Synthesis of cyclohexapeptides as antimalarial and anti-trypanosomal agents

Peña, Stella; Fagundez, Catherine; Medeiros, Andrea; Comini, Marcelo A.; Scarone, Laura; Sellanes, Diver; Manta, Eduardo; Tulla‐Puche, Judit; Alberício, Fernando; Stewart, Lindsay B.; Yardley, Vanessa; Serra, Gloria

doi:10.1039/c4md00135d

Cited by 14 publications

(6 citation statements)

References 33 publications

(38 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In 2014, Peña et al reported the synthesis and antimalarial and antitrypanosomal activity of seven novel cyclohexapeptides 15 – 21 with 20 and 21 incorporating interesting thiazole functionality [ 37 ]. The study was prompted by earlier reports of cyanobacterium Microcystis aeruginosa PCC 7806 natural products, aerucyclamides A–D ( Figure 4 ), which displayed promising micromolar IC 50 (50% of maximal inhibitory concentration) values against a K1 chloroquine-resistant strain of Plasmodium falciparum [ 38 , 39 ].…”

Section: Solid-phase Synthesis Of Cyclohexapeptides Using Solutionmentioning

confidence: 99%

“…After cleavage of linear hexapeptides from the resin using 1% TFA in DCM, macrocyclizations were performed using HBTU, DIPEA, and catalytic 4-dimethylaminopyridine (DMAP) in DCM under dilute conditions (1–5 mM). The coupling site for macrocyclization was chosen to occur at N -terminal glycine for 15 , C -terminal glycine for 17 – 19 , or C -terminal thiazole for 20 – 21 , as this provided the least degree of steric hindrance, resulting in favorable yields [ 37 ]. Moreover, cyclization of linear precursors to afford 17 – 21 took place at a C -terminal glycine or thiazole to prevent epimerization.…”

Section: Solid-phase Synthesis Of Cyclohexapeptides Using Solutionmentioning

confidence: 99%

“…Cyclohexapeptides 15 – 21 were screened with P. falciparum K1 and infective T. b. brucei assays. Of particular interest was the promising antimalarial activity shown by 17 , 20 , and 21 against P. falciparum K1, with EC 50 (50% of maximal effective concentration) values of 0.19, 0.19, and 0.41 µM, respectively, and no observed cell cytotoxicity against murine macrophages [ 37 ]. Also noteworthy was the antitrypanosomal activity of 15 and 19 – 21 against T. b. brucei , with EC 50 values of 1.06, 2.1, 3.0, and 2.8 µM, respectively [ 37 ].…”

Section: Solid-phase Synthesis Of Cyclohexapeptides Using Solutionmentioning

confidence: 99%

See 2 more Smart Citations

Recent Reports of Solid-Phase Cyclohexapeptide Synthesis and Applications

et al. 2018

View full text Add to dashboard Cite

Macrocyclic peptides are privileged scaffolds for drug development and constitute a significant portion of macrocyclic drugs on the market today in fields spanning from infectious disease to oncology. Developing orally bioavailable peptide-based drugs remains a challenging task; however, macrocyclization of linear peptides can be an effective strategy to improve membrane permeability, proteolytic stability, oral bioavailability, and overall drug-like characteristics for this class. Significant advances in solid-phase peptide synthesis (SPPS) have enabled the efficient construction of macrocyclic peptide and peptidomimetic libraries with macrolactamization being performed on-resin or in solution phase. The primary goal of this review is to summarize solid-phase cyclohexapeptide synthesis using the on-resin and solution-phase macrocyclization methodologies published since 2013. We also highlight their broad applications ranging from natural product total synthesis, synthetic methodology development, and medicinal chemistry, to drug development and analyses of conformational and physiochemical properties.

show abstract

Section: Solid-phase Synthesis Of Cyclohexapeptides Using Solutionmentioning

confidence: 99%

Section: Solid-phase Synthesis Of Cyclohexapeptides Using Solutionmentioning

confidence: 99%

Section: Solid-phase Synthesis Of Cyclohexapeptides Using Solutionmentioning

confidence: 99%

See 1 more Smart Citation

Recent Reports of Solid-Phase Cyclohexapeptide Synthesis and Applications

et al. 2018

View full text Add to dashboard Cite

show abstract

“…1) [35], as promising antimalarials with EC 50 values in the low micromolar or submicromolar range, respectively [36]. Considering these results, we decided to explore the "old" and versatile drug Ntz, its metabolite Tiz and bis-heterocycles analogs as part of a research program for the synthesis of potential antimalarials [37][38][39][40][41][42][43][44][45][46][47].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and antiplasmodial assessment of nitazoxanide and analogs as new antimalarial candidates

et al. 2022

View full text Add to dashboard Cite

During the last years, the progression to control malaria disease seems to be slowed and WHO (World Health Organization) reported a modeling analysis with the prediction of the increase in malaria morbidity and mortality in sub-Saharan Africa during the COVID-19 pandemic. A rapid way to the discovery of new drugs could be carried out by performing investigations to identify drugs based on repurposing of "old" drugs. The 5-nitrothiazole drug, Nitazoxanide was shown to be active against intestinal protozoa, human helminths, anaerobic bacteria, viruses, etc. In this work, Nitazoxanide and analogs were prepared using two methodologies and evaluated against P. falciparum 3D7. A bithiazole analog, showed attractive inhibitory activity with an EC 50 value of 5.9 μM, low propensity to show toxic effect against HepG2 cells at 25 μM, and no cross-resistance with standard antimalarials.

show abstract

“…As part of a research program for the synthesis of potential antimalarials [37][38][39][40][41][42][43][44][45][46][47], in this work, we present the synthesis and biological evaluation against P. falciparum 3 D7 of Ntz, Tiz and 2-aminothiazole analogues, Figure 2. Compounds of A series do not present the nitro substituent in the thiazole ring in order to study the in uence of that group in the antimalarial activity.…”

Section: Introductionmentioning

confidence: 99%

Synthesis And Antiplasmodial Assessment of Nitazoxanide And Analogues As New Antimalarial Candidates

Irabuena

Scarone

Souza

et al. 2021

Preprint

View full text Add to dashboard Cite

During the last years, the progression to control malaria disease seems to be slowed and WHO (World Health Organization) reported a modelling analysis with the prediction of the increase in malaria morbidity and mortality in sub-Saharan Africa during the COVID-19 pandemic. A rapid way to the discovery of new drugs could be carried out by performing investigations to identify drugs based on repurposing of “old” drugs. The 5-nitrothiazole drug, Nitazoxanide was shown to be active against intestinal protozoa, human helminths, anaerobic bacteria, viruses, etc. In this work, Nitazoxanide and analogues were prepared using two methodologies and evaluated against P. falciparum 3 D7. A bithiazole analogue, showed attractive inhibitory activity with an EC50 value of 5.9 mM and low propensity to show toxic effect against HepG2 cells at 25 mM.

show abstract

Synthesis of cyclohexapeptides as antimalarial and anti-trypanosomal agents

Abstract: Azolic and non-azolic cyclohexapeptides were obtained and/or evaluated as promising antimalarial and/or anti-trypanosomal agents.

Cited by 14 publications

References 33 publications

Recent Reports of Solid-Phase Cyclohexapeptide Synthesis and Applications

Recent Reports of Solid-Phase Cyclohexapeptide Synthesis and Applications

Synthesis and antiplasmodial assessment of nitazoxanide and analogs as new antimalarial candidates

Synthesis And Antiplasmodial Assessment of Nitazoxanide And Analogues As New Antimalarial Candidates

Contact Info

Product

Resources

About