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

[Display omitted] •Five nitrothiazole-NSAID chimeras were designed as antiparasitic compounds.•Compounds 1, 3 and 4 showed potent giardicidal activities in the in vitro assay.•Compound 4 performed an ED50=1.70μg/kg in the in vivo mouse model.•Hybrids showed broad antiprotozoal activity (Leishmania,...

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Published in:Bioorganic & medicinal chemistry letters 2017-08, Vol.27 (15), p.3490-3494
Main Authors: 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
Format: Article
Language:English
Subjects:
Animals
Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal - chemistry
Anti-Inflammatory Agents, Non-Steroidal - pharmacology
Anti-Inflammatory Agents, Non-Steroidal - therapeutic use
Antiparasitic
Antiprotozoal Agents - chemical synthesis
Antiprotozoal Agents - chemistry
Antiprotozoal Agents - pharmacology
Antiprotozoal Agents - therapeutic use
Drug Design
Drug discovery
Female
Giardia
Giardia lamblia - drug effects
Giardiasis - drug therapy
Humans
In vivo
Leishmania - drug effects
Mice
Nitazoxanide
Protozoan Infections - drug therapy
Thiazoles - chemical synthesis
Thiazoles - chemistry
Thiazoles - pharmacology
Thiazoles - therapeutic use
Trichomonas vaginalis - drug effects
Trypanosoma cruzi - drug effects
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Summary:[Display omitted] •Five nitrothiazole-NSAID chimeras were designed as antiparasitic compounds.•Compounds 1, 3 and 4 showed potent giardicidal activities in the in vitro assay.•Compound 4 performed an ED50=1.70μg/kg in the in vivo mouse model.•Hybrids showed broad antiprotozoal activity (Leishmania, Trichomonas, Trypanosoma). 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2017.05.071