There is some variability in the functional group seen in the intermediate chain, as shown below. Esters are the most common functional group. The carbonyl must be in conjugation with the aromatic ring for activity. Reverse esters are inactive, and compounds with a methylene inserted between the carbonyl and the aromatic ring have poor activity and anticholinergic side effects. Thioesters have increased activity, but are more rapidly hydrolyzed than esters.
Amides can also be active, but their activity depends on the overall structure.
Conversion of procain to procainamide destroys anesthetic activity and reduces lipid solubility, but does increase the stability of the analogue. However, dibucaine has sufficient lipid solubility for anesthetic activity, even though it is an amide. Reverse amides are active in the lidocaine series, but the ortho positions must be substituted to reduce hydrolysis of the amide. Replacement of the ester by a ketone, ether, thioether or sulfone results in analogues with little or no activity. Modifications of the Aromatic Ring Simple esters of benzoic acid, such as benzocaine, have low but discernable activity.