Marine
alkaloids belonging to the lamellarins family, which incorporate a 5,6-dihydro-1-phenylpyrrolo[2,1-a]
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 para-phenylene DHPPIQ
Schiff base 14 exhibited a noncompetitive/mixed inhibition of human
acetylcholinesterase (AChE) with Ki in the low micromolar range (4.69 μM). Interestingly, besides a certain inhibition of
MAO A (50% inhibition of the cell population growth (IC50) = 12 μM), the bis-DHPPIQ 14 showed a good inhibitory activity on self-induced β-
amyloid (Aβ)1-40 aggregation (IC50 = 13 μM), which resulted 3.5-fold stronger than the respective mono-DHPPIQ
Schiff base 9.