Arylpyrrole derivatives as anti-malarial agents- in vivo and in silico investigations

Plasmodium falciparum, has been found to be resistant to practically every antimalarial medication now on the market. Consequently, it is imperative to develop new antimalarial agents with novel mechanistic pathway to stem the tide of P. falciparum resistance. In this study, the capacity of arylpyrrole-3-carbaldehydes, DPPC(A) to DPPC(E), to target P. falciparum protein kinase 7 was tested. The molecules were optimized using DFT/B3LYP/6-31G(d) level of theory while the pharmacokinetics properties were generated. The compounds were also screened against kinase 7 protease and compared with Pyrimethamine, a standard antimalarial drug via molecular docking technique. Molecular dynamics (MD) simulation was used to investigate the lead molecule’s stability. DPPC(E) was synthesized and in vivo study was carried out. The DFT results revealed the compounds chemical reactivity sites. Pharmacokinetics evaluation showed all the compounds had good drug-like properties and were non-toxic. Molecular docking revealed that DPPC(E) had the best protein interaction with a docking score of − 7.395 kcal/mol while pyrimethamine bound with a score of − 9.511 kcal/mol. MD simulation showed the molecule was stable in the protein core (95 ns) before its exit while pyrimethamine was stable at the binding domain for the simulation period (100 ns). The parasitemia count and percentage parasitemia suppression showed that DPPC(E) significantly (P < 0.05) reduced the parasitemia level but not total clearance from the red blood cells. These results showed DPPC(E) as an ideal candidate for the discovery of new antimalarial drugs. Therefore, it could be used as a template in developing novel antimalarial agents that targets plasmodial kinases.