Hydroxyethylamine Based Phthalimides as New Class of Plasmepsin Hits: Design, Synthesis and Antimalarial Evaluation

Abstract

A novel class of phthalimides functionalized with privileged scaffolds was designed, synthesized and evaluated as potential inhibitors of plasmepsin 2 (Ki: 0.99 ± 0.1 μM for 6u) and plasmepsin 4 (Ki: 3.3 ± 0.3 μM for 6t), enzymes found in the digestive vacuole of the plasmodium parasite and considered as crucial drug targets. Three compounds were identified as potential candidates for further development. The listed compounds were also assayed for their antimalarial efficacy against chloroquine (CQ) sensitive strain (3D7) of Plasmodium falciparum. Assay of twenty seven hydroxyethylamine derivatives revealed four (5e, 6j, 6o and 6s) as strongly active, which were further evaluated against CQ resistant strain (7GB) of P. falciparum. Compound 5e possessing the piperidinopiperidine moiety exhibited promising antimalarial activity with an IC50 of 1.16 ± 0.04 μM. Further, compounds 5e, 6j, 6o and 6s exhibited low cytotoxic effect on MCF-7 cell line. Compound 6s possessing C 2 symmetry was identified as the least cytotoxic with significant antimalarial activity (IC50: 1.30 ± 0.03 μM). The combined presence of hydroxyethylamine and cyclic amines (piperazines and piperidines) was observed as crucial for the activity. The current studies suggest that hydroxyethylamine based molecules act as potent antimalarial agent and may be helpful in drug development.

Microwave‐Assisted Highly Efficient Route to 4‐Aminoquinoline‐Phthalimide Conjugates: Synthesis and Anti‐Tubercular Evaluation

“…Thalidomide was the most distinguished member of this class of compounds, developed originally as sedative but was later withdrawn for human use because of its teratogenicity. Phthalimides have been recently repurposed for erythema nodosum leprosum, multiple myeloma (MM), and myelodyspasia, while bis‐hydroxyethylamine based phthalimide has shown antimalarial potential against chloroquine‐resistant strain of P. falciparum . Phthalimide and its derivatives have also shown promising potential as anti‐tubercular agents .…”

Synergistic blending of high-valued heterocycles inhibits growth of Plasmodium falciparum in culture and P. berghei infection in mouse model

“…Phthalimide (Pht) skeleton is an imperative nucleus for various bioactive molecules 14 – 17 , starting material for alkaloids, pharmacophores 18 , 19 and antimalarials 20 . We also recently reported Pht analogues tailored with cyclic amines as moderate inhibitors of P. falciparum 21 , 22 . The presence of additional high-valued bioactive heterocycles may intensify the efficacy of the Phts.…”

Multistage antiplasmodial activity of hydroxyethylamine compounds, in vitro and in vivo evaluations

“…The compounds ( Fig. 1) possess HEA scaffold 23,25 that is crucial to achieving the potent antiplasmodial activity. 24 Both compounds 1 and 2 displayed IC 50 values of 1.16 mM and 1.25 mM, respectively against P. falciparum (3D7) strain and $3 mM against P. falciparum (7GB) strain aer 48 h of treatment as reported earlier.…”