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

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.

Silver nanoparticles effect on drug release of metronidazole in natural rubber latex dressing

“…Metronidazole (MET) is an azomycin-derived nitroimidazole discovered in 1962, which is commonly used to treat skin, bones and tissues infections. It can act as antimicrobial [1], antiprotozoal [2], antiviral [3], antileishmanial [4], antigiardial [5], antioxidant [6], anti-inflammatory [7], antiplasmodial and antimycobacterial [8]. Regularly, besides the mentioned applications, MET is highly indicated for the treatment of infections caused by drug-resistant bacteria (anaerobic Grampositive and Gram-negative bacteria), tuberculosis, protozoan infections (trichomoniasis, amoebiasis, bacterial vaginosis, giardiasis, non-gonococcal urethritis) and visceral leishmaniasis [9].…”

Anti-GiardiaDrug Discovery: Current Status and Gut Feelings

“…Most of the hybrid compounds that have been investigated include a nitroheterocycle compound pharmacophore. This includes studies that have investigated chloroquine and nitroheterocycle hybrids, hybrids containing two nitroheterocycle pharmacophores, and those investigating hybrids containing a nitroheterocycle and benzimidazole , or a carbamate pharmacophore . However, there have also been some limited studies of hybrids not containing a nitroheterocycle pharmacophore, including benzimidazole and pentamidine hybrids and benzimidazole and propamidine hybrids .…”

Improving the Solubility, Dissolution, and Bioavailability of Metronidazole via Cocrystallization with Ethyl Gallate

“…MTZ is also commonly used in cats [ 10 ], dogs [ 11 , 12 ], cows [ 13 ] and horses [ 14 ], despite the known genotoxic, carcinogenic and mutagenic properties of nitroimidazoles and their metabolites to mammals and humans [ 15 , 16 ]. To reduce the side effects in humans and animals, minimize the environmental impact and mitigate the threat of drug-resisting microbials, efforts have been made to either improve the bioavailability of MTZ [ 17 ] or synthesize new compounds with better safety profiles [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ].…”