Novel sugar-conjugated Knoevenagel condensate curcumin derivatives as promising bioactive hybrids with antimalarial potential.

Malaria research is facing a concerning challenge due to the continuously increasing annual reported number of cases and deaths, along with the Plasmodium parasite's resistance against current first-line treatments, which emphasise the need for novel effective antimalarials to combat this resistance. While curcumin, a polyphenolic compound from Curcuma longa, has previously demonstrated in vivo efficacy in mediating malaria infections through glycogen synthase kinase-3 beta (GSK-3β) inhibition, the potential was suboptimal due to its bioavailability constraints