Solutions For An Introduction to Medicinal Chemistry Chapter 17 Problem 6Q

Figure-1: shows the structure I and II

After replacing the phenyl group by a pyridine ring in structures I and II, the water solubility of these structures improves. This is because nitrogen can act as hydrogen bond acceptor. This is due to the presence of lone pair electrons on the nitrogen.

Figure-2: The structures after replacement of phenyl group by pyridine ring

Thus, nitrogen will form hydrogen bonding with the hydrogen of water molecules. Energy penalty will be involved as the hydrophobic pocket in the binding site has to interact with the concerned ring. Also, before this, the stripping away of the water molecules has to take place. Hence, reducing the compound’s binding strength and its activity.

Also, the alternative way is to add any polar group to the non-interacting binding portions of the molecule. These are those regions that are exposed to the external aqueous environment. Further even if the molecules are bounded to the binding site, it will remain solvated.