TY - JOUR
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
N1 - Publisher Copyright:
© 2017 Elsevier Ltd
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Antiparasitic
KW - Drug discovery
KW - Giardia
KW - In vivo
KW - Nitazoxanide
UR - http://www.scopus.com/inward/record.url?scp=85020916133&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2017.05.071
DO - 10.1016/j.bmcl.2017.05.071
M3 - Artículo
SN - 0960-894X
VL - 27
SP - 3490
EP - 3494
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 15
ER -