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Metronidazole and Secnidazole Carbamates: Synthesis, Antiprotozoal Activity, and Molecular Dynamics Studies

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Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico
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Cátedra CONACyT, Departamento de Recursos del Mar, Centro de Investigación y de Estudios Avanzados del IPN, Unidad Mérida, Yucatán 97310, Mexico
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Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México, México City 04510, Mexico
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Laboratorio de Apoyo a la Vigilancia Epidemiológica, Hospital de Especialidades 1, Centro Médico Nacional Ignacio García Téllez, Instituto Mexicano del Seguro Social, Mérida 97150, Yucatán, Mexico
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Unidad de Investigación Médica Yucatán, Unidad Médica de Alta Especialidad, Centro Médico Nacional Ignacio García Téllez, Instituto Mexicano del Seguro Social, Mérida 97000, Yucatán, Mexico
*
Author to whom correspondence should be addressed.
Molecules 2020, 25(4), 793; https://doi.org/10.3390/molecules25040793 (registering DOI)
Received: 23 January 2020 / Revised: 5 February 2020 / Accepted: 11 February 2020 / Published: 12 February 2020
(This article belongs to the Special Issue Development and Application of Anti-protozoan Agents)
We prepared a series of 10 carbamates derivatives based on two common antiprotozoal drugs: metronidazole (15) and secnidazole (610). The compounds were tested in vitro against a set of two amitochondriate protozoa: Giardia duodenalis and Trichomonas vaginalis. Compounds 110 showed strong antiprotozoal activities, with potency values in the low micromolar-to-nanomolar range, being more active than their parent drugs. Metronidazole carbamate (1) was the most active of the series, with nanomolar activities against G. duodenalis (IC50 = 460 nM) and T. vaginalis (IC50 = 60 nM). The potency of compound 1 was 10 times greater than that of metronidazole against both parasites. None of compounds showed in vitro cytotoxicity against VERO cells tested at 100 µM. Molecular dynamics of compounds 110, secnidazole, and metronidazole onto the ligand binding site of pyruvate–ferredoxin oxidoreductase of T. vaginalis and the modeled β-tubulin of G. duodenalis revealed putative molecular interactions with key residues in the binding site of both proteins implicated in the mode of action of the parent drugs. View Full-Text
Keywords: carbamates; metronidazole; molecular dynamics; parasites; secnidazole carbamates; metronidazole; molecular dynamics; parasites; secnidazole
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Rocha-Garduño, G.; Hernández-Martínez, N.A.; Colín-Lozano, B.; Estrada-Soto, S.; Hernández-Núñez, E.; Prieto-Martínez, F.D.; Medina-Franco, J.L.; Chale-Dzul, J.B.; Moo-Puc, R.; Navarrete-Vázquez, G. Metronidazole and Secnidazole Carbamates: Synthesis, Antiprotozoal Activity, and Molecular Dynamics Studies. Molecules 2020, 25, 793.

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