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
  • 1. Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico. Electronic address: [email protected].
  • 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.