Novel sulfonamide inhibitors of CYP19A1: design, synthesis, biological assays, and in silico study

Aromatase (CYP19A1) is one of the target enzymes in breast cancer fight. Several aromatase inhibitors (AIs), either steroidal or non-steroidal AI, have been discovered in recent years, nevertheless avoiding adverse effects, and overcoming resistance mechanism still remain a challenging. As a continuation of the discovery of novel anti-breast cancer drugs, a library of sulfonamide compounds able to inhibit the aromatase enzyme by the interaction with the HEME group, was designed and synthesized. The general structure of compounds is characterized by the presence of a phenyl, or a benzyl ring linked to the sulfur atom of the sulfonamide group, while the nitrogen atom is substituted with an aromatic or non-aromatic heterocycle. The one-pot synthesis is realized by the reaction between the appropriate amine and the aryl sulfonyl chloride. All compounds were tested for the enzymatic IC₅₀, cellular IC₅₀ in MCF7 breast cancer cell line, and for the evaluation of the cell viability (MTT assay). To understand the binding mode and finding out the molecular interactions responsible for the effective binding to the active site of aromatase enzyme, computational simulations were carried out using Maestro by Schrödinger. Additionally, using QikProp, the physicochemical parameters of drug candidates were calculated in order to examine their pharmacokinetic characteristics.