Cation–π interactions drive hydrophobic self-assembly and aggregation of niclosamide in water

Vuai, Said; Sahini, Mtabazi G.; Onoka, Isaac; Kiruri, Lucy W.; Shadrack, Daniel M.

doi:10.1039/d1ra05358b

Cited by 6 publications

(5 citation statements)

References 49 publications

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“…The alpha conformation associated with hydrogen bonding between phenolic proton and carbonyl group, while the beta conformation associated with phenolic and amido proton (Figure 5). This deprotonation therefore induce an anion-cation anti-parallel interaction thereby breaking the π-π stacks between the NIC molecules in the NIC-MgO structure, making them more water soluble, as previously suggested by Vuai et al [35]. Similar cation-anion interaction between NIC molecules were previously reported [36].…”

Section: Resultssupporting

confidence: 79%

“…This deprotonation therefore induce an anion-cation anti-parallel interaction thereby breaking the π-π stacks between the NIC molecules in the NIC-MgO structure, making them more water soluble, as previously suggested by Vuai et al [35]. Similar cation-anion interaction between NIC molecules were previously reported [36].…”

Section: Resultssupporting

confidence: 75%

“…A metastable parallel conformation would be dominant if there is an increased NIC monomers in the clusters, followed by the T-shaped conformation, which resembles to those found in proteins. Such micro clusters can be stabilized by strong hydrophobic π-π interactions within the NIC phenyl rings of NIC [35,36]. However, MgO being basic in nature, could induce deprotonation of phenolic proton in NIC.…”

Section: Resultsmentioning

confidence: 99%

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Orally administered niclosamide-based organic/inorganic hybrid suppresses SARS-CoV-2 infection

Jin¹,

Choi

Piao

et al. 2022

Preprint

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The COVID-19 pandemic is a serious global health threat mainly due to the surging cases along with new variants of COVID-19. Though global vaccinations have indeed some effects on the virus spread, its longevity is still unknown. Therefore an orally administrable anti-viral agent against SARS-CoV-2 would be of substantial benefit in controlling the COVID-19 pandemic. Herein, we repurposed niclosamide (NIC), an FDA approved anthelmintic drug in to MgO, which was further coated with hydroxyl propyl methyl cellulose (HPMC) to get the de-sired product called NIC-MgO-HPMC, which has improved anti-SARS-CoV-2 replication in the Syrian hamster model. The inhibitory effect of NIC-MgO-HPMC on SARS-CoV-2 replication leads to the prevention of inflammation as well as lung injury. These data strongly support that repurposed NIC-MgO-HPMC could be highly beneficial for controlling the ongoing pandemic thereby achieving an endemic phase.

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Section: Resultssupporting

confidence: 79%

Section: Resultssupporting

confidence: 75%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Orally administered niclosamide-based organic/inorganic hybrid suppresses SARS-CoV-2 infection

Jin¹,

Choi

Piao

et al. 2022

Preprint

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“…Importantly, niclosamide is characterized as a poor glass former, which means that it has a high tendency for recrystallization [35]. Niclosamide tends to recrystallize by forming strong hydrophobic π-π interactions [36]. Consequently, Figures 1 and 2 demonstrate that niclosamide can avoid recrystallization by generating these amorphous nanoparticles that can act as reservoirs to increase its oral bioavailability.…”

Section: Niclosamide Asd Generated Amorphous Nanoparticles In Biorele...mentioning

confidence: 99%

Oral Delivery of Niclosamide as an Amorphous Solid Dispersion That Generates Amorphous Nanoparticles during Dissolution

