Dithiocarbamate fungicides suppress aromatase activity in human and rat aromatase activity depending on structures: 3D-QSAR analysis and molecular simulation.

Dithiocarbamate fungicides have been widely used in agricultural practices due to their effective control of fungal diseases, thereby contributing to global food security and agricultural productivity. In this study, the inhibitory potency of eight compounds on human and rat aromatase (CYP19A1) activity was evaluated. The results revealed that zineb exhibited the highest inhibitory potency on human CYP19A1 (IC₅₀, 2.79 μM). Maneb (IC₅₀, 3.09 μM), thiram (IC₅₀, 4.76 μM), and ferbam (IC₅₀, 6.04 μM) also demonstrated potent inhibition on human CYP19A1. For the rat CYP19A1, disulfiram (IC₅₀, 1.90 μM) displayed the strongest inhibition followed by maneb (2.16 μM), zineb (2.54 μM), and thiram (6.99 μM). These dithiocarbamates acted as mixed/non-competitive inhibitors of human and rat CYP19A1. Dithiothreitol (DTT), a reducing agent, partially rescued thiram-mediated inhibition when incubated at the same. Moreover, positive correlations were observed between log P, topological polar surface area, molecular weight, and heavy atoms and IC₅₀ values. 3D-QSAR analysis revealed the hydrogen bond acceptor and donor play critical roles in the binding of dithiocarbamates to human CYP19A1. In silico analysis showed that dithiocarbamates bind to the haem binding site, containing Cys437 residues. In conclusion, some dithiocarbamates potently inhibit human and rat CYP19A1 via interacting with haem-binding Cys437 residues.