In a reexamination of some data on the inhibition of carbonic anhydrase (CA) isozymes I and II by some phenyl and pyridyl substituted sulfanilamide Schiff's bases we have found that activity can better be explained by considering the directions of the nodes in pi-like near frontier orbitals in the molecules. The near-frontier orbitals involved are those that are analogous to the degenerate pairs of HOMO and LUMO orbitals of benzene. This effect seems common in compounds which contain variously substituted benzene rings and is probably critical to understanding the activity of any aromatic molecule which is bound to its receptor by pi-pi charge transfer interactions.