Research

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15 pages, 2587 KiB

Open AccessArticle

Investigation of 1,4-Substituted 1,2,3-Triazole Derivatives as Antiarrhythmics: Synthesis, Structure, and Properties

by Elena O. Shestakova, Sergey G. Il’yasov, Irina A. Shchurova, Vera S. Glukhacheva, Dmitri S. Il’yasov, Egor E. Zhukov, Arkady O. Bryzgalov, Tatiana G. Tolstikova and Yuri V. Gatilov

Pharmaceuticals 2022, 15(12), 1443; https://doi.org/10.3390/ph15121443 - 22 Nov 2022

Viewed by 1123

Abstract

Here, we investigated the reaction of 1,3-dipolar cycloaddition of 1,3-diazido-2-nitro-2- azapropane (DANP) to propargyl alcohol over a copper-based catalyst and identified the optimum reaction conditions that enable the synthesis of 2-nitro-1,3-bis(4,4′-dihydroxymethyl)-1,2,3-triazolyl-2-azapropane (1) in more than 84% yield. The reaction between DANP, [...] Read more.

Here, we investigated the reaction of 1,3-dipolar cycloaddition of 1,3-diazido-2-nitro-2- azapropane (DANP) to propargyl alcohol over a copper-based catalyst and identified the optimum reaction conditions that enable the synthesis of 2-nitro-1,3-bis(4,4′-dihydroxymethyl)-1,2,3-triazolyl-2-azapropane (1) in more than 84% yield. The reaction between DANP, 1,5-diazido-3-nitrazapentane, and phenylacetylene produced the respective 1,2,3-triazole derivatives in 83% and 71% yields, respectively. The structures of the resultant compounds were validated by infrared and NMR spectroscopies and elemental analysis. The structure of 1 was proved by single-crystal X-ray diffraction. This study demonstrated that 1 exhibits a dose-dependent antiarrhythmic activity towards calcium-chloride-induced arrhythmia and refers to Class III: moderately hazardous substances. Full article

(This article belongs to the Special Issue Nitro Group Containing Drugs)

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24 pages, 3566 KiB

Open AccessArticle

Improving Aqueous Solubility and In Vitro Pharmacokinetic Properties of the 3-Nitroimidazo[1,2-a]pyridine Antileishmanial Pharmacophore

by Romain Paoli-Lombardo, Nicolas Primas, Sandra Bourgeade-Delmas, Sébastien Hutter, Alix Sournia-Saquet, Clotilde Boudot, Emilie Brenot, Caroline Castera-Ducros, Sophie Corvaisier, Marc Since, Aurélie Malzert-Fréon, Bertrand Courtioux, Alexis Valentin, Pierre Verhaeghe, Nadine Azas, Pascal Rathelot and Patrice Vanelle

Pharmaceuticals 2022, 15(8), 998; https://doi.org/10.3390/ph15080998 - 13 Aug 2022

Cited by 2 | Viewed by 1471

Abstract

An antileishmanial structure–activity relationship (SAR) study focused on positions 2 and 8 of the imidazo[1,2-a]pyridine ring was conducted through the synthesis of 22 new derivatives. After being screened on the promatigote and axenic amastigote stages of Leishmania donovani and L. infantum, [...] Read more.

An antileishmanial structure–activity relationship (SAR) study focused on positions 2 and 8 of the imidazo[1,2-a]pyridine ring was conducted through the synthesis of 22 new derivatives. After being screened on the promatigote and axenic amastigote stages of Leishmania donovani and L. infantum, the best compounds were tested against the intracellular amastigote stage of L. infantum and evaluated regarding their in vitro physicochemical and pharmacokinetic properties, leading to the discovery of a new antileishmanial6-chloro-3-nitro-8-(pyridin-4-yl)-2-[(3,3,3-trifluoropropylsulfonyl)methyl]imidazo[1,2-a]pyridine hit. It displayed low cytotoxicities on both HepG2 and THP1 cell lines (CC₅₀ > 100 µM) associated with a good activity against the intracellular amastigote stage of L. infantum (EC₅₀ = 3.7 µM versus 0.4 and 15.9 µM for miltefosine and fexinidazole, used as antileishmanial drug references). Moreover, in comparison with previously reported derivatives in the studied series, this compound displayed greatly improved aqueous solubility, good mouse microsomal stability (T_1/2 > 40 min) and high gastrointestinal permeability in a PAMPA model, making it an ideal candidate for further in vivo studies on an infectious mouse model. Full article

(This article belongs to the Special Issue Nitro Group Containing Drugs)

