidence: 99%

“…After filtration, the filters were washed with 10 mL methanol, left to dry, then placed in scintillation vials containing 5 mL of Econo-Safe scintillation fluor (Research Products International Corp, Mount Prospect, IL), and radioactivity was counted using an LS5801 Beckman scintillation counter. The effect of the compounds on the growth of the parasite was estimated as percentage reduction in the uptake of radiolabeled uracil by treated parasites as compared to the untreated controls [19,20,31,32]. Radiolabel incorporation closely correlates with parasite growth [19,20,31,32].…”

Section: Evaluation Of N 6 -Benzyladenosine Analogues As Potential Anmentioning

confidence: 99%

“…Specifically, the activity of adenosine kinase (EC.2.7.1.20), the enzyme responsible for the salvage of adenosine in this parasite, is 10-fold higher than those of other enzymes in the purine salvage pathways, and hence contributes more significantly to the salvage of purines in T. gondii than any other enzyme of the purine salvage pathways [12][13][14][15][16]. Secondly, structure-activity relationships [17,18], comparative enzymatic [18][19][20], metabolic [19][20][21], molecular [22], and X-ray structural studies [23][24][25] have demonstrated that there are sufficient differences between the active sites and substrate specificities of human and T. gondii adenosine kinases that can be exploited to design specific "subversive substrates" for the T. gondii enzyme [12,13].…”

Section: Introductionmentioning

confidence: 99%

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Synthesis, biological evaluation and molecular modeling studies of N6-benzyladenosine analogues as potential anti-toxoplasma agents

Kim

Sharon

Chu

et al. 2007

Biochemical Pharmacology

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Toxoplasma gondii is an opportunistic pathogen responsible for toxoplasmosis. T. gondii is a purine auxotroph incapable of de novo purine biosynthesis and depends on salvage pathways for its purine requirements. Adenosine kinase (EC.2.7.1.20) is the major enzyme in the salvage of purines in these parasites. 6-Benzylthioinosine and analogues were established as "subversive substrates" for the T. gondii, but not for the human adenosine kinase. Therefore, these compounds act as selective antitoxoplasma agents. In the present study, a series of N 6 -benzyladenosine analogues were synthesized from 6-chloropurine riboside with substituted benzylamines & − solution phase parallel synthesis. These N 6 -benzyladenosine analogues were evaluated for their binding affinity to purified T. gondii adenosine kinase. Furthermore, the anti-toxoplasma efficacy and host toxicity of these compounds were tested in cell culture. Certain substituents on the aromatic ring improved binding affinity to T. gondii adenosine kinase when compared to the unsubstituted N 6 -benzyladenosine. Similarly, varying the type and position of the substituents on the aromatic ring led to different degrees of potency and selectivity as anti-toxoplasma agents. Among the synthesized analogues, N 6 -(2,4-dimethoxybenzyl) adenosine exhibited the most favorable anti-toxoplasma activity without host toxicity. The binding mode of the synthesized N 6 -benzyladenosine analogues were characterized to illustrate the role of additional hydrophobic effect and van der Waals interaction within an active site of T. gondii adenosine kinase by induced fit molecular modeling.

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Section: Evaluation Of the N 6 -Benzyladenosine Analogues As Alternatsupporting

confidence: 59%

Section: Evaluation Of N 6 -Benzyladenosine Analogues As Potential Anmentioning

confidence: 99%

Section: Evaluation Of N 6 -Benzyladenosine Analogues As Potential Anmentioning

confidence: 99%

Section: Evaluation Of N 6 -Benzyladenosine Analogues As Potential Anmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Synthesis, biological evaluation and molecular modeling studies of N6-benzyladenosine analogues as potential anti-toxoplasma agents

Kim

Sharon

Chu

et al. 2007

Biochemical Pharmacology

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Antiparasitic Chemotherapy:

