An anti-leishmanial compound 4',7-dihydroxyflavone elicits ROS-mediated apoptosis-like death in Leishmania parasite

The treatment for leishmaniasis is currently plagued by side effects such as toxicity and the emergence of drug resistance to the available repertoire of drugs, as well as the expense of these drugs. Considering such rising concerns, we report the anti-leishmanial activity and mechanism of a flavone compound 4',7-dihydroxyflavone (TI 4). Four flavanoids were initially screened for anti-leishmanial activity and cytotoxicity. The results showed that the compound TI 4 exhibited higher activity and selectivity index at the same time as maintaining low cytotoxicity. Preliminary microscopic studies and fluorescence-activated cell sorting analysis reported that the parasite underwent apoptosis on TI 4 treatment. Further in-depth studies revealed high reactive oxygen species (ROS) production and thiol levels in the parasites, suggesting ROS-mediated apoptosis in the parasites upon TI 4 treatment. Other apoptotic indicators such as intracellular Ca²⁺ and mitochondrial membrane potential also indicated the onset of apoptosis in the treated parasites. The mRNA expression levels signified that the redox metabolism genes were upregulated by two-fold along with the apoptotic genes. In summary, the use of TI 4 on Leishmania parasites induces ROS-mediated apoptosis; therefore, the compound has immense potential to be an anti-leishmanial drug. However, in vivo studies would be required to ascertain its safety and efficacy before we can exploit the compound against the growing leishmaniasis crisis.