Further optimization of plakortin pharmacophore: Structurally simple 4-oxymethyl-1,2-dioxanes with promising antimalarial activity

Persico, Marco; Parapini, Silvia; Chianese, Giuseppina; Fattorusso, Caterina; Lombardo, Marco; Petrizza, Luca; Quintavalla, Arianna; Rondinelli, Francesca; Basilico, Nicoletta; Taramelli, Donatella; Trombini, Claudio; Fattorusso, Ernesto; Taglialatela‐Scafati, Orazio

doi:10.1016/j.ejmech.2013.10.050

Cited by 13 publications

(23 citation statements)

References 37 publications

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“…In order to test the generality of the mechanism of action of 3-methoxy-1,2- dioxane scaffold16171819, we selected the active compound 4a (Fig. 1), a recently developed synthetic analogue of 2 , to reproduce the experiment of interaction with heme-Fe II -Cl.…”

Section: Resultsmentioning

confidence: 99%

“…The new synthetic derivatives showed in vitro antimalarial activity on Pf CQ-resistant strains comparable to that of the natural leads. Computational and SAR studies performed on the new series of synthetic 1,2-dioxane derivatives indicated that, as in the case of plakortins, the antimalarial activity is related to their ability to react with Fe II generating carbon centered radicals (in this case at C3 and/or at C6 alkyl chain)16171819. Nevertheless, the reaction of 4a with FeCl 2 did not evidence any product whose formation could be related to the antimalarial activity16.…”

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confidence: 96%

“…1) with heme-Fe II chloride dimethyl ester (hereafter heme-Fe II -Cl), by NMR spectroscopy and MS analyses. Obtained data are discussed in the frame of our previous results1213141516171819 and a molecular interaction model of heme-Fe II in complex with the studied ligands was generated.…”

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confidence: 98%

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The interaction of heme with plakortin and a synthetic endoperoxide analogue: new insights into the heme-activated antimalarial mechanism

Persico

Fattorusso

Taglialatela‐Scafati

et al. 2017

Sci Rep

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In the present work we performed a combined experimental and computational study on the interaction of the natural antimalarial endoperoxide plakortin and its synthetic analogue 4a with heme. Obtained results indicate that the studied compounds produce reactive carbon radical species after being reductively activated by heme. In particular, similarly to artemisinin, the formation of radicals prone to inter-molecular reactions should represent the key event responsible for Plasmodium death. To our knowledge this is the first experimental investigation on the reductive activation of simple antimalarial endoperoxides (1,2-dioxanes) by heme and results were compared to the ones previously obtained from the reaction with FeCl2. The obtained experimental data and the calculated molecular interaction models represent crucial tools for the rational optimization of our promising class of low-cost synthetic antimalarial endoperoxides.

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Section: Resultsmentioning

confidence: 99%

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confidence: 96%

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The interaction of heme with plakortin and a synthetic endoperoxide analogue: new insights into the heme-activated antimalarial mechanism

Persico

Fattorusso

Taglialatela‐Scafati

et al. 2017

Sci Rep

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“…In this regard, the observations that replacing all the n-butyl groups by methyl [7][8][9] or propyl 12 chains led to virtually inactive molecules, were especially meaningful. Moreover, the 3D-SAR study proved the active role of the C4 substituent in determining the antimalarial activity, allowing us to obtain IC 50 on the chloroquine resistant (CQ-R) strain in the low micromolar range and, at the same time, very low toxicity against human cells.…”

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confidence: 99%

“…Although in these early studies the antimalarial activity (IC 50 ) of 4 was only in the micromolar range, we took advantage of the synthetically exible structure in our hands, and we started a broader investigation based on our previously developed plakortin pharmacophore model. 6 The ester functionality at C4 was modied into an alcohol (5), 8 ether (6) 8 or amide group (7) 9 and a 3D-SAR study was performed on all the members of our library of about 50 compounds 4-7.…”

