Revisiting Nitroaromatic Drugs: Mechanisms of Bioactivation, Metabolism and Toxicity and Methods to Synthesize Nitroaromatic Fragments

Nitroaromatic drugs represent an important class of therapeutic agents, endowed with different pharmacological properties such as antibacterial, antiprotozoal, anti-Parkinson, anticancer, etc. However, the nitroheterocycle and nitroarene fragments are considered potentially toxic, with reports of mutagenicity and genotoxicity. The bioreduction process of the nitro group plays a central role in the antimicrobial and toxicological mechanism of action of nitroaromatic drugs. This article will review the nitroaromatic drugs approved by the Food and Drug Administration (FDA) in the last 30 years, the mechanisms of bioactivation, metabolism and toxicity and, finally, it will revisit the main methodologies for obtaining the nitroaromatic fragment from aromatic nitration reaction and oxidation of arylamines and/or heteroarylamines.

Keywords:
nitroarene; nitroheterocycle; FDA; bioreduction; aromatic nitration reaction; aryl/heteroarylamine oxidation

Authorship

Saulo T. Abreu

Saulo Tavares Abreu is a Master’s degree student in the Postgraduate Program in Pharmacology and Medicinal Chemistry at the Federal University of Rio de Janeiro with the research focused on Neglected Tropical Diseases. He is graduated in Pharmacy from the Federal Rural University of Rio de Janeiro. He is a member of the project “Transforming through Chemistry” and was a member of the Plant Genotoxic Activity Laboratory in the project “Genotoxic and Cytotoxic Assessment of plant extracts using the Allium cepa test”. In 2018 he was a FAPERJ fellow at the Coccidia Biology Laboratory with emphasis on Molecular and Microorganism Genetics.

# These authors contributed equally to the work. This review is part of the special edition of JBCS dedicated to Professor Eliezer Barreiro, founder of the Summer School in Pharmaceutical and Medicinal Chemistry.

Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio®), Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro (UFRJ), CCS, Cidade Universitária, 21941-902 Rio de Janeiro-RJ, BrazilUniversidade Federal do Rio de Janeiro (UFRJ)BrazilRio de Janeiro, RJ, BrazilLaboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio®), Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro (UFRJ), CCS, Cidade Universitária, 21941-902 Rio de Janeiro-RJ, Brazil

Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro-RJ, BrazilUniversidade Federal do Rio de JaneiroBrazilRio de Janeiro, RJ, BrazilPós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro-RJ, Brazil

https://orcid.org/0000-0001-6702-6983

Luis Gabriel V. Gelves

Luis Gabriel Valdivieso Gelves is graduated in Chemistry, MSc, PhD and specialist in EaD. He has a post-doctoral from FAPERJ. He works in RD&I (Organic Chemistry/Biocatalysis), with a focus on organic synthesis (incremental/radical), preparation of immobilized catalysts, unequivocal characterization of molecules and kinetic studies to optimize processes for the chemical and pharmaceutical industries. He has received special recognition for his work, such as the Kurt Politzer Technology Award/2015, industry category, for the optimization of chemical/enzymatic processes with cost minimization and vision for Scale-up. He is the author and inventor of patents, articles and book chapters on teaching and chemical synthesis.

https://orcid.org/0000-0002-6013-2879

Eliezer J. Barreiro

Eliezer J. Barreiro was pharmacist with MSc in Chemistry of Natural Products from the Federal University of Rio de Janeiro (UFRJ), and Docteur d’Ètat in Chimie Médicale from the Université de Grenoble I (France). He was Professor Emeritus of Medicinal Chemistry at UFRJ and was the author of > 350 publications and ca. 20 patents. He has been research supervisor of ca. 100 graduate students. He is the Scientific Coordinator of the National Institute of Science and Technology in Drugs and Medicines (INCT-INOFAR) and was the founder and Scientific Director of the Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio®, ICB, UFRJ).

https://orcid.org/0000-0003-1759-0038

Lídia M. Lima ^** e-mail: lidialima@ufrj.br, lmlima23@gmail.com

Lidia Moreira Lima is a Full Professor at the Federal University of Rio de Janeiro (UFRJ). She obtained her PhD in Science from the Chemistry Institute of UFRJ and has a Post-Doctorate in Medicinal Chemistry from the University of Navarra (Spain). She is a CNPq level 1D researcher, a FAPERJ Scientist of Our State and the Scientific Superintendent of the INCT-INOFAR. She works at LASSBio® (ICB, UFRJ) on research projects in Medicinal Chemistry on the following topics: new leishmanicides, antitumor, anti-inflammatory and hypoglycemic agents. Her research activities focus on rational design, synthesis, lead-optimization, drug-like properties and DMPK studies.

https://orcid.org/0000-0002-8625-6351

* e-mail: lidialima@ufrj.br, lmlima23@gmail.com

#
These authors contributed equally to the work. This review is part of the special edition of JBCS dedicated to Professor Eliezer Barreiro, founder of the Summer School in Pharmaceutical and Medicinal Chemistry.

Editor handled this article: Brenno A. D. Neto

SCIMAGO INSTITUTIONS RANKINGS

Figures

Figures (63)