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

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Genaro Rocha-GarduñoGabriel Navarrete-Vázquez

Abstract

We prepared a series of 10 carbamates derivatives based on two common antiprotozoal drugs: metronidazole (1-5) and secnidazole (6-10). The compounds were tested in vitro against a set of two amitochondriate protozoa: Giardiaduodenalis and Trichomonas vaginalis. Compounds 1-10 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 1-10, secnidazole, and metronidazole onto the ligand binding site of pyruvate-ferredoxin oxidoreductase of T. vaginalis and the modeled -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.

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Citations

Nov 26, 2020·European Journal of Medicinal Chemistry·Om P S PatelRichard M Beteck
Sep 2, 2020·Journal of Medicinal Chemistry·Andrew RichesTina S Skinner-Adams

Methods Mentioned

BETA
Assay

Related Concepts

Antiprotozoal Agents
Carbamates
Giardia lamblia
Metronidazole
Parasites
Polycyclic Hydrocarbons, Aromatic
Protozoa
Saponins
Trichomonas vaginalis
Pyruvate synthase

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