Caracterização da inibição da enzima di-hibroneopterina aldolase (EC 4.1.2.25) de Mycobacterium tuberculosis por compostos da classe 8-mercaptoguanina

Abstract

Dihydroneopterin aldolase (DHNA, EC 4.1.2.25) catalyzes the conversion of 7,8-dihydroneopterin (DHNP) to 6-hydroxymethyl-7,8-dihydropterin (HP) and glycolaldehyde (GA) in the folate pathway. DHNA is essential for Mycobacterium tuberculosis (Mtb) bacilli survival and represents an important molecular target for drug development, mainly because this pathway is absent in mammals. 8-mercaptoguanine and its derivatives were identified as inhibitors of DHNA and other enzymes of the folate biosynthesis pathway in Staphylococcus aureus and Escherichia coli. However, no inhibitors have been identified for DHNA from Mtb (MtDHNA). Here, a series of 19 8-mercaptoguanine derivatives S8-functionalized were synthetized and the inhibitory potential against MtDHNA was evaluated. 8 compounds showed IC50 values in the submicromolar range. The mode and inhibition constants were determined for 4 compounds that exhibited the highest enzymatic inhibitory potency, which demonstrated a non-competitive or competitive inhibition profile for DHNP. Further, molecular docking analyses were performed to suggest enzyme-inhibitor interactions and ligand conformations. Additionally, the compounds were evaluated for the potential to inhibit the growth of M. tuberculosis H37Rv, and the compounds presented no activity against Mtb cells.