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: Giardia duodenalis 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 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.
Highlights
Giardia duodenalis is an intestinal parasite that infects several mammalian hosts including humans, and it is considered a leading cause of waterborne diarrheal disease and malabsorption syndrome [1].Trichomonas vaginalis is the etiologic agent of the most common non-viral sexually transmitted disease in humans [2]
The chemotherapy against giardiasis and trichomoniasis is based on the use of 5-nitroimidazole drugs [3], such as metronidazole and secnidazole (Figure 1)
5-nitroimidazole, we suggest the modification of its alcohol tail by carbamates, antiprotozoal of this 5-nitroimidazole, we suggest the modification of several its alcohol tail by increasing the lipophilicity of compounds and exploring the participation of the carbamate in the the several carbamates, increasing the lipophilicity of compounds and exploring the participation of activity through potential inhibition β-tubulininhibition polymerization plus thepolymerization inhibition of pyruvate–ferredoxin oxidoreductase (PFOR)
Summary
Giardia duodenalis is an intestinal parasite that infects several mammalian hosts including humans, and it is considered a leading cause of waterborne diarrheal disease and malabsorption syndrome [1]. 5-nitroimidazole drugs [3], such as metronidazole and secnidazole (Figure 1). The chemotherapy against giardiasis and trichomoniasis is based on the use of 5-nitroimidazole drugs [3], such as metronidazole and secnidazole (Figure 1). The mode of action of 5-nitroimidazoles is multifactorial butofone the accepted mechanisms is inhibition of the of pyruvate–ferredoxin oxidoreductase (PFOR)(PFOR). -tubulin polymerization [10].toInimprove an effortthe to antiprotozoal improve the activity of thisactivity. Carbamate in thethe activity through the of potential of -tubulin plusThus, the the in vitroofantiparasitic effects newly designed carbamates onnewly intestinal protozoa. VERO cells, and the molecular intestinal protozoa G. duodenalis, urogenital tract protozoa T. vaginalis, the cytotoxicity over docking andVERO dynamics of this mode of binding over PFOR and β-tubulin are reported in mammalian cells, prediction and the molecular docking and dynamics prediction of this mode of binding this work.
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