Synthesis, extracorporeal nephrotoxicity, and 3D‐QSAR of andrographolide derivatives

Abstract Andrographolide is a traditional Chinese medicine monomer with many pharmacological activities, but has potential nephrotoxicity. Here, we aim to investigate the relationship between modification of andrographolide structure and its nephrotoxicity. Twenty‐three andrographolide derivatives were synthesized, and their structures were confirmed by 1 H‐NMR and HRMS. Nephrotoxicity of these compounds against human renal tubular epithelial (HK‐2) cells was evaluated using the MTT assay. The results indicated that most of them had significantly reduced nephrotoxicity, especially compounds III , V , and IX c , with IC 50 values of 1,985, 1,300, and 806.9 μmol/L, respectively, which were obviously superior to andrographolide (IC 50 30.60 μmol/L). However, compounds I a – I f (IC 50 values < 30 μmol/L), the 14‐OH derivatives of andrographolide, showed higher nephrotoxicity than that of andrographolide. Three‐dimensional quantitative structure‐activity relationship (3D‐QSAR) models of COMFA and COMSIA were established (COMFA: q 2 = 0.639, r 2 = 0.951; COMSIA: q 2 = 0.569, r 2 = 0.857). This model allowed proposing five new compounds with lower theoretical nephrotoxicity, which would be worthwhile to synthesize and evaluate. We believe that predicted models will help us to understand the structural modification requirements of andrographolide to reduce the nephrotoxicity, and further investigations will be needed to determine the mechanism involved in the effect of less nephrotoxic compounds.