title: Synthesis of nitro(benzo)thiazole acetamides and in vitro antiprotozoal effect against amitochondriate parasites Giardia intestinalis and Trichomonas vaginalis.
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.
authors: Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico. Electronic address: gabriel_navarrete@uaem.mx.
authors: Gabriel
authors: G
authors: Navarrete-Vázquez
authors: Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico.
authors: Fabiola
authors: F
authors: Chávez-Silva
authors: Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico.
authors: Blanca
authors: B
authors: Colín-Lozano
authors: Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico.
authors: Samuel
authors: S
authors: Estrada-Soto
authors: 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.
authors: Sergio
authors: S
authors: Hidalgo-Figueroa
authors: Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico.
authors: Jorge
authors: J
authors: Guerrero-Álvarez
authors: Laboratorio de Bioquímica-Genética, Instituto Nacional de Pediatría, Secretaría de Salud, 04530 México, D.F., Mexico.
authors: Sara T
authors: ST
authors: Méndez
authors: Laboratorio de Bioquímica-Genética, Instituto Nacional de Pediatría, Secretaría de Salud, 04530 México, D.F., Mexico.
authors: Horacio
authors: H
authors: Reyes-Vivas
authors: Laboratorio de Bioquímica-Genética, Instituto Nacional de Pediatría, Secretaría de Salud, 04530 México, D.F., Mexico.
authors: Jesús
authors: J
authors: Oria-Hernández
authors: Facultad de Química, Universidad Autónoma de Yucatán, Mérida, Yucatán 97150, Mexico.
authors: Jaqueline
authors: J
authors: Canul-Canché
authors: Facultad de Química, Universidad Autónoma de Yucatán, Mérida, Yucatán 97150, Mexico.
authors: Rolffy
authors: R
authors: Ortiz-Andrade
authors: Unidad de Investigación Médica Yucatán, IMSS Mérida, Yucatán 97000, Mexico.
authors: Rosa
authors: R
authors: Moo-Puc
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005634:Fructose-Bisphosphate Aldolase / Q000037:antagonists & inhibitors / Q000378:metabolism; D016829:Giardia lamblia / Q000187:drug effects* / Q000201:enzymology; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009574:Nitro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014246:Trichomonas vaginalis / Q000187:drug effects* / Q000201:enzymology; D014709:Vero Cells
chemical_list: C581042:5-nitrothiazole; D000081:Acetamides; D000981:Antiprotozoal Agents; D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D009574:Nitro Compounds; D013844:Thiazoles; D005634:Fructose-Bisphosphate Aldolase
keywords: Aldolase; Docking; Giardia; Nitazoxanide