A series of new chemosensitizers (modulators) against chloroquine-resistant Plasmodium falciparum were designed and synthesized in an attempt to fabricate modulators with enhancing drug-resistant reversing efficacy and minimal side effects. Four aromatic amine ring systems-phenothiazine, iminodibenzyl, iminostilbene, and diphenylamine-were examined. Various tertiary amino groups including either noncyclic or cyclic aliphatic amines were introduced to explore the steric tolerance at the end of the side chain. The new compounds showed better drug-resistant reversing activity in chloroquine-resistant than in mefloquine-resistant cell lines and were generally more effective against chloroquine-resistant P. falciparum isolates from Southeast Asian (W2 and TM91C235) than those from South America (PC49 and RCS). Structure-activity relationship studies revealed that elongation of the alkyl side chain of the molecule retained the chemosensitizing activity, and analogues with four-carbon side chains showed superior activity. Furthermore, new modulators with phenothiazine ring exhibited the best chemosensitizing activity among the four different ring systems examined. Terminal amino function has limited steric tolerance as evidenced by the dramatic lose of the modulating activity, when the size of substituent at the amino group increases. The best new modulator synthesized in this study possesses all three optimized structural features, which consist of a phenothiazine ring and a pyrrolidinyl group joined by a four-carbon alkyl bridge. The fractional inhibitory concentration (FIC) index of the best compound is 0.21, which is superior to that of verapamil (0.51), one of the best-known multi-drug-resistant reversing agents. Some of the analogues displayed moderate intrinsic in vitro antimalarial activity against a W-2 clone of P. falciparum.