In silico study, Synthesis and evaluation purine analogues as potential antimalarial agents

The challenges concerning the control of malaria remain due to the continuous emergence of drug resistant strains. Available treatments for this disease present several limitations such as lack of efficacy, toxic side effects and drug resistance. One of the most striking differences was found in the purine metabolism, because parasites are incapable of de novo purine biosynthesis in which enzyme HGPRT is central to the purine salvage pathway and whose activity is critical for the production of the nucleotides required for DNA/RNA synthesis within this protozoan parasite. Thus, new drugs are urgently needed. Herein we have designed, docked, synthesized and screened 9-alkyl purine derivatives for antimalarial activity against pfHGPRT. We have reported four compounds with promising activity against the highly artimisnin resistant P. falciparum namely: compounds 2,6-dichloro-9-(propan-2-yl)-9H-purine (1a), 9-Butyl-2,6-dichloro-9H-purine (1b), 2,6-dichloro-9-(2-methylbutyl)-9H-purine (1c), 2,6-dichloro-9-pentyl-9H-purine (1d) and binding energies to predictable antimalarial agents (-5.1, -5.3, -5.5 and -5.6 kcal/mole and rmsd 1.198, 1.238, 1.354 and 1.554 respectively). These analogs have acceptable binding interactions, Moreover, an in silico docking study revealed that P. falciparum and hypoxanthine guanine phosphoribosyltransferase enzymes could be the potential targets of those compounds. Our study identified novel, purine-based chemotypes that could be further optimized to generate potent and diversified anti-parasitic drugs against malaria.