title: 2-acylamino-5-nitro-1,3-thiazoles: preparation and in vitro bioevaluation against four neglected protozoan parasites.
abstract: The 2-acylamino-5-nitro-1,3-thiazole derivatives (1-14) were prepared using a one step reaction. All compounds were tested in vitro against four neglected protozoan parasites (Giardia intestinalis, Trichomonas vaginalis, Leishmania amazonensis and Trypanosoma cruzi). Acetamide (9), valeroylamide (10), benzamide (12), methylcarbamate (13) and ethyloxamate (14) derivatives were the most active compounds against G. intestinalis and T. vaginalis, showing nanomolar inhibition. Compound 13 (IC50=10nM), was 536-times more active than metronidazole, and 121-fold more effective than nitazoxanide against G. intestinalis. Compound 14 was 29-times more active than metronidazole and 6.5-fold more potent than nitazoxanide against T. vaginalis. Ureic derivatives 2, 3 and 5 showed moderate activity against L. amazonensis. None of them were active against T. cruzi. Ligand efficiency indexes analysis revealed higher intrinsic quality of the most active 2-acylamino derivatives than nitazoxanide and metronidazole. In silico toxicity profile was also computed for the most active compounds. A very low in vitro mammalian cytotoxicity was obtained for 13 and 14, showing selectivity indexes (SI) of 246,300 and 141,500, respectively. Nitazoxanide showed an excellent leishmanicidal and trypanocidal effect, repurposing this drug as potential new antikinetoplastid parasite compound.
authors: Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico.
authors: Carlos
authors: C
authors: Nava-Zuazo
authors: Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico.
authors: Fabiola
authors: F
authors: Chávez-Silva
authors: Unidad de Investigación Médica Yucatán, Unidad Médica de Alta Especialidad del Centro Médico Nacional Ignacio García Téllez, IMSS Mérida, Yucatán 97000, Mexico.
authors: Rosa
authors: R
authors: Moo-Puc
authors: Departamento de Microbiología Ambiental y Biotecnología, Universidad Autónoma de Campeche, Campeche 24030, Mexico.
authors: Manuel Jesús
authors: MJ
authors: Chan-Bacab
authors: Departamento de Microbiología Ambiental y Biotecnología, Universidad Autónoma de Campeche, Campeche 24030, Mexico.
authors: Benjamín Otto
authors: BO
authors: Ortega-Morales
authors: Instituto de Química Aplicada, Universidad del Papaloapan, Tuxtepec, Oaxaca 68301, Mexico.
authors: Hermenegilda
authors: H
authors: Moreno-Díaz
authors: Instituto de Química Aplicada, Universidad del Papaloapan, Tuxtepec, Oaxaca 68301, Mexico.
authors: Daniel
authors: D
authors: Díaz-Coutiño
authors: Facultad de Ingeniería, Universidad Autónoma de Yucatán, Mérida, Yucatán 97000, Mexico.
authors: Emanuel
authors: E
authors: Hernández-Núñez
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
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D011528:Protozoan Infections / Q000276:immunology*; D013844:Thiazoles / Q000737:chemistry*
chemical_list: D000981:Antiprotozoal Agents; D013844:Thiazoles
keywords: 5-Nitrothiazole; Giardia; LiPE; Neglected diseases; Nitazoxanide