A lead compound of a drug contained an aromatic ring. Three analogues with different configurations were synthesized. These analogues consisted of an aromatic ring of five carbon atoms and one nitrogen atom. Additionally, the drug functional group substituted the aromatic ring at either the ortho, meta, or para positions relative to the nitrogen atom.
Analogues I and II were ortho and meta substitutions respectively and their activity was reported to be similar to that of the original lead compound. However, analogue III, which was a para substitution, was reported to show significantly higher activity.
The nitrogen atom in the aromatic ring is more electrophilic than the other carbon atoms, making it a key determinant in the reactivity and stability of the drug molecule. Hence, the ortho meta and para substitutions of the drug functional group are taken with respect to the nitrogen atom.
Out of these, the para substitution improves the drug activity both due to its added stability, and the additionally electro-negativity of the nitrogen atom. The functional group of the drug is electron-withdrawing in nature.
In the para position, it is positioned symmetrically to the nitrogen atom, improving the stability of the core aromatic ring. However, the nitrogen atom also becomes more electrophilic, enhancing its reactivity and allowing it to better interact with the drug target molecule.