2. Academic Validation
  3. Synthesis of nitro(benzo)thiazole acetamides and in vitro antiprotozoal effect against amitochondriate parasites Giardia intestinalis and Trichomonas vaginalis

Synthesis of nitro(benzo)thiazole acetamides and in vitro antiprotozoal effect against amitochondriate parasites Giardia intestinalis and Trichomonas vaginalis

  • Bioorg Med Chem. 2015 May 1;23(9):2204-10. doi: 10.1016/j.bmc.2015.02.059.
Gabriel Navarrete-Vázquez 1,  Fabiola Chávez-Silva 2,  Blanca Colín-Lozano 2,  Samuel Estrada-Soto 2,  Sergio Hidalgo-Figueroa 3,  Jorge Guerrero-Álvarez 4,  Sara T Méndez 5,  Horacio Reyes-Vivas 5,  Jesús Oria-Hernández 5,  Jaqueline Canul-Canché 6,  Rolffy Ortiz-Andrade 6,  Rosa Moo-Puc 7
Affiliations

Affiliations

  • 1 Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico. Electronic address: gabriel_navarrete@uaem.mx.
  • 2 Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico.
  • 3 Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico; Laboratorio de Farmacología, Depto. Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, 09340 México, D.F., Mexico.
  • 4 Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico.
  • 5 Laboratorio de Bioquímica-Genética, Instituto Nacional de Pediatría, Secretaría de Salud, 04530 México, D.F., Mexico.
  • 6 Facultad de Química, Universidad Autónoma de Yucatán, Mérida, Yucatán 97150, Mexico.
  • 7 Unidad de Investigación Médica Yucatán, IMSS Mérida, Yucatán 97000, Mexico.
PMID: 25801157 DOI: 10.1016/j.bmc.2015.02.059
Abstract

We synthesized four 5-nitrothiazole (1-4) and four 6-nitrobenzothiazole acetamides (5-8) using an easy two step synthetic route. All compounds were tested in vitro against amitochondriate parasites Giardia intestinalis and Trichomonas vaginalis, showing excellent antiprotozoal effects. IC₅₀'s of the most potent compounds range from nanomolar to low micromolar order, being more active than their drugs of choice. Compound 1 (IC₅₀=122 nM), was 44-times more active than Metronidazole, and 10-fold more effective than Nitazoxanide against G. intestinalis and showed good trichomonicidal activity (IC₅₀=2.24 μM). This compound did not display in vitro cytotoxicity against VERO cells. The in vitro inhibitory effect of compounds 1-8 and Nitazoxanide against G. intestinalis fructose-1,6-biphosphate aldolase (GiFBPA) was evaluated as potential drug target, showing a clear inhibitory effect over the Enzyme activity. Molecular docking of compounds 1, 4 and Nitazoxanide into the ligand binding pocket of GiFBPA, revealed contacts with the active site residues of the Enzyme. Ligand efficiency metrics of 1 revealed optimal combinations of physicochemical and antiprotozoal properties, better than Nitazoxanide.

Keywords

Aldolase; Docking; Giardia; Nitazoxanide.

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