Synthesis, in vitro and in vivo giardicidal activity of nitrothiazole-NSAID chimeras displaying broad antiprotozoal spectrum

  • Bioorg Med Chem Lett. 2017 Aug 1;27(15):3490-3494. doi: 10.1016/j.bmcl.2017.05.071.
Blanca Colín-Lozano  1 ,  Ismael León-Rivera  2 ,  Manuel Jesús Chan-Bacab  3 ,  Benjamín Otto Ortega-Morales  3 ,  Rosa Moo-Puc  4 ,  Vanessa López-Guerrero  5 ,  Emanuel Hernández-Núñez  6 ,  Raúl Argüello-Garcia  7 ,  Thomas Scior  8 ,  Elizabeth Barbosa-Cabrera  9 ,  Gabriel Navarrete-Vázquez  10
Affiliations
  • 1. Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico.
  • 2. Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico.
  • 3. Departamento de Microbiología Ambiental y Biotecnología, Universidad Autónoma de Campeche, Campeche 24039, Mexico.
  • 4. Unidad de Investigación Médica Yucatán, IMSS Mérida, Yucatán 97000, Mexico.
  • 5. Facultad de Nutrición, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico.
  • 6. Cátedra CONACyT, Departamento de Recursos del Mar, Centro de Investigación y de Estudios Avanzados del IPN, Unidad Mérida, 97310 Yucatán, Mexico.
  • 7. Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados del IPN, Mexico City 07360, Mexico.
  • 8. Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Puebla, Puebla 72000, Mexico.
  • 9. Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, IPN, Mexico City 11340, Mexico.
  • 10. Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico. Electronic address: [email protected].
PMID: 28645659 DOI: 10.1016/j.bmcl.2017.05.071
Abstract

We designed and synthesized five new 5-nitrothiazole-NSAID chimeras as analogues of nitazoxanide, using a DCC-activated amidation. Compounds 1-5 were tested in vitro against a panel of five protozoa: 2 amitochondriates (Giardia intestinalis, Trichomonas vaginalis) and 3 kinetoplastids (Leishmania mexicana, Leishmania amazonensis and Trypanosoma cruzi). All chimeras showed broad spectrum and potent antiprotozoal activities, with IC50 values ranging from the low micromolar to nanomolar order. Compounds 1-5 were even more active than metronidazole and nitazoxanide, two marketed first-line drugs against giardiasis. In particular, compound 4 (an indomethacin hybrid) was one of the most potent of the series, inhibiting G. intestinalis growth in vitro with an IC50 of 0.145μM. Compound 4 was 38-times more potent than metronidazole and 8-times more active than nitazoxanide. The in vivo giardicidal effect of 4 was evaluated in a CD-1 mouse model obtaining a median effective dose of 1.709μg/kg (3.53nmol/kg), a 321-fold and 1015-fold increase in effectiveness after intragastric administration over metronidazole and nitazoxanide, respectively. Compounds 1 and 3 (hybrids of ibuprofen and clofibric acid), showed potent giardicidal activities in the in vitro as well as in the in vivo assays after oral administration. Therefore, compounds 1-5 constitute promising drug candidates for further testing in experimental chemotherapy against giardiasis, trichomoniasis, leishmaniasis and even trypanosomiasis infections.

Keywords
Antiparasitic; Drug discovery; Giardia; In vivo; Nitazoxanide.