Human African Trypanosomiasis (HAT) and Leishmaniasis are protozoal parasitic infections. Designated neglected tropical diseases and global in their impact, these diseases afflict the poorest people in the world. Treatments have remained essentially unchanged for decades and have poor efficacy and questionable safety profiles. In the first study, seventeen novel 2-[2-acylamidoethyl]-6(phenyl)pyridine analogues were designed using a ‘hit to lead’ strategy, synthesized and submitted for evaluation in vitro against Trypanosoma brucei rhodesiense (T. b. r.) for potential treatment against second stage HAT. Eight compounds gave T. b. r. IC₅₀ values of 100nM or less; the best three compounds exhibited values of 64 nM, 12 nM, and 9 nM. In the second study, four novel N-(4-(5-(4-((5-(1H-azole-1-yl)pentyl)oxy)phenyl)furan-2-yl)phenyl) picolinimidamide hydrochloride hybrid analogues were designed using a molecular hybridization strategy for dual targeting, synthesized and submitted for evaluation in vitro against Leishmania. Four compounds exhibited IC₅₀ values in the low micromolar range.