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

Blanca Colín-Lozano, Ismael León-Rivera, Manuel Jesús Chan-Bacab, Benjamín Otto Ortega-Morales, Rosa Moo-Puc, Vanessa López-Guerrero, Emanuel Hernández-Núñez, Raúl Argüello-Garcia, Thomas Scior, Elizabeth Barbosa-Cabrera, Gabriel Navarrete-Vázquez

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Abstract

© 2017 Elsevier Ltd 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.
Original languageAmerican English
Pages (from-to)3490-3494
Number of pages3140
JournalBioorganic and Medicinal Chemistry Letters
DOIs
StatePublished - 1 Jan 2017

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nitazoxanide
Non-Steroidal Anti-Inflammatory Agents
Metronidazole
Leishmania mexicana
Giardiasis
Giardia lamblia
Inhibitory Concentration 50
Clofibric Acid
Protozoa
Trichomonas vaginalis
Leishmaniasis
Chemotherapy
Trypanosomiasis
Ibuprofen
Trypanosoma cruzi
Indomethacin
Pharmaceutical Preparations
Oral Administration
Assays
Drug Therapy

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Colín-Lozano, B., León-Rivera, I., Chan-Bacab, M. J., Ortega-Morales, B. O., Moo-Puc, R., López-Guerrero, V., ... Navarrete-Vázquez, G. (2017). Synthesis, in vitro and in vivo giardicidal activity of nitrothiazole-NSAID chimeras displaying broad antiprotozoal spectrum. Bioorganic and Medicinal Chemistry Letters, 3490-3494. https://doi.org/10.1016/j.bmcl.2017.05.071
Colín-Lozano, Blanca ; León-Rivera, Ismael ; Chan-Bacab, Manuel Jesús ; Ortega-Morales, Benjamín Otto ; Moo-Puc, Rosa ; López-Guerrero, Vanessa ; Hernández-Núñez, Emanuel ; Argüello-Garcia, Raúl ; Scior, Thomas ; Barbosa-Cabrera, Elizabeth ; Navarrete-Vázquez, Gabriel. / Synthesis, in vitro and in vivo giardicidal activity of nitrothiazole-NSAID chimeras displaying broad antiprotozoal spectrum. In: Bioorganic and Medicinal Chemistry Letters. 2017 ; pp. 3490-3494.
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Colín-Lozano, B, León-Rivera, I, Chan-Bacab, MJ, Ortega-Morales, BO, Moo-Puc, R, López-Guerrero, V, Hernández-Núñez, E, Argüello-Garcia, R, Scior, T, Barbosa-Cabrera, E & Navarrete-Vázquez, G 2017, 'Synthesis, in vitro and in vivo giardicidal activity of nitrothiazole-NSAID chimeras displaying broad antiprotozoal spectrum', Bioorganic and Medicinal Chemistry Letters, pp. 3490-3494. https://doi.org/10.1016/j.bmcl.2017.05.071

Synthesis, in vitro and in vivo giardicidal activity of nitrothiazole-NSAID chimeras displaying broad antiprotozoal spectrum. / Colín-Lozano, Blanca; León-Rivera, Ismael; Chan-Bacab, Manuel Jesús; Ortega-Morales, Benjamín Otto; Moo-Puc, Rosa; López-Guerrero, Vanessa; Hernández-Núñez, Emanuel; Argüello-Garcia, Raúl; Scior, Thomas; Barbosa-Cabrera, Elizabeth; Navarrete-Vázquez, Gabriel.

In: Bioorganic and Medicinal Chemistry Letters, 01.01.2017, p. 3490-3494.

Research output: Contribution to journalArticle

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T1 - Synthesis, in vitro and in vivo giardicidal activity of nitrothiazole-NSAID chimeras displaying broad antiprotozoal spectrum

AU - Colín-Lozano, Blanca

AU - León-Rivera, Ismael

AU - Chan-Bacab, Manuel Jesús

AU - Ortega-Morales, Benjamín Otto

AU - Moo-Puc, Rosa

AU - López-Guerrero, Vanessa

AU - Hernández-Núñez, Emanuel

AU - Argüello-Garcia, Raúl

AU - Scior, Thomas

AU - Barbosa-Cabrera, Elizabeth

AU - Navarrete-Vázquez, Gabriel

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