Antiplasmodial activity of alkoxy-substituted 3’,4’-dihydro-2’H-spiro[indoline-3,1’-isoquinolin]-2-ones: effect of conformational restriction and positional isomerism

Being a major cause of infant mortality in sub-Saharan African countries, and with the emergence of resistance to some of the frontline treatments like artemisinin combination therapies, there is a need for the development of new medications against malaria that target previously unexplored metabolic pathways. An example is the Plasmodium falciparum Na ⁺ -ATPase, which acts by regulating the outflow of Na ⁺ ions from parasite cells. Compounds that inhibit this enzyme would lead to an increase in the Na ⁺ ion concentration in the parasite cells, thus killing them. Based on the observed activities of analogues of 3’,4’-dihydro-2’ H -spiro[indoline-3,1’-isoquinolin]-2-one (DSIIQ, 1 ), (±)-moxiquindole ( 2 ) and (±)-homoquindole ( 3 ), with in vivo antimalarial activities and known to inhibit P. falciparum Na ⁺ -ATPase, we have designed and synthesized 20 spirooxindoles to investigate the structural determinants behind the inhibition of P. falciparum Na ⁺ -ATPase and the antiplasmodial activity of the synthesized compounds. It was observed that 2 of the analogues were weakly active while the rest were inactive. Based on the similarity of the synthesized compounds with the previously described analogues that had shown P. falciparum Na ⁺ -ATPase inhibition, we attempted an explanation for the absence of antimalarial activities in these compounds by molecular modeling studies followed by binding free energy calculation towards the target protein by using the molecular mechanics Generalized Born solvation area (MM-GBSA) approach towards the homology model of both the wild type and the mutant proteins in addition to the decomposition of the protein-ligand interaction energies amongst the binding site amino acid residues. These studies were then used to suggest structural modifications that could lead to the improvement of the antimalarial activities of the spiro compounds as well as their P. falciparum Na ⁺ -ATPase inhibitory profiles.