The Hydrogen Bond Environments of 1H-Tetrazole and Tetrazolate Rings: The Structural Basis for Tetrazole–Carboxylic Acid Bioisosterism

Abstract

Bioisosterism involving replacement of a carboxylic acid substituent by 1H-tetrazole, yielding deprotonated carboxylate and tetrazolate under physiological conditions, is a well-known synthetic strategy in medicinal chemistry. To improve our overall understanding of bioisosterism, we have used this example to study the geometrical and energetic aspects of the functional group replacement. Specifically, we use crystal structure informatics and high-level ab initio calculations to study the hydrogen bond (H-bond) energy landscapes of the protonated and deprotonated bioisosteric pairs. Each pair exhibits very similar H-bond environments in crystal structures retrieved from the CSD, and the attractive energies of these H-bonds are also very similar. However, by comparison with -COOH and -COO(-), the H-bond environments around 1H-tetrazole and tetrazolate substituents extend further, by about 1.2 Å, from the core of the connected molecule. Analysis of pairs of PDB structures containing ligands which differ only in having a tetrazole or a carboxyl substituent and which are bound to the same protein indicates that the protein binding site must flex sufficiently to form strong H-bonds to either substituent. A survey of DrugBank shows a rather small number of tetrazole-containing drugs in the 'approved' and 'experimental' drug sections of that database.