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New antimalarial 3-methoxy-1,2-dioxanes: optimization of cellular pharmacokinetics and pharmacodynamics properties by incorporation of amino and N-heterocyclic moieties at C4

et al. 2015

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A new series of nineteen 3-methoxy-1,2-dioxanes containing an amino moiety at C4 was designed, synthesized and tested for in vitro antimalarial activity against chloroquine sensitive (CQ-S) D10 and chloroquine resistant (CQ-R) W2 strains of Plasmodium falciparum (Pf). Cytotoxicity against the human endothelial cell line (HMEC-1) was also evaluated. The introduced modifications resulted in a notable improvement of the antimalarial activity. In particular, compound 9a with an amino-imidazole side-chain at C4 displays antimalarial activity in the high nanomolar range against the CQ-R Pf strain (W2 IC 50 ¼ 200 nM), being more active against CQ-R than CQ-S Pf strains and devoid of cytotoxicity against human HMEC-1 cells. On the other hand, some of the hybrids with 4-amino-7-chloroquinoline (9k-p) show an IC 50 comparable to that of chloroquine against the CQ-S Pf strain (9k-p, D10 IC 50 ¼ 50-90 nM) but without losing potency against the CQ-R Pf strain (9k-p, resistance index ¼ 1.2-2.6), with low cytotoxicity against HMEC-1. Structure-activity relationship studies show that the improved antimalarial activity of the new compounds is the result of a combination of cellular pharmacokinetics and pharmacodynamics effects.

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Design, synthesis, and anti‐breast cancer activity evaluation of endoperoxide‐type pyrido/pyrrolo[2,3‐d]pyrimidine derivatives

Song

Xia

et al. 2023

Journal of Heterocyclic Chem

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Cyclin‐dependent kinase 4 and 6 (CDK 4/6) overactivation in breast cancer cells has given birth to the successful development of CDK 4/6 inhibitors. Based on the intrinsic relationship of CDK 4/6 and cyclin D, we designed and synthesized a series of endoperoxide‐type pyrido/pyrrolo[2,3‐d]pyrimidine derivatives via extracting active fragments from canonical CDK 4/6 inhibitors and endoperoxide‐type natural products such as artemisinin and plakortin. Eleven novel endoperoxide‐type hybrids were synthesized and characterized by mass spectrometry (MS), high resolution mass spectrometry (HRMS), infrared spectroscopy (IR), hydrogen‐1 nuclear magnetic resonance (1H NMR), and carbon‐13 nuclear magnetic resonance (13C NMR) data. Antiproliferative activities and CDK 4/6 inhibitory effects of target compounds were evaluated via T47D, MDA‐MB‐436 breast cancer cell lines, and CDK6/cyclin D3 kinase respectively. The results showed that S1 and Y7 were the most potent compounds against CDK6/cyclin D3 kinase, with Half maximal inhibitory concentration (IC50) values of 0.126 ± 0.022 and 0.109 ± 0.007 μM respectively, they were about a half or third as potent as positive control palbociclib (0.045 μM). The antiproliferative effects of S2 were close to positive controls palbociclib and ribociclib, with Growth inhibitory dose 50% (GI50) values of 8.42 ± 0.93 and 18.74 ± 1.78 μM towards T47D cells and MDA‐MB‐436 cells respectively. Finally, antiproliferative activities against MCF‐10A cells indicated that our newly synthesized compounds were harmless to normal human mammary epithelial cells.

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Further optimization of plakortin pharmacophore: Structurally simple 4-oxymethyl-1,2-dioxanes with promising antimalarial activity

Cited by 13 publications

References 37 publications

The interaction of heme with plakortin and a synthetic endoperoxide analogue: new insights into the heme-activated antimalarial mechanism

The interaction of heme with plakortin and a synthetic endoperoxide analogue: new insights into the heme-activated antimalarial mechanism

New antimalarial 3-methoxy-1,2-dioxanes: optimization of cellular pharmacokinetics and pharmacodynamics properties by incorporation of amino and N-heterocyclic moieties at C4

Design, synthesis, and anti‐breast cancer activity evaluation of endoperoxide‐type pyrido/pyrrolo[2,3‐d]pyrimidine derivatives

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