Biotransformation of hydroxychloroquine to evaluate the cytotoxicity of its metabolites and mimic mammalian metabolism

Hydroxychloroquine (HCQ) displays attractive anti-inflammatory and antiviral effects. Because of that, such a drug made part of some clinical trials for combating Sars-CoV-2 during the COVID-19 pandemic. The present study aimed to conduct the biotransformation of HCQ by filamentous fungi reported as microbial models of mammalian drug metabolism to evaluate its cytotoxic after metabolization. Cunninghamella echinulata var. elegans ATCC 8688a could efficiently biotransform HCQ into one main metabolite identified as the new 4-(1,2,3,4-tetrahydroquinolin-4-ylamino)pentan-1-ol (HCQ-M). The microbial transformation occurred through N-dealkylation, 7-chloro-elimination, and reduction of the two conjugated double-bond from the quinoline system of HCQ. The cytotoxic profiles of HCQ and its metabolite were evaluated using CCD-1059Sk cells (human fibroblasts) through sulforhodamine B, trypan blue, and Live/Dead assays. Both HCQ and HCQ-M displayed cytotoxic activities in human fibroblasts, but HCQ-M was significantly more toxic than HCQ. The reported findings should be considered for further clinical studies of HCQ and will be important for guidance in achieving new derivatives from it.