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Physicochemical characterization and in vitro biological evaluation of solid compounds from furazolidone-based cyclodextrins for use as leishmanicidal agents

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Abstract

The discovery of new drugs and dosage forms for the treatment of neglected tropical diseases, such as human and animal leishmaniasis, is gaining interest in the chemical, biological, pharmaceutical, and medical fields. Many pharmaceutical companies are exploring the use of old drugs to establishing new drug dosage forms and drug delivery systems, in particular for use in neglected diseases. The formation of complexes with cyclodextrins is widely used to improve the stability, solubility, and bioavailability of pharmaceutical drugs, as well as reduce both the toxicity and side effects of many of these drugs. The aim of this study was to characterize solid compounds obtained from the association between furazolidone (FZD) and β-cyclodextrin (β-CD) or hydroxypropyl-β-cyclodextrin (HP-β-CD). The solid compounds were prepared in molar ratios of 1:1 and 1:2 (drug:CD) by kneading and lyophilization. Molecular docking was used to predict the preferred relative orientation of FZD when bound in both studied cyclodextrins. The resulting solid compounds were qualitatively characterized by scanning electron microscopy (SEM), thermal analysis (DSC and TG/DTG), X-ray diffraction (XRD), Raman spectroscopy with image mapping (Raman mapping), and 13C nuclear magnetic resonance spectroscopy (13C NMR) in the solid state. The cytotoxicity of the compounds against THP-1 macrophages and the 50% growth inhibition (IC50) against Leishmania amazonensis promastigote forms were subsequently investigated using in vitro techniques. For all of the solid compounds obtained, the existence of an association between FZD and CD were confirmed by one or more characterization techniques (TG/DTG, DSC, SEM, XRD, RAMAN, and 13C NMR), particularly by a significant decrease in the crystallinity of these materials and a reduction in the melting enthalpy associated with furazolidone thermal events. The formation of more effective interactions occurred in the compounds prepared by lyophilization, in a 1:2 molar ratio of the two CDs studied. However, the formation of an inclusion complex was confirmed only for the solid compound obtained from HP-β-CD prepared by lyophilization (LHFZD1:2). The absence of cytotoxicity on the THP-1 macrophage lineages and the leishmanicidal activity were confirmed for all compounds. MHFZD1:2 and LHFZD1:2 were found to be very active against promastigote forms of L. amazonensis, while all others were considered only active. These results are in line with the literature, demonstrating the existence of biological activity for associations between drugs and CDs in the form of complexes and non-complexes. All solid compounds obtained were found to be promising for use as leishmanicidal agents against promastigote forms of L. amazonensis.

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Funding

The authors are thankful to Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil (CAPES; financing modality 001), Fundação de Amparo à Pesquisa e Inovação do Espírito Santo, Brazil (FAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil (CNPq). The authors also acknowledge the support from the Laboratory for Research and Development of Methodologies for Crude Oil Analysis (LabPetro) and from the Laboratory of Cellular Ultrastructure Carlos Alberto Redins (LUCCAR), Federal University of Espírito Santo (UFES).

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Authors and Affiliations

  1. Department of Drugs and Medicines, School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara, SP, 14800-903, Brazil

    Suzana Gonçalves Carvalho

  2. Postgraduate Program in Veterinary Sciences, Department of Veterinary Sciences, Federal University of Espírito Santo (UFES), Alegre, ES, 29500-000, Brazil

    Suzana Gonçalves Carvalho, Marcos Santos Zanini & Janaína Cecília Oliveira Villanova

  3. Laboratory of Carbon and Ceramic Materials, Department of Physics, Federal University of Espírito Santo (UFES), Vitória, ES, 29075-910, Brazil

    Daniel Fernandes Cipriano, Jair Carlos Checon de Freitas, Miguel Ângelo Schettino Junior & Enrique Ronald Yapuchura Ocaris

  4. Malaria and Leishmaniasis Bioassay Platform (PBML), Oswaldo Cruz Foundation Rondônia (FIOCRUZ), Porto Velho, Rondônia, Brazil

    Carolina Bioni Garcia Teles & Aurileya de Jesus Gouveia

  5. Biodiversity and Biotechnology - Bionorte Network, Porto Velho, Rondônia, Brazil

    Carolina Bioni Garcia Teles

  6. National Institute of Science and Technology in Epidemiology of the Western Amazonia (INCT-EpiAmO), Porto Velho, Rondônia, Brazil

    Carolina Bioni Garcia Teles

  7. Graduate Program in Pharmaceutical Sciences, Federal University of Espírito Santo (UFES), Vitória, ES, 29043-900, Brazil

    Ricardo Pereira Rodrigues

  8. Laboratory of Pharmaceutical Production, Department of Pharmacy and Nutrition, Federal University of Espírito Santo (UFES), Alegre, ES, 29500-000, Brazil

    Janaína Cecília Oliveira Villanova

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  1. Suzana Gonçalves Carvalho
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  2. Daniel Fernandes Cipriano
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  3. Jair Carlos Checon de Freitas
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  5. Enrique Ronald Yapuchura Ocaris
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  7. Aurileya de Jesus Gouveia
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  9. Marcos Santos Zanini
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  10. Janaína Cecília Oliveira Villanova
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Correspondence to Suzana Gonçalves Carvalho.

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Carvalho, S.G., Cipriano, D.F., de Freitas, J.C.C. et al. Physicochemical characterization and in vitro biological evaluation of solid compounds from furazolidone-based cyclodextrins for use as leishmanicidal agents. Drug Deliv. and Transl. Res. 10, 1788–1809 (2020). https://doi.org/10.1007/s13346-020-00841-1

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