| Summary: | Marine alkaloids belonging to the lamellarins family, which incorporate a 5,6-dihydro-1-phenylpyrrolo[2,1-<i>a</i>]isoquinoline (DHPPIQ) moiety, possess various biological activities, spanning from antiviral and antibiotic activities to cytotoxicity against tumor cells and the reversal of multidrug resistance. Expanding a series of previously reported imino adducts of DHPPIQ 2-carbaldehyde, novel aliphatic and aromatic Schiff bases were synthesized and evaluated herein for their cytotoxicity in five diverse tumor cell lines. Most of the newly synthesized compounds were found noncytotoxic in the low micromolar range (<30 μM). Based on a Multi-fingerprint Similarity Search aLgorithm (MuSSeL), mainly conceived for making protein drug target prediction, some DHPPIQ derivatives, especially bis-DHPPIQ Schiff bases linked by a phenylene bridge, were prioritized as potential hits addressing Alzheimer’s disease-related target proteins, such as cholinesterases (ChEs) and monoamine oxidases (MAOs). In agreement with MuSSeL predictions, homobivalent <i>para</i>-phenylene DHPPIQ Schiff base <b>14</b> exhibited a noncompetitive/mixed inhibition of human acetylcholinesterase (AChE) with <i>K</i><sub>i</sub> in the low micromolar range (4.69 μM). Interestingly, besides a certain inhibition of MAO A (50% inhibition of the cell population growth (IC<sub>50</sub>) = 12 μM), the bis-DHPPIQ <b>14</b> showed a good inhibitory activity on self-induced β-amyloid (Aβ)<sub>1–40</sub> aggregation (IC<sub>50</sub> = 13 μM), which resulted 3.5-fold stronger than the respective mono-DHPPIQ Schiff base <b>9</b>.
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