In this study, maintaining the already explored R1, R2 and R3 substituents in structure 4 (Figure 1), we focused on the evaluation of possible replacements of the electrophilic aldehyde group in the C2 position, synthesizing and screening in vitro for their cytotoxicity in RD, HCT116, HeLa and A549 tumor cells, inhibition of MDR efflux pumps (P-gp, MRP1) and ADME-related physicochemical properties (e.g., water solubility, lipophilicity) of a number of 1-Ph-DHPIQ derivatives bearing C2 carboxylic groups (COOH, COOEt), nitrile (CN) and a morpholinomethyl moiety. This evidence concerns the gene PGP and neoplasm.