Linker-driven modulation of cinnamoyl–chloroquinoline hybrids: Synthesis, UV irradiation effect, biological evaluation, and molecular modelling.

Abstract

A new series of cinnamoyl–chloroquinoline hybrids was synthesized to evaluate the effects of alkyl chain spacers, UV-induced geometrical isomerization, antiplasmodial activity, and computational drug-likeness. The compounds were prepared via nucleopHilic amination of 4,7-dichloroquinoline followed by conjugation with substituted cinnamoyl chlorides. Irradiation at 245 nm generated E/Z isomeric mixtures, confirmed by changes in 1 H NMR coupling patterns and UHPLC-QTOF-MS retention times, consistent with increased polarity and partial Z -isomer formation. All compounds were evaluated against Plasmodium falciparum NF54 and multidrug-resistant K1 strains. While activity against NF54 was moderate, the hybrids consistently showed improved activity relative to chloroquine against the K1 strain (IC₅₀ = 178 nM). Hybrids containing a hexane alkyl spacer exhibited the highest potency, with compounds 7o (IC₅₀ = 10 nM), 7r (IC₅₀ = 12 nM), and 7 s (IC₅₀ = 26 nM) demonstrating sub-30 nM activity. Structure–activity relationship analysis identified spacer length and aromatic substitution as key determinants of potency. Computational evaluation indicated favorable drug-like properties, with all compounds satisfying Lipinski's rule of five. Compound 7 m showed strong docking affinity and stable molecular dynamics behavior. These findings identify cinnamoyl–chloroquinoline hybrids as promising candidates for further antimalarial lead optimization. • New cinnamoyl–chloroquinoline hybrids synthesized with alkyl spacers. • UV-driven E/Z isomerization verified by NMR and UHPLC-QTOF-MS. • Hexane spacers gave strongest activity (IC₅₀ < 30 nM, K1 strain). • E/Z mixtures showed high SI (up to 3291) and favorable ADME. • Docking and MD simulations revealed stable PfLDH–ligand interactions.