Pharmacomodulation on the 3-acetylursolic acid skeleton: Design, synthesis, and biological evaluation of novel N-{3-[4-(3-aminopropyl)piperazinyl]propyl}-3-O-acetylursolamide derivatives as antimalarial agents

Gnoatto, Simone Cristina Baggio; Susplugas, Sophie; Vechia, Luciana Dalla; Ferreira, Thaís B.; Dassonville‐Klimpt, Alexandra; Zimmer, Karine Rigon; Demailly, Catherine; Nascimento, Sophie Da; Guillon, Jean; Grellier, Philippe; Verli, Hugo; Gosmann, Grace; Sonnet, Pascal

doi:10.1016/j.bmc.2007.10.031

Cited by 44 publications

(52 citation statements)

References 43 publications

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“…3-Acetylursolic acid 2 was synthesized by stirring ursolic acid 1 previously extracted from the south American species Ilex paraguariensis [24,25], with acetic anhydride in dry pyridine at room temperature. Compound 3 was prepared by treating 3-acetylursolic acid 2 with oxalyl chloride in dry dichloromethane, following by the treatment of this intermediate acid chloride with N-Boc-bis(aminopropyl)piperazine [25,26]. The N-Boc-amino protecting group was removed by treatment of 3 with a TFA (10%)/CH 2 Cl 2 mixture to yield the deprotected analogue 4 [25,26].…”

Section: Chemistrymentioning

confidence: 99%

“…In these series, seven new bis-(aminopropyl)piperazinyl analogues of ursolic acid showed significant activity in the nanomolar range suggesting the antiprotozoal activity role of this pharmacophoric group [24,25]. Based on these previous studies, we further examined members of these pentacyclic triterpenes family with respect to their inhibitory effects on Leishmania amazonensis and Leishmania infantum.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and preliminary evaluation of new ursolic and oleanolic acids derivatives as antileishmanial agents

Gnoatto

Vechia

Lencina

et al. 2008

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of new ursolic and oleanolic acids derivatives was synthesized via ursolic or oleanolic acids, previously extracted from South American Ilex species. These new compounds were tested for in vitro antiparasitic activity on Leishmania amazonensis and Leishmania infantum strains. Some of these compounds showed activity against the promastigote forms of L. amazonensis or L. infantum, with IC 50 ranging from 5 to 12 mM. As expected, most of the compounds showed a significant level of cytotoxicity against monocytes (IC 50 ¼ 2-50 mM). From a structure-activity relationships point of view, these pharmacological results enlightened mainly the importance of an acetylation at position 3 of the oleanolic acid skeleton in the activity against the L. amazonensis strain, and of a bis-(3-aminopropyl)piperazine moiety on the carboxylic function of ursolic acid against the L. infantum strain.

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Section: Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis and preliminary evaluation of new ursolic and oleanolic acids derivatives as antileishmanial agents

Gnoatto

Vechia

Lencina

et al. 2008

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Moreover, LAFIS 01 was also submitted to an in vitro evaluation of its capabilities to inhibit β-hematin formation in order to further explore the mechanism of action, comparing the results to chloroquine. Considering the results obtained, it can be postulated that most of the antimalarial activity observed for LAFIS 01 is due to the inhibition of heme assembly in β-hematin [8].…”

Section: Introductionmentioning

confidence: 94%

“…The full details of the obtaining and structural elucidation of the LAFIS 01 have been described previously [8]. Dexamethasone (internal standard [IS]) was obtained from Sigma-Aldrich (São Paulo, Brazil).…”

Section: Experimental Chemicals and Reagentsmentioning

confidence: 99%

“…The in vitro antimalarial activity (IC 50 ) of ursolic acid (3β-hydroxy-urs-12-en-28-oic acid) (Fig. 1), named here as LA-FIS 01, against chloroquine-resistant (FcB1) [8] and chloroquine-sensitive (3D7) [9] P. falciparum strains was found to be 53 µM and 36 μM, respectively. Moreover, LAFIS 01 was also submitted to an in vitro evaluation of its capabilities to inhibit β-hematin formation in order to further explore the mechanism of action, comparing the results to chloroquine.…”

