Malaria, one of the most widespread and deadly infectious diseases continues to kill over 1 million people every year. This scenario is getting even worse as P. falciparum develops resistance to existing drugs. Thus, there is an imperative need for novel and more effective antimalarials. Farnesyltransferase (PFT) appears to be a promising therapeutic target to development of antimalarial drugs and many analogs of PFT inhibitors have proved active against P. falciparum. In order to shed some light on the structure-activity relationships of 192 tetrahydroquinoline and ethylenediamine derivatives that are active against P.falciparum, exploratory analysis as well as classical and hologram QSAR strategies were employed. No global QSAR could be developed for the whole dataset, instead local QSAR models were developed for 118 compounds (classical QSAR r2=0.78, q2=0.75, r2 pred= 0.77 with 2 PCs; HQSAR r2=0.82, q2=0.72, r2 pred= 0.79 with 3 PCs) and 74 compounds (r2=0.79, q2=0.74, r2 pred= 0.57 with 2PCs; r2=0.86, q2=0.77, r2 pred= 0.75 with 4 PCs) using partial least square (PLS) regression. Furthermore, the careful and integrated analysis of contribution maps and regression vector suggest that these inhibitors might have dissimilar requirements to their biological activity.