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Synthesis and in silico ADME/Tox profiling studies of heterocyclic hybrids based on chloroquine scaffolds with potential antimalarial activity

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Abstract

A series of heterocyclic chloroquine hybrids containing either a β-phenethylamine fragment or a 2-aminoindane moiety were synthesized and screened in vitro as inhibitors of β-hematin formation and in vivo for their antimalarial activity against chloroquine-sensitive strains of Plasmodium berghei ANKA. Although these new compounds were not found to be more active than chloroquine in vivo, all new compounds significantly reduced heme crystallization with IC50 values < 1 μM. Compounds 12 and 13 were able to inhibit heme crystallization with IC50 values of 0.39 ± 0.09 and 0.48 ± 0.02 μM, respectively, and these values were comparable to that of chloroquine with an IC50 value of 0.18 ± 0.03. It was also determined that the physicochemical and pharmacokinetic properties were moderately favorable after in silico evaluation, derivatives 8 and 10 did not present hepatotoxicity, and the in vitro hemolytic activity against red blood cells was found to be low. Spectral (infrared, nuclear magnetic resonance, and elemental analysis) data for all final compounds were consistent with the proposed structures.

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Acknowledgments

We thank the Instituto de Investigaciones Farmacéuticas (IIF) and Consejo de Desarrollo Científico y Humanístico de la Universidad Central de Venezuela.

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Authors and Affiliations

  1. Organic Synthesis Laboratory, Faculty of Pharmacy, Central University of Venezuela, Caracas, 472061041-A, Los Chaguaramos, Venezuela

    Hegira Ramírez & Jaime E. Charris

  2. Facultad de Medicina, Universidad de Las Américas, Quito, Ecuador

    Hegira Ramírez

  3. Escuela de Medicina, Universidad Espíritu Santo, Samborondón, Ecuador

    Esteban Fernandez-Moreira

  4. Departamento de Tecnología de Procesos Biológicos y Bioquímicos, División de Ciencias Biológicas, Universidad Simón Bolívar, Valle de Sartenejas, Caracas, 9063971, Venezuela

    Juan R. Rodrigues

  5. Biotechnology Unit, Faculty of Pharmacy, Central University of Venezuela, Caracas, 472061041-A, Los Chaguaramos, Venezuela

    Michael R. Mijares

  6. Organic Synthesis Laboratory, Design and Pharmacological Evaluation of New Products, Experimental Faculty of Science, Central University of Venezuela, Zulia University, Maracaibo, Venezuela

    Jorge E. Ángel

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  1. Hegira Ramírez
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Below is the link to the electronic supplementary material. NMR spectra (1H and 13C NMR) for all compounds described and Table 2 are available in the Supplementary information.

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Ramírez, H., Fernandez-Moreira, E., Rodrigues, J.R. et al. Synthesis and in silico ADME/Tox profiling studies of heterocyclic hybrids based on chloroquine scaffolds with potential antimalarial activity. Parasitol Res 121, 441–451 (2022). https://doi.org/10.1007/s00436-021-07374-7

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