Relationship between structure, toxicity and activity

30 Jan 2015 Scientists in NUS have discovered that subtle changes in the chemical structure of drugs can significantly and differentially affect compounds’ intended pharmacology and unintended toxicity.

Diclofenac, derived from the 2-phenylaminophenylacetic acid chemical scaffold, is a widely available non-steroidal anti-inflammatory drug (NSAID). On the other hand, lumiracoxib, which is chemically similar to diclofenac, is a COX-2 selective NSAID that has been withdrawn from the market due to severe adverse events. Toxicities in the liver have been associated with usage of either drug, albeit with marked difference in severity. Several studies have attributed their toxicities to the bioactivation of both drugs to reactive intermediates. However, the structural predisposition for toxicity and relationship between this toxicity and COX inhibitory activity has not been elucidated.

A team led by Prof HO Han Kiat from the Department of Pharmacy in NUS has found that subtle changes such as a single substitution of a small halogen or alkyl group lead to significant changes in the toxicity of 2-phenylaminophenylacetic acid derived analogues observed in two liver cell lines. In general, a larger substituent led to an increase in toxicity, possibly by the increased contribution to lipophilicity as determined by a QSTR (quantitative structure toxicity relationship) model. A safety index was also determined to investigate the relationship between subtle changes in structure, toxicity and activity. It was found that the improvement to selectivity of the compounds towards COX-2 decreased the activity and increased the toxicity of the compounds, resulting in lower safety indices. This study reaffirms the significant effect that any single change in substituent, however small, can perturb toxicity and pharmacological profiles. Therefore, a balanced consideration between activity and toxicity would be needed in preclinical drug development to minimize unnecessary costs downstream.

 HoHK big

Figure shows the subtle structural differences of diclofenac and lumiracoxib. Lumiracoxib has an additional methyl group (highlighted in red) and a fluorine in place of a chlorine (highlighted in green). (Image credit: HO Han Kiat)



Pang YY, Yeo WK, Loh KY, Go ML, Ho HK. “Structure–toxicity relationship and structure–activity relationship study of 2-phenylaminophenylacetic acid derived compounds”. Food and Chemical Toxicology. 71 (2014) 207.