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.

Applications of Nuclear Magnetic Resonance Spectroscopy to Traditional Chinese Medicine

“…Andrographolide is a TCM monomer with a variety of pharmacological activities, but it has a certain degree of nephrotoxicity. Gu et al 61 accurately confirmed the structure, activity and the degree of nephrotoxicity of the 23 andrographolide derivatives with 1 H-NMR, HRMS, and MTT assay. Among them, compounds III, V, and IXc showed a significant reduction in nephrotoxicity and, ultimately, 5 new compounds were designed and their biological activities were predicted.…”

Andrographolide, a natural anti-inflammatory agent: An Update

“…Mitochondria are the main targets of ASB-induced nephrotoxicity ( Xing et al, 2015 ). A study that chemically altered the structure of andrographolide to construct new andrographolide derivatives showed that most andrographolide derivatives were less nephrotoxic to HK-2 cells than andrographolide ( Gu et al, 2021 ). In terms of reproductive toxicity, studies have shown that Andrographis paniculata has no dose-dependent effect on the reproductive toxicity of male Wistar rats, and the sperm quality and reproductive function of rats are not affected when the maximum dose is 1,000 mg/kg/day; at the same time, a phase I clinical study also confirmed that taking different doses of Andrographis paniculata had no significant effect on human fertility parameters ( Allan et al, 2009 ).…”

Application of Machine Learning Methods to Predict the Air Half-Lives of Persistent Organic Pollutants

“…QSAR studies have demonstrated several characteristics such as comprehensiveness, theoretical basis, intelligence, programmability, and practicality [8][9][10]. Therefore, they are considered cost-effective tools for preventing human health and environmental safety hazards caused by toxic substances [11][12][13]. Molecular fingerprint QSAR (MF-QSAR) is simpler and more efficient approach to QSAR modeling, where molecular fingerprints encode the molecular features of compounds as binary vectors, with the positions and values of the vectors representing the structural information of the compounds.…”