Datta

Sen

Advances in Experimental Medicine and Biology

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Distinguishable differences between infectine organisms and their respective hosts with respect to metabolism and macromolecular structure provide scopes for detailed characterization of target proteins and/or macromolecules as the focus for the development of selective inhibitors. In order to develop a rational approach to antiparasitic chemotherapy, finding differences in the biochemical pathways of the parasite with respect to the host it infects is therefore of primary importance. Like most parasitic protozoan, the genus Leishmania is an obligate auxotroph of purines and hence for requirement of purine bases depends on its own purine salvage pathways. Among various purine acquisition routes used by the parasite, the pathway involved in assimilation of adenosine nucleotide is unique and differs significantly in the extracellular form of the parasite (promastigotes) from its corresponding intracellular form (amastigotes). Adenosine kinase (AdK) is the gateway enzyme of this pathway and displays stage-specific activity pattern. Therefore, understanding the catalytic mechanism of the enzyme, its structural complexities and mode of its regulation have emerged as one of the major areas of investigation. This review, in general, discusses possible strategies to validate several purine salvage enzymes as targets for chemotherapeutic manipulation with special reference to adenosine kinase of Leishmania donovani. Systemic endotheliosis, commonly known as Kala-azar in India, is caused by the parasitic protozoon Leishmania donovani. The spread of leishmaniases follows the distribution of these vectors in the temperate, tropical and subtropical regions of the world leading to loss of thousands of human lives.' WHO has declared leishmaniasis among one of the six major diseases namely leishmaniasis, malaria, amoebiasis, filariasis, Chagas disease and schistosomiasis in its Special Programme for Research and Training in Tropical Diseases. Strategies for better prophylaxis and urgent therapies must be therefore devised to control this menace among poor and under privileged population. However, the possible availability of antiparasitic vaccines appears remote in near future. Therefore, chemotherapy remains the mainstay for the treatment of most parasitic diseases. Selectivity of an antiparasitic compound must depend upon its mode of specific inhibition of parasite replication leaving host processes unaffected. In principle, these agents are expected to exert their selective actions against growth of the invading organisms by having one or both of the following properties: (i) Selective activation of compounds in question by enzyme (s) from the invading organisms, which are not present in the uninfected cells. (ii) Selective inhibition of vital enzyme(s), which are essential for replication of the parasites. In order to design specific compounds with the above characteristics, it is essential to have a thorough knowledge of the properties of the enzyme(s) and/or macromolecules which are unique to the parasite. Phylogenetic stu...

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Molecular modeling of the Toxoplasma gondii adenosine kinase inhibitors

2011

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Toxoplasma gondii is the most common cause of secondary central nervous system infection in immunocompromised people such as AIDS patients. Since purine salvage is essential for T. gondii and other parasitic protozoa, inhibition of its salvage pathway, by blocking adenosine kinase (EC 2.7.1.20), the main responsible for the metabolism of adenosine (purine nucleoside) can block the parasite growth. Having this in mind, four-dimensional quantitative structure-activity relationship (4D-QSAR) analysis was applied to a series of 41 inhibitors of T. gondii adenosine kinase. Optimized 4D-QSAR models were constructed by genetic algorithm (GA) optimization and partial least squares (PLS) fitting, and evaluated by the leave-one-out cross-validation method. Moreover, we have used docking approaches to study the binding orientations and predict the interaction energies of some benzyladenosines with adenosine kinase.

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6-Benzylthioinosine analogues as subversive substrate of Toxoplasma gondii adenosine kinase: Activities and selective toxicities

Cited by 31 publications

References 14 publications

Synthesis, biological evaluation and molecular modeling studies of N6-benzyladenosine analogues as potential anti-toxoplasma agents

Synthesis, biological evaluation and molecular modeling studies of N6-benzyladenosine analogues as potential anti-toxoplasma agents

Antiparasitic Chemotherapy:

Molecular modeling of the Toxoplasma gondii adenosine kinase inhibitors

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