The successful synthesis of isocryptolepineanalogs with favorable yields necessitates both mono- and di-substitutions. Through a systematic structure-activity relationship (SAR) investigation, a set of indole[3,2-c] quinolones was generated. This investigation revealed significant findings: the methyl groups addition on the N11 position, various substitution moieties (F, Cl, Br, (-CH4) Me, (-OCH3) MeO, and NO2) at the C2 position, and side chain modifications of x-aminoalkylamines on C6 position. In-vitro, anti-plasmodial against the chloroquine-susceptible strain RKL-2 was examined. Notably, PN-6, identified as 11-benzoyl-2-fluoro11H-indolo[3,2-c]-quinolin-6-yl) amino)propyl)3-phenyl urea exhibited the lowest IC50 (0.46 nM/antimalarial) and the highest selectivity index. The halogenated derivative emerged as the most effective compound. The introduction of diversesubstitutions at different positions elucidated varying degrees of antiplasmodial activity. Substitutions at the N11 and C2 positions, as well as modifications to the side chains at the C6 spot, demonstrated significant impacts on the efficacy of the synthesized compounds. These findings underscore the importance of strategic molecular design in optimizing the anti-malarial potential of isocryptolepine derivatives. Within our study on novel isocriptolepine compounds, these show great promise as malaria lead candidates