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12 pages, 1716 KiB

Open AccessArticle

Low-Energy Electron Induced Reactions in Metronidazole at Different Solvation Conditions

by Christine Lochmann, Thomas F. M. Luxford, Samanta Makurat, Andriy Pysanenko, Jaroslav Kočišek, Janusz Rak and Stephan Denifl

Pharmaceuticals 2022, 15(6), 701; https://doi.org/10.3390/ph15060701 - 02 Jun 2022

Cited by 6 | Viewed by 1965

Abstract

Metronidazole belongs to the class of nitroimidazole molecules and has been considered as a potential radiosensitizer for radiation therapy. During the irradiation of biological tissue, secondary electrons are released that may interact with molecules of the surrounding environment. Here, we present a study [...] Read more.

Metronidazole belongs to the class of nitroimidazole molecules and has been considered as a potential radiosensitizer for radiation therapy. During the irradiation of biological tissue, secondary electrons are released that may interact with molecules of the surrounding environment. Here, we present a study of electron attachment to metronidazole that aims to investigate possible reactions in the molecule upon anion formation. Another purpose is to elucidate the effect of microhydration on electron-induced reactions in metronidazole. We use two crossed electron/molecular beam devices with the mass-spectrometric analysis of formed anions. The experiments are supported by quantum chemical calculations on thermodynamic properties such as electron affinities and thresholds of anion formation. For the single molecule, as well as the microhydrated condition, we observe the parent radical anion as the most abundant product anion upon electron attachment. A variety of fragment anions are observed for the isolated molecule, with NO₂⁻ as the most abundant fragment species. NO₂⁻ and all other fragment anions except weakly abundant OH⁻ are quenched upon microhydration. The relative abundances suggest the parent radical anion of metronidazole as a biologically relevant species after the physicochemical stage of radiation damage. We also conclude from the present results that metronidazole is highly susceptible to low-energy electrons. Full article

(This article belongs to the Special Issue Nitro Group Containing Drugs)

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13 pages, 1785 KiB

Open AccessArticle

Nitro-Group-Containing Thiopeptide Derivatives as Promising Agents to Target Clostridioides difficile

by Dahyun Kim, Young-Rok Kim, Hee-Jong Hwang, Marco A. Ciufolini, Jusuk Lee, Hakyeong Lee, Shyaka Clovis, Sungji Jung, Sang-Hun Oh, Young-Jin Son and Jin-Hwan Kwak

Pharmaceuticals 2022, 15(5), 623; https://doi.org/10.3390/ph15050623 - 19 May 2022

Cited by 4 | Viewed by 2001

Abstract

The US Centers for Disease Control and Prevention (CDC) lists Clostridioides difficile as an urgent bacterial threat. Yet, only two drugs, vancomycin and fidaxomicin, are approved by the FDA for the treatment of C. difficile infections as of this writing, while the global [...] Read more.

The US Centers for Disease Control and Prevention (CDC) lists Clostridioides difficile as an urgent bacterial threat. Yet, only two drugs, vancomycin and fidaxomicin, are approved by the FDA for the treatment of C. difficile infections as of this writing, while the global pipeline of new drugs is sparse at best. Thus, there is a clear and urgent need for new antibiotics against that organism. Herein, we disclose that AJ-024, a nitroimidazole derivative of a 26-membered thiopeptide, is a promising anti-C. difficile lead compound. Despite their unique mode of action, thiopeptides remain largely unexploited as anti-infective agents. AJ-024 combines potent in vitro activity against various strains of C. difficile with a noteworthy safety profile and desirable pharmacokinetic properties. Its time-kill kinetics against a hypervirulent C. difficile ribotype 027 and in vivo (mouse) efficacy compare favorably to vancomycin, and they define AJ-024 as a valuable platform for the development of new anti-C. difficile antibiotics. Full article

(This article belongs to the Special Issue Nitro Group Containing Drugs)

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15 pages, 3494 KiB

Open AccessArticle

Synthesis, In Vitro, In Vivo and In Silico Antidiabetic Bioassays of 4-Nitro(thio)phenoxyisobutyric Acids Acting as Unexpected PPARγ Modulators: An In Combo Study

by Blanca Colin-Lozano, Héctor Torres-Gomez, Sergio Hidalgo-Figueroa, Fabiola Chávez-Silva, Samuel Estrada-Soto, Julio Cesar Almanza-Pérez and Gabriel Navarrete-Vazquez

Pharmaceuticals 2022, 15(1), 102; https://doi.org/10.3390/ph15010102 - 15 Jan 2022

Cited by 4 | Viewed by 3450

Abstract

Four isobutyric acids (two nitro and two acetamido derivatives) were prepared in two steps and characterized using spectral analysis. The mRNA concentrations of PPARγ and GLUT-4 (two proteins documented as key diabetes targets) were increased by 3T3-L1 adipocytes treated with compounds 1– [...] Read more.

