Synthesis and molecular docking of N,N'-disubstituted thiourea derivatives as novel aromatase inhibitors.

A three series of thioureas, monothiourea type I (4a-g), 1,4-bisthiourea type II (5a-h) and 1,3-bisthiourea type III (6a-h) were synthesized. Their aromatase inhibitory activities have been evaluated. Interestingly, eight thiourea derivatives (4e, 5f-h, 6d, 6f-h) exhibited the aromatase inhibitory activities with IC range of 0.6-10.2 μM. The meta-bisthiourea bearing 4-NO group (6f) and 3,5-diCF groups (6h) were shown to be the most potent compounds with sub-micromolar IC values of 0.8 and 0.6 μM, respectively. Molecular docking also revealed that one of the thiourea moieties of these two compounds could mimic steroidal backbone of the natural androstenedione (ASD) via hydrophobic interactions with enzyme residues (Val370, Leu477, Thr310, and Phe221 for 6f, Val370, Leu477, Ser478, and Ile133 for 6h). This is the first time that the bisthioureas have been reported for their potential to be developed as aromatase inhibitors, in which the 4-NO and 3,5-diCF analogs have been highlighted as promising candidates.