Thenitro group has always been a functionality of paramount importance for theorganic chemist in viewof its contribution towards various organic transformations and stereoselectivereactions employed for the synthesis of natural products and medicinallyvaluable compounds. Specifically, organocatalyticand transition metal catalyzed assymetricmichael addition , nitro — Michael addition, henry, aza henry reactions exemplifysome of the C-C- bond forming reactions that have been efficiently developedutilizing nitro compounds and successfully employed in the accomplishment ofsynthetic protocols for clinically approved agents or agents in clinicaltrials/preclinical investigations 1-4. Nitrogroup possesses strong electron attracting ability that creates localizedelectron deficient sites within the molecules and interact with the biological nucleophilespresent in the living system i.e., proteins, amino acids, nuclei acids,enzymes, etc. The interaction occurs via nucleophilic addition and electrontransfer involving oxidation and reduction, or merely molecular complexation toinduce desired or undesired biological changes 5, 6.
Owing to this,numerous medicinal chemistry campaigns have been initiated to investigate nitrogroup containing compounds. As such, the nitro group containing drugs have a longhistoryof use as antineoplastic, antibiotic, andantiparasitic drugs, as well as tranquilizers, fungicides, insecticides,herbicides, and other 5-12. Moreover, nitrogroups that are reduced at a brisk rate may serve as prodrug owing to their bioactivation by enzymatic reductiongenerating reactive species ultimately inducing biological effects. It is wellproved that nitroaromatic/heteroaromatic compounds induce cytotoxic,antitumor, and antiparasitic effects due to redox cycling of singleelectron reduction by different flavoenzymes or from the alkylation of DNAand/or other cellular nucleophiles by the products of their bioreductiveactivation process 13. Recentliterature indicates the majority of the efforts have been directed towards theexploration of nitro group containing compounds asanticancer agents, antitubercular agents and antiinfective agents. Though thesecompounds induces their cell killing effects via diverse mechanisms such astopoisomerase inhibition, histone deacetylase inhibition, DNA Alkylation, tubulinpolymerization inhibition and so on, the core potential of such agents relieson hypoxia induced effects attributed to their bioreductive activationpotential. The antitubercular potential of some clinically successful drugsalso relies on their bioactivation with many undergoing detailed preclinicalinvestigations or being examined in clinical trials. Nitroimidazole is one suchversatile heterocyclic moiety which has been widely employed to exert diversebiological effects and has been often categorized as the most exploredbioreductive arm.
This is clearly evidenced by number of clinically approvednitroimidazole containing compounds mostly for infectious diseases in additionto a large repository of such compounds endowed with exciting and optimisticpreclinical potential. Not only the research literature but also the patentliterature emphasizes on the effects of nitro containing compound largelyrelying on their bio reduction.Despite these wide applications, there is no denying the fact thatnitro group containing drugs can induce several toxicity issues includingcarcinogenicity, hepatotoxicity, mutagenicity, and bone-marrow suppression andthis is indubitably the reason for their avoidance in some cases.Concomitantly, selective toxicity with nitro aromaticand heteroaromatic compounds also forms the basis of chemotherapy resulting inpoisoning of bacteria, parasites, or tumor cells without harming the hostorganism or normal cells 12. In this view, themedicinal chemist has been constantly striving hard and putting the best oftheir efforts to explore the bioactive potential of nitro aromatic andheteroaromatic compounds in diverse complications right from the treatment ofparasitic infections to cancer and many enzyme expression dependent diseases. Often,the nitro functional group has been found to be instrumental in potentiatingthe bioactivity and the structure activity relationship studies conducted bythe researchers have made this evident by substantial effects of the nitrogroup containing derivatives.
Overall, theaspects related to such agents are indeed contradictory as the nitro group isconsidered both as a pharmacophore or an integral part of the pharmacophore andtoxicophore or a structural alert. 14In this perspective,we focus on various aspects of nitro group containing agents ascertaining theirimportance in the field of medicinal chemistry. This compilation emphasizes onthe bio reductive mechanisms leading to activation of nitro compounds, nitrogroup containing FDA approved drugs and insights into issues leading to their withdrawalalong with a section on the recent developments in the field of nitro groupcontaining anticancer, antitubercular and antiparasitic agents. A library of nitro group containing agents demonstrating bioactivepotential as anticancer, antitibercular and antiparasitic agents in preclinicaland preliminary screening assays has been presented to create awareness aboutthose structures and further enabling the medicinal chemist working in tandemwith the biologist to capitalize on the promise demonstrated by such agentsrather than passing them off as missed opportunities. The prespective alsocovers a recent patent survey and discussion on ways to combat the toxicity andselective targeting by Nitro compounds. The data presented clearly indicatesthat several nitro group containing compounds displays enough clinical andpreclinical promise which in turn ascertains their role as a pharmacophore indrug design and discovery outshining their categorization as toxicophore.