Synthesis, in vitro and in vivo giardicidal activity of nitrothiazole-NSAID chimeras displaying broad antiprotozoal spectrum
Por:
Colín-Lozano B., León-Rivera I., Chan-Bacab M.J., Ortega-Morales B.O., Moo-Puc R., López-Guerrero V., Hernández-Núñez E., Argüello-Garcia R., Scior T., Barbosa-Cabrera E., Navarrete-Vázquez G.
Publicada:
1 ene 2017
Resumen:
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 0.145 µM. 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 1.709 µg/kg (3.53 nmol/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. © 2017 Elsevier Ltd
Filiaciones:
Colín-Lozano B.:
Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico
León-Rivera I.:
Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico
Chan-Bacab M.J.:
Departamento de Microbiología Ambiental y Biotecnología, Universidad Autónoma de CampecheCampeche 24039, Mexico
Ortega-Morales B.O.:
Departamento de Microbiología Ambiental y Biotecnología, Universidad Autónoma de CampecheCampeche 24039, Mexico
Moo-Puc R.:
Unidad de Investigación Médica Yucatán, IMSS MéridaYucatán 97000, Mexico
López-Guerrero V.:
Facultad de Nutrición, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico
Hernández-Núñez E.:
Cátedra CONACyT, Departamento de Recursos del Mar, Centro de Investigación y de Estudios Avanzados del IPN, Unidad MéridaYucatán 97310, Mexico
Argüello-Garcia R.:
Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados del IPN, Mexico City, 07360, Mexico
Scior T.:
Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Puebla, Puebla 72000, Mexico
Barbosa-Cabrera E.:
Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, IPN, Mexico City, 11340, Mexico
Navarrete-Vázquez G.:
Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico
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