The cysteine proteases, cruzain and <i>Tbr</i>CATL (rhodesain), are therapeutic targets for Chagas disease and Human African Trypanosomiasis, respectively. Among the known inhibitors for these proteases, we have described <i>N</i><sup>4</sup>-benzyl-<i>N</i><sup>2</sup>-phenylquinazoline-2,4-diamine (compound <b>7</b> in the original publication, <b>1a</b> in this study), as a competitive cruzain inhibitor (<i>K</i><sub>i</sub> = 1.4 μM). Here, we describe the synthesis and biological evaluation of 22 analogs of <b>1a</b>, containing modifications in the quinazoline core, and in the substituents in positions 2 and 4 of this ring. The analogs demonstrate low micromolar inhibition of the target proteases and cidal activity against <i>Trypanosoma cruzi</i> with up to two log selectivity indices in counterscreens with myoblasts. Fourteen compounds were active against <i>Trypanosoma brucei</i> at low to mid micromolar concentrations. During the optimization of <b>1a</b>, structure-based design and prediction of physicochemical properties were employed to maintain potency against the enzymes while removing colloidal aggregator characteristics observed for some molecules in this series.