Functionalized hydroxyethylamine based peptide nanostructures as potential inhibitors of falcipain-3, an essential proteases of Plasmodium falciparum

Rathi, Brijesh; Singh, Anil Kumar; Kishan, Ram; Singh, Neelu; Narayanan, Latha; Srinivasan, Subhashini; Pandey, Kailash C.; Tiwari, Hemandra K.; Singh, Brajendra K.

doi:10.1016/j.bmc.2013.05.052

Cited by 16 publications

(15 citation statements)

References 40 publications

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“…Synthesis of compound 5a and 5f was performed following the literature procedure [ 30 ]. To a solution of Boc-protected epoxide, 1 (500 mg, 1.9 mmol) in 50 mL of isopropanol, 1-methylpiperazine (0.315 mL, 2.85 mmol) was added and the contents were refluxed for 12 h ( Fig 1 ).…”

Section: Methodsmentioning

confidence: 99%

“…In hydroxyethylamines, the secondary alcohol is the essential structural element, which plays a crucial role in inhibiting the proteolytic activity of aspartic proteases by mimicking the tetrahedral intermediate during peptide bond cleavage [ 27 , 29 ]. Encouraged by our previous results [ 30 ], a new series of functionalized phthalimides possessing chemical variability has been designed anticipating their strong antimalarial actions. In this paper, we report the rational design and synthesis of novel hydroxyethylamine derivatives and their in vitro antimalarial evaluation.…”

Section: Introductionmentioning

confidence: 99%

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Hydroxyethylamine Based Phthalimides as New Class of Plasmepsin Hits: Design, Synthesis and Antimalarial Evaluation

et al. 2015

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A novel class of phthalimides functionalized with privileged scaffolds was designed, synthesized and evaluated as potential inhibitors of plasmepsin 2 (Ki: 0.99 ± 0.1 μM for 6u) and plasmepsin 4 (Ki: 3.3 ± 0.3 μM for 6t), enzymes found in the digestive vacuole of the plasmodium parasite and considered as crucial drug targets. Three compounds were identified as potential candidates for further development. The listed compounds were also assayed for their antimalarial efficacy against chloroquine (CQ) sensitive strain (3D7) of Plasmodium falciparum. Assay of twenty seven hydroxyethylamine derivatives revealed four (5e, 6j, 6o and 6s) as strongly active, which were further evaluated against CQ resistant strain (7GB) of P. falciparum. Compound 5e possessing the piperidinopiperidine moiety exhibited promising antimalarial activity with an IC50 of 1.16 ± 0.04 μM. Further, compounds 5e, 6j, 6o and 6s exhibited low cytotoxic effect on MCF-7 cell line. Compound 6s possessing C 2 symmetry was identified as the least cytotoxic with significant antimalarial activity (IC50: 1.30 ± 0.03 μM). The combined presence of hydroxyethylamine and cyclic amines (piperazines and piperidines) was observed as crucial for the activity. The current studies suggest that hydroxyethylamine based molecules act as potent antimalarial agent and may be helpful in drug development.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hydroxyethylamine Based Phthalimides as New Class of Plasmepsin Hits: Design, Synthesis and Antimalarial Evaluation

et al. 2015

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“…Hydroxyethylamine derivative has been used in different biological approaches, as HIV-1 protease inhibitor ( Ghosh et al 2014 ) and inhibitor of β-secretase 1, an enzyme associated with neurodegeneration ( Nordeman et al 2014 ). As well, the hydroxyethylamine-based compounds has been tested as antimalarial drugs since this compounds are able to inhibit the activity of plasmepsin ( Muthas et al 2005 ) and falcipain ( Rathi et al 2013 ), main enzymes involved in parasite development ( Blackman 2008 ). It was previously showed that hydroxyethylamine derivatives (ciclohexyl group inserted in hydroxyethylamine core) synthesised from alkylamines presented antimalarial activity (de Souza et al 2012 ).…”

Section: Discussionmentioning

confidence: 99%

“…Hydroxyethylamines have been described as human immunodeficiency virus (HIV) protease inhibitors ( Ghosh et al 2014 ) and, over the last several years, this class have been studied for their antimalarial activity (de Souza et al 2012 ). The antimalarial mechanism of action of hydroxyethylamines comprises the selective inhibition of plasmodium proteases such as falcipain and plasmepsin without interfering with human proteases ( Muthas et al 2005 , Rathi et al 2013 ). Indeed, the study of hydroxyethylamine derivatives as a new class of antimalarial drugs could represent a safe antimalarial drug.…”

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confidence: 99%

Study of the antimalarial properties of hydroxyethylamine derivatives using green fluorescent protein transformed Plasmodium berghei

Souza¹,

Pádua²,

Torres³

et al. 2015

Mem. Inst. Oswaldo Cruz

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A rapid decrease in parasitaemia remains the major goal for new antimalarial drugs and thus, in vivo models must provide precise results concerning parasitaemia modulation. Hydroxyethylamine comprise an important group of alkanolamine compounds that exhibit pharmacological properties as proteases inhibitors that has already been proposed as a new class of antimalarial drugs. Herein, it was tested the antimalarial property of new nine different hydroxyethylamine derivatives using the green fluorescent protein (GFP)-expressing Plasmodium berghei strain. By comparing flow cytometry and microscopic analysis to evaluate parasitaemia recrudescence, it was observed that flow cytometry was a more sensitive methodology. The nine hydroxyethylamine derivatives were obtained by inserting one of the following radical in the para position: H, 4Cl, 4-Br, 4-F, 4-CH3, 4-OCH3, 4-NO2, 4-NH2 and 3-Br. The antimalarial test showed that the compound that received the methyl group (4-CH3) inhibited 70% of parasite growth. Our results suggest that GFP-transfected P. berghei is a useful tool to study the recrudescence of novel antimalarial drugs through parasitaemia examination by flow cytometry. Furthermore, it was demonstrated that the insertion of a methyl group at the para position of the sulfonamide ring appears to be critical for the antimalarial activity of this class of compounds.

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“…41,42 The spontaneous self-association (gelation) of small molecules is directed by weak physical interactions such as hydrogen bonding (HB), van der Waals forces, p-p stacking, electrostatic interaction, dipole-dipole interaction, solvophobic interaction, and host-guest interaction. [43][44][45][46][47][48] The gel strength is dependent on the nature of the chemical groups that facilitate non-covalent interactions in solvent media. Gelation could be a result of the assembly of small molecules into cross-linked structures maintained by the abovementioned weak forces in the presence of solvent molecules.…”

Section: Introductionmentioning

confidence: 99%

Theoretical and experimental studies of an oseltamivir–triazole-based thermoresponsive organogel

Kumar

Sharma

et al. 2019

RSC Adv.

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Functionalized hydroxyethylamine based peptide nanostructures as potential inhibitors of falcipain-3, an essential proteases of Plasmodium falciparum

Cited by 16 publications

References 40 publications

Hydroxyethylamine Based Phthalimides as New Class of Plasmepsin Hits: Design, Synthesis and Antimalarial Evaluation

Hydroxyethylamine Based Phthalimides as New Class of Plasmepsin Hits: Design, Synthesis and Antimalarial Evaluation

Study of the antimalarial properties of hydroxyethylamine derivatives using green fluorescent protein transformed Plasmodium berghei

Theoretical and experimental studies of an oseltamivir–triazole-based thermoresponsive organogel

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