Crystal structure of dihydroneopterin aldolase from associated with 8-mercaptoguanine, and development of novel S8-functionalized analogues as inhibitors: Synthesis, enzyme inhibition, toxicity and antitubercular activity.

The crystallographic structure of the FolB enzyme from (FolB), complexed with its inhibitor 8-mercaptoguanine (8-MG), was elucidated at a resolution of 1.95 Å. A novel series of S8-functionalized 8-MG derivatives were synthesised and evaluated as inhibitors of dihydroneopterin aldolase (DHNA, EC 4.1.2.25) activity of FolB. These compounds exhibited IC values in the submicromolar range. Evaluation of the activity for five compounds indicated their inhibition mode and inhibition constants. Molecular docking analyses were performed to determine the enzyme-inhibitor intermolecular interactions and ligand conformations upon complex formation. The inhibitory activities of all compounds against the H37Rv strain were evaluated. Compound exhibited a minimum inhibitory concentration in the micromolar range. Finally, Compound showed no apparent toxicity in both HepG2 and Vero cells. The findings presented herein will advance the quest for novel, specific inhibitors targeting FolB, an attractive molecular target for TB drug development.