The
nitro group has always been a functionality of paramount importance for the
organic chemist  in view
of its contribution towards various organic transformations and stereoselective
reactions employed for the synthesis of natural products and medicinally
valuable compounds. Specifically,  organocatalytic
and transition  metal catalyzed assymetric
michael addition , nitro — Michael addition, henry, aza henry reactions exemplify
some of the C-C- bond forming reactions that have been efficiently developed
utilizing nitro compounds and successfully employed in the accomplishment of
synthetic protocols for clinically approved agents or agents in clinical
trials/preclinical investigations 1-4.

Nitro
group possesses strong electron attracting ability that creates localized
electron deficient sites within the molecules and interact with the biological nucleophiles
present in the living system i.e., proteins, amino acids, nuclei acids,
enzymes, etc. The interaction occurs via nucleophilic addition and electron
transfer involving oxidation and reduction, or merely molecular complexation to
induce desired or undesired biological changes 5, 6. Owing to this,
numerous medicinal chemistry campaigns have been initiated to investigate nitro
group containing compounds. As such, the nitro group containing drugs have a long
history
of use as antineoplastic, antibiotic, and
antiparasitic drugs, as well as tranquilizers, fungicides, insecticides,
herbicides, and other 5-12. Moreover, nitro
groups that are reduced at a brisk rate may serve as prodrug owing to their bioactivation by enzymatic reduction
generating reactive species ultimately inducing biological effects. It is well
proved that nitroaromatic/heteroaromatic compounds induce cytotoxic,
antitumor, and antiparasitic  effects 
due to redox cycling of  single
electron reduction by different flavoenzymes or from the alkylation of DNA
and/or other cellular nucleophiles by the products of their bioreductive
activation process 13.

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Recent
literature indicates the majority of the efforts have been directed towards the
exploration of nitro group containing compounds as
anticancer agents, antitubercular agents and antiinfective agents. Though these
compounds induces their cell killing effects via diverse mechanisms such as
topoisomerase inhibition, histone deacetylase inhibition, DNA Alkylation, tubulin
polymerization inhibition and so on, the core potential of such agents relies
on hypoxia induced effects attributed to their bioreductive activation
potential. The antitubercular potential of some clinically successful drugs
also relies on their bioactivation with many undergoing detailed preclinical
investigations or being examined in clinical trials. Nitroimidazole is one such
versatile heterocyclic moiety which has been widely employed to exert diverse
biological effects and has been often categorized as the most explored
bioreductive arm. This is clearly evidenced by number of clinically approved
nitroimidazole containing compounds mostly for infectious diseases in addition
to a large repository of such compounds endowed with exciting and optimistic
preclinical potential. Not only the research literature but also the patent
literature emphasizes on the effects of nitro containing compound largely
relying on their bio reduction.

Despite these wide applications, there is no denying the fact that
nitro group containing drugs can induce several toxicity issues including
carcinogenicity, hepatotoxicity, mutagenicity, and bone-marrow suppression and
this is indubitably the reason for their avoidance in some cases.
Concomitantly, selective toxicity with nitro aromatic
and heteroaromatic compounds also forms the basis of chemotherapy resulting in
poisoning of bacteria, parasites, or tumor cells without harming the host
organism or normal cells 12. In this view, the
medicinal chemist has been constantly striving hard and putting the best of
their efforts to explore the bioactive potential of nitro aromatic and
heteroaromatic compounds in diverse complications right from the treatment of
parasitic infections to cancer and many enzyme expression dependent diseases. Often,
the nitro functional group has been found to be instrumental in potentiating
the bioactivity and the structure activity relationship studies conducted by
the researchers have made this evident by substantial effects of the nitro
group containing derivatives. Overall, the
aspects related to such agents are indeed contradictory as the nitro group is
considered both as a pharmacophore or an integral part of the pharmacophore and
toxicophore or a structural alert. 14

In this perspective,
we focus on various aspects of nitro group containing agents ascertaining their
importance in the field of medicinal chemistry. This compilation emphasizes on
the bio reductive mechanisms leading to activation of nitro compounds, nitro
group containing FDA approved drugs and insights into issues leading to their withdrawal
along with a section on the recent developments in the field of nitro group
containing anticancer, antitubercular and antiparasitic agents. A library of nitro group containing agents demonstrating bioactive
potential as anticancer, antitibercular and antiparasitic agents in preclinical
and preliminary screening assays has been presented to create awareness about
those structures and further enabling the medicinal chemist working in tandem
with the biologist to capitalize on the promise demonstrated by such agents
rather than passing them off as missed opportunities. The prespective also
covers a recent patent survey and discussion on ways to combat the toxicity and
selective targeting by Nitro compounds. The data presented clearly indicates
that several nitro group containing compounds displays enough clinical and
preclinical promise which in turn ascertains their role as a pharmacophore in
drug design and discovery outshining their categorization as toxicophore.