Nitro Group Containing Drugs

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (25 October 2022) | Viewed by 29977

Special Issue Editors

CNRS, ICR UMR 7273, Team Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, Aix Marseille University, 27 Boulevard Jean Moulin, CS30064, CEDEX 05, 13385 Marseille, France
Interests: medicinal chemistry; anti-infectious; anti-proliferative, anti-viral, heterocycles; nitroimidazoles; monoelectronic transfer; organic electron donors
Special Issues, Collections and Topics in MDPI journals
1. CNRS, ICR UMR 7273, Team Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, Aix Marseille University, 27 Boulevard Jean Moulin, CS30064, CEDEX 05, 13385 Marseille, France
2. APHM, Pharmacy Department, Service Central de la Qualité et de l' Information Pharmaceutiques, 147 Bd Baille, 13005 Marseille, France
Interests: medicinal chemistry; heterocyclic chemistry; Plasmodium; Leishmania; Trypanosoma; nitroheterocycles
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The nitro group is a very unique functional group in medicinal chemistry as a strong electron-withdrawing and quite polar group. Although found in medicines for a long time, due to metabolic liabilities, the nitro group has toxicity issues. It is often considered a structural alert or toxicophore leading to mutagenicity and genotoxicity in most medicinal chemists’ minds.

However, numerous nitro-drugs take advantage of bioreductive activation mechanisms mainly in the antibacterial and antiparasitic fields. Recently, renewed interest in nitro drugs has led to the approval of fexinidazole to treat human African trypanosomiasis (HAT), a neglected tropical disease. Due to its unique properties, the nitro group has found great interest in the development of anticancer, antitubercular and antiparasitic agents, as well as hypoxia-activated prodrugs. Nitro groups have also been found in the development of self-immolative spacers (linkers) to overcome limitations for drug delivery and have attracted wide interest in medicinal chemistry. In this context, many studies have been undertaken on the structure–mutagenicity or structure–genotoxicity relationships of drugs containing nitro groups.

The aim of this Special Issue is to summarize the state of the art and the latest findings in the field of biologically active nitro-containing molecules, as well as to elucidate future directions.

Areas of interest include, but are not limited to:

  • Drug discovery
  • Medicinal chemistry
  • Drug synthesis
  • SAR studies
  • In vitro/in vivo activity
  • Chemotherapeutic targets
  • Toxicity studies
  • Toxicity management
  • Prodrugs
  • Self-immolative spacers
  • Probes

Prof. Dr. Patrice Vanelle
Dr. Nicolas Primas
Guest Editors

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Keywords

  • nitro group
  • nitro- drugs
  • nitroreductases
  • bio-reduction
  • pro-drugs
  • mutagenicity
  • genotoxicity
  • antiparasitic
  • antibacterial
  • anti-cancer

Published Papers (10 papers)

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Research

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15 pages, 2587 KiB  
Article
Investigation of 1,4-Substituted 1,2,3-Triazole Derivatives as Antiarrhythmics: Synthesis, Structure, and Properties
Pharmaceuticals 2022, 15(12), 1443; https://doi.org/10.3390/ph15121443 - 22 Nov 2022
Viewed by 1026
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  
Article
Improving Aqueous Solubility and In Vitro Pharmacokinetic Properties of the 3-Nitroimidazo[1,2-a]pyridine Antileishmanial Pharmacophore
Pharmaceuticals 2022, 15(8), 998; https://doi.org/10.3390/ph15080998 - 13 Aug 2022
Cited by 2 | Viewed by 1354
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 (T1/2 > 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  
Article
Low-Energy Electron Induced Reactions in Metronidazole at Different Solvation Conditions
Pharmaceuticals 2022, 15(6), 701; https://doi.org/10.3390/ph15060701 - 02 Jun 2022
Cited by 5 | Viewed by 1857
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  
Article
Nitro-Group-Containing Thiopeptide Derivatives as Promising Agents to Target Clostridioides difficile
Pharmaceuticals 2022, 15(5), 623; https://doi.org/10.3390/ph15050623 - 19 May 2022
Cited by 4 | Viewed by 1867
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  
Article
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
Pharmaceuticals 2022, 15(1), 102; https://doi.org/10.3390/ph15010102 - 15 Jan 2022
Cited by 4 | Viewed by 3218
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 14, 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 14 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  
Review
Nitro-Containing Self-Immolative Systems for Biological Applications
Pharmaceuticals 2022, 15(11), 1404; https://doi.org/10.3390/ph15111404 - 14 Nov 2022
Cited by 1 | Viewed by 1841
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  
Review
The Diverse Biological Activity of Recently Synthesized Nitro Compounds
Pharmaceuticals 2022, 15(6), 717; https://doi.org/10.3390/ph15060717 - 05 Jun 2022
Cited by 19 | Viewed by 3181
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  
Review
Recent Progress in the Synthesis of Drugs and Bioactive Molecules Incorporating Nitro(het)arene Core
Pharmaceuticals 2022, 15(6), 705; https://doi.org/10.3390/ph15060705 - 03 Jun 2022
Cited by 4 | Viewed by 2924
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  
Review
Functionalized Nitroimidazole Scaffold Construction and Their Pharmaceutical Applications: A 1950–2021 Comprehensive Overview
Pharmaceuticals 2022, 15(5), 561; https://doi.org/10.3390/ph15050561 - 30 Apr 2022
Cited by 8 | Viewed by 3876
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  
Review
Nitroaromatic Hypoxia-Activated Prodrugs for Cancer Therapy
Pharmaceuticals 2022, 15(2), 187; https://doi.org/10.3390/ph15020187 - 02 Feb 2022
Cited by 18 | Viewed by 5846
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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