Jara

Warnken²,

Sahakijpijarn³

et al. 2022

Pharmaceutics

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Niclosamide is an FDA-approved anthelmintic that is being studied in clinical trials as a chemotherapeutic and broad-spectrum antiviral. Additionally, several other applications are currently in the preclinical stage. Unfortunately, niclosamide is a poorly water soluble molecule, with reduced oral bioavailability, which hinders its use for new indications. Moreover, niclosamide is a poor glass former; in other words, the molecule has a high tendency to recrystallize, and it is virtually impossible to generate a stable amorphous solid employing the neat molecule. Previously, our group reported the development of an amorphous solid dispersion (ASD) of niclosamide (niclosamide ASD) that generates nanoparticles during its dissolution, not only increasing niclosamide’s apparent solubility from 6.6 ± 0.4 to 481.7 ± 22.2 µg/mL in fasted state simulated intestinal fluid (FaSSIF) but also its oral bioavailability 2.6-fold in Sprague–Dawley rats after being administered as a suspension. Nevertheless, niclosamide ASD undergoes recrystallization in acidic media, and an enteric oral dosage form is needed for its translation into the clinic. In this work, we further characterized the nanoparticles that generated during the dissolution of the niclosamide ASD. Cryogenic transmission electron microscopy (Cryo-TEM) and wide-angle X-ray scattering (WAXS) revealed that the nanoparticles were amorphous and had a particle size of ~150 nm. The oral dosage forms of niclosamide ASD were formulated using commercial enteric capsules (Capsuline® and EudracapTM) and as enteric-coated tablets. The enteric dosage forms were tested using pH-shift dissolution and acid-uptake tests, using the USP type II dissolution apparatus and the disintegration apparatus, respectively. The capsules exhibited a higher percentage of weight gain, and visual rupture of the Capsuline capsules was observed. Eudracap capsules protected the formulation from the acidic media, but polymer gelling and the formation of a nondispersible plug were noted during dissolution testing. In contrast, enteric-coated tablets protected the formulation from acid ingress and maintained the performance of niclosamide ASD granules during dissolution in FaSSIF media. These enteric-coated tablets were administered to beagle dogs at a niclosamide dose of 75 mg/kg, resulting in plasma concentrations of niclosamide higher than those reported in the literature using solubilized niclosamide at a higher dose (i.e., 100 mg/kg). In summary, an enteric oral dosage form of niclosamide ASD was formulated without hindering the generation of nanoparticles while maintaining the increase in the niclosamide’s apparent solubility. The enteric-coated tablets successfully increased the niclosamide plasma levels in dogs when compared to a niclosamide solution prepared using organic solvents.

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“…The good solubility of glycine and simple organic molecules in water suggests the use of relatively small cells (a solute and ~100 water molecules) [ 10 , 11 ], which makes it possible to perform DFT-based MD simulations and to evaluate IR spectra of such systems including the THz region [ 12 ]. Relatively large organic molecules [ 13 , 14 , 15 ] and most zwitterions of amino acids [ 16 ] require the use of much larger cells (a solute and ~>1000 water molecules), which implies performance of computer simulations with classical force fields. Although such studies sometimes calculate the IR spectra of solutes [ 17 , 18 ], more reliable results can be obtained using the polarizable force fields [ 19 , 20 ], which take into account the dipolar couplings between the solute and the solvent [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Diclofenac Ion Hydration: Experimental and Theoretical Search for Anion Pairs

et al. 2022

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Self-assembly of organic ions in aqueous solutions is a hot topic at the present time, and substances that are well-soluble in water are usually studied. In this work, aqueous solutions of sodium diclofenac are investigated, which, like most medicinal compounds, is poorly soluble in water. Classical MD modeling of an aqueous solution of diclofenac sodium showed equilibrium between the hydrated anion and the hydrated dimer of the diclofenac anion. The assignment and interpretation of the bands in the UV, NIR, and IR spectra are based on DFT calculations in the discrete-continuum approximation. It has been shown that the combined use of spectroscopic methods in various frequency ranges with classical MD simulations and DFT calculations provides valuable information on the association processes of medical compounds in aqueous solutions. Additionally, such a combined application of experimental and calculation methods allowed us to put forward a hypothesis about the mechanism of the effect of diclofenac sodium in high dilutions on a solution of diclofenac sodium.

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Cation–π interactions drive hydrophobic self-assembly and aggregation of niclosamide in water

Abstract: In this work, we have studied the aggregation properties of niclosamide in water by varying the number of monomers.

Cited by 6 publications

References 49 publications

Orally administered niclosamide-based organic/inorganic hybrid suppresses SARS-CoV-2 infection

Orally administered niclosamide-based organic/inorganic hybrid suppresses SARS-CoV-2 infection

Oral Delivery of Niclosamide as an Amorphous Solid Dispersion That Generates Amorphous Nanoparticles during Dissolution

Diclofenac Ion Hydration: Experimental and Theoretical Search for Anion Pairs

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