Four isobutyric acids (two nitro and two acetamido derivatives) were prepared in two steps and characterized using spectral analysis. The mRNA concentrations of PPARγ and GLUT-4 (two proteins documented as key diabetes targets) were increased by 3T3-L1 adipocytes treated with compounds 1–4, but an absence of in vitro expression of PPARα was observed. Docking and molecular dynamics studies revealed the plausible interaction between the synthesized compounds and PPARγ. In vivo studies established that compounds 1–4 have antihyperglycemic modes of action associated with insulin sensitization. Nitrocompound 2 was the most promising of the series, being orally active, and one of multiple modes of action could be selective PPARγ modulation due to its extra anchoring with Gln-286. In conclusion, we demonstrated that nitrocompound 2 showed strong in vitro and in vivo effects and can be considered as an experimental antidiabetic candidate. Full article

(This article belongs to the Special Issue Nitro Group Containing Drugs)

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Review

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19 pages, 5650 KiB

Open AccessReview

Nitro-Containing Self-Immolative Systems for Biological Applications

by Cédric Spitz, Nicolas Primas, Thierry Terme and Patrice Vanelle

Pharmaceuticals 2022, 15(11), 1404; https://doi.org/10.3390/ph15111404 - 14 Nov 2022

Cited by 1 | Viewed by 2016

Abstract

Since its introduction in 1981, the chemistry of self-immolative systems has received increasing attention in different application areas, such as analytical chemistry, medicinal chemistry, and materials science. This strategy is based on a stimulation that triggers a cascade of disassembling reactions leading to [...] Read more.

Since its introduction in 1981, the chemistry of self-immolative systems has received increasing attention in different application areas, such as analytical chemistry, medicinal chemistry, and materials science. This strategy is based on a stimulation that triggers a cascade of disassembling reactions leading to the release of smaller molecules. The particular reactivity of the nitro group, due to its powerful electron-withdrawing nature, has been exploited in the field of self-immolative chemistry. In this context, the present review describes the major role of the nitro group in self-immolative processes depending on its position. Full article

(This article belongs to the Special Issue Nitro Group Containing Drugs)

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14 pages, 2501 KiB

Open AccessReview

The Diverse Biological Activity of Recently Synthesized Nitro Compounds

by Saúl Noriega, Jaime Cardoso-Ortiz, Argelia López-Luna, Ma Del Refugio Cuevas-Flores and Juan Armando Flores De La Torre

Pharmaceuticals 2022, 15(6), 717; https://doi.org/10.3390/ph15060717 - 05 Jun 2022

Cited by 20 | Viewed by 3568

Abstract

The search for new and efficient pharmaceuticals is a constant struggle for medicinal chemists. New substances are needed in order to treat different pathologies affecting the health of humans and animals, and these new compounds should be safe, effective and have the fewest [...] Read more.

The search for new and efficient pharmaceuticals is a constant struggle for medicinal chemists. New substances are needed in order to treat different pathologies affecting the health of humans and animals, and these new compounds should be safe, effective and have the fewest side effects possible. Some functional groups are known for having biological activity; in this matter, the nitro group (NO₂) is an efficient scaffold when synthesizing new bioactive molecules. Nitro compounds display a wide spectrum of activities that include antineoplastic, antibiotic, antihypertensive, antiparasitic, tranquilizers and even herbicides, among many others. Most nitro molecules exhibit antimicrobial activity, and several of the compounds mentioned in this review may be further studied as lead compounds for the treatment of H. pylori, P. aeruginosa, M. tuberculosis and S. mutans infections, among others. The NO₂ moiety triggers redox reactions within cells causing toxicity and the posterior death of microorganisms, not only bacteria but also multicellular organisms such as parasites. The same effect may be present in humans as well, so the nitro groups can be considered both a pharmacophore and a toxicophore at the same time. The role of the nitro group itself also has a deep effect on the polarity and electronic properties of the resulting molecules, and hence favors interactions with some amino acids in proteins. For these reasons, it is fundamental to analyze the recently synthesized nitro molecules that show any potential activity in order to develop new pharmacological treatments that enhance human health. Full article

(This article belongs to the Special Issue Nitro Group Containing Drugs)

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24 pages, 14375 KiB

Open AccessReview

Recent Progress in the Synthesis of Drugs and Bioactive Molecules Incorporating Nitro(het)arene Core

by Maxim Bastrakov and Alexey Starosotnikov

Pharmaceuticals 2022, 15(6), 705; https://doi.org/10.3390/ph15060705 - 03 Jun 2022

Cited by 4 | Viewed by 3236

Abstract

Aromatic nitro compounds play a unique role in the synthesis of drugs and pharmaceutically oriented molecules. This field of organic chemistry continues to be in demand and relevant. A significant number of papers are published annually on new general methods for the synthesis [...] Read more.

Aromatic nitro compounds play a unique role in the synthesis of drugs and pharmaceutically oriented molecules. This field of organic chemistry continues to be in demand and relevant. A significant number of papers are published annually on new general methods for the synthesis of nitrodrugs and related biomolecules. This review is an analysis of the literature on methods for the synthesis of both new and already-known aromatic and heteroaromatic nitrodrugs covering the period from 2010 to the present. Full article

(This article belongs to the Special Issue Nitro Group Containing Drugs)

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94 pages, 48628 KiB

Open AccessReview

Functionalized Nitroimidazole Scaffold Construction and Their Pharmaceutical Applications: A 1950–2021 Comprehensive Overview

by Ria Gupta, Sumit Sharma, Rohit Singh, Ram A. Vishwakarma, Serge Mignani and Parvinder Pal Singh

Pharmaceuticals 2022, 15(5), 561; https://doi.org/10.3390/ph15050561 - 30 Apr 2022

Cited by 12 | Viewed by 4142

Abstract

Nitroimidazole represents one of the most essential and unique scaffolds in drug discovery since its discovery in the 1950s. It was K. Maeda in Japan who reported in 1953 the first nitroimidazole as a natural product from Nocardia mesenterica with antibacterial activity, which [...] Read more.

Nitroimidazole represents one of the most essential and unique scaffolds in drug discovery since its discovery in the 1950s. It was K. Maeda in Japan who reported in 1953 the first nitroimidazole as a natural product from Nocardia mesenterica with antibacterial activity, which was later identified as Azomycin 1 (2-nitroimidazole) and remained in focus until now. This natural antibiotic was the starting point for synthesizing numerous analogs and regio-isomers, leading to several life-saving drugs and clinical candidates against a number of diseases, including infections (bacterial, viral, parasitic) and cancers, as well as imaging agents in medicine/diagnosis. In the present decade, the nitroimidazole scaffold has again been given two life-saving drugs (Delamanid and Pretomanid) used to treat MDR (multi-drug resistant) tuberculosis. Keeping in view the highly successful track-record of the nitroimidazole scaffold in providing breakthrough therapeutic drugs, this comprehensive review focuses explicitly on presenting the activity profile and synthetic chemistry of functionalized nitroimidazole (2-, 4- and 5-nitroimidazoles as well as the fused nitroimidazoles) based drugs and leads published from 1950 to 2021. The present review also presents the miscellaneous examples in each class. In addition, the mutagenic profile of nitroimidazole-based drugs and leads and derivatives is also discussed. Full article

(This article belongs to the Special Issue Nitro Group Containing Drugs)

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19 pages, 3038 KiB

Open AccessReview

Nitroaromatic Hypoxia-Activated Prodrugs for Cancer Therapy

by William A. Denny

Pharmaceuticals 2022, 15(2), 187; https://doi.org/10.3390/ph15020187 - 02 Feb 2022

Cited by 19 | Viewed by 6138

Abstract

The presence of “hypoxic” tissue (with O₂ levels of <0.1 mmHg) in solid tumours, resulting in quiescent tumour cells distant from blood vessels, but capable of being reactivated by reoxygenation following conventional therapy (radiation or drugs), have long been known as a [...] Read more.

The presence of “hypoxic” tissue (with O₂ levels of <0.1 mmHg) in solid tumours, resulting in quiescent tumour cells distant from blood vessels, but capable of being reactivated by reoxygenation following conventional therapy (radiation or drugs), have long been known as a limitation to successful cancer chemotherapy. This has resulted in a sustained effort to develop nitroaromatic “hypoxia-activated prodrugs” designed to undergo enzyme-based nitro group reduction selectively in these hypoxic regions, to generate active drugs. Such nitro-based prodrugs can be classified into two major groups; those activated either by electron redistribution or by fragmentation following nitro group reduction, relying on the extraordinary difference in electron demand between an aromatic nitro group and its reduction products. The vast majority of hypoxia-activated fall into the latter category and are discussed here classed by the nature of their nitroaromatic trigger units. Full article

(This article belongs to the Special Issue Nitro Group Containing Drugs)

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