Section: Introductionmentioning

confidence: 99%

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Development and validation of a sensitive and selective LC—MS/MS method for the determination of an antimalarial drug candidate in rat plasma, and its application to a preclinical pharmacokinetic study

Pires¹,

Kaiser²,

Grünspan³

et al. 2016

Acta Chromatographica

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Summary. An accurate and reliable LC-MS/MS assay was firstly developed and validated for quantitative determination of a new antimalarial prototype drug, 3β-hydroxyurs-12-en-28-oic acid (LAFIS 01), in rat plasma. Dexamethasone was employed as internal standard. Simple protein precipitation by acetonitrile for the sample preparation was used. Effective separation was achieved with Phenomenex Luna C 18 (50 × 2 mm, 5 μm) column. The mobile phase consisted of (A) water and (B) acetonitrile, both containing 0.1% acetic acid, delivered by gradient elution. The column temperature was maintained at 40 °C. The LAFIS 01 was monitored by electrospray ionization interface, operating in the negative mode (ESI−) in multiple reactions monitoring (MRM), checking the transitions 455 > 455 for LAFIS 01 and 451 > 361 for the IS. Once LAFIS 01 demonstrated low fragmentation by collision-induced dissociation (CID) nonpresenting abundant highintensity fragments to meet the desired concentration levels quantification, only pseudomolecular ion was monitored. The flow rate was 500 μL min −1 . The lower limit of quantitation achieved was 10 ng mL −1 and linearity was observed from 10 to 500 ng mL −1 . The relative standard deviation (RSD) values of the intra-and inter-assay precisions of the method were below 8.42 and 7.94%, respectively. The accuracy ranged from 92.05 to 102.94%. The extraction recovery of LAFIS 01 and IS was up to 90%. The method showed linearity, precision, accuracy, sensitivity, and stability required to quantify LA-FIS 01 in preclinical pharmacokinetic study.

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Development and validation of a bioanalytical method by LC‐MS/MS for the quantification of the LAFIS 10 – an antimalarial candidate – and its pharmacokinetics first evaluation

Laureano

Barreto

Gnoatto

et al. 2014

Biomedical Chromatography

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A rapid and highly sensitive method by LC-MS/MS was developed and validated for the quantification of an antimalarial candidate (LAFIS10) in rat plasma using dexamethasone as internal standard (IS). The chromatographic separation was performed with a Poroshell 120 EC-C18 column. The mobile phase consisted of water (A) and acetonitrile (B), both containing 10 m m of ammonium formate and 0.1% formic acid, delivered in the form of elution gradient. The LAFIS10 was monitored using an electrospray ionization interface operating in the positive mode in multiple reaction monitoring mode, monitoring the transitions 681.47 → 538.2 for LAFIS10 and 393.20 → 355.30 for the IS. The flow rate was 500 μL/min. The column temperature was kept at 40 °C and the injection volume was 2 μL. The lower limit of quantification was of 10 ng/mL and linearity between 10 and 1000 ng/mL was observed, with an R(2) > 0.99. The accuracy of the method was >90%. The relative standard deviations intra- and interday were <8.80 and <6.37%, respectively. The method showed sensitivity, linearity, precision, accuracy and selectivity required to quantify LAFIS 10 in preclinical pharmacokinetic studies according to criteria established by the US Food and Drug Administration and European Medicines Agency.

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Pharmacomodulation on the 3-acetylursolic acid skeleton: Design, synthesis, and biological evaluation of novel N-{3-[4-(3-aminopropyl)piperazinyl]propyl}-3-O-acetylursolamide derivatives as antimalarial agents

Cited by 44 publications

References 43 publications

Synthesis and preliminary evaluation of new ursolic and oleanolic acids derivatives as antileishmanial agents

Synthesis and preliminary evaluation of new ursolic and oleanolic acids derivatives as antileishmanial agents

Development and validation of a sensitive and selective LC—MS/MS method for the determination of an antimalarial drug candidate in rat plasma, and its application to a preclinical pharmacokinetic study

Development and validation of a bioanalytical method by LC‐MS/MS for the quantification of the LAFIS 10 – an antimalarial candidate – and its pharmacokinetics first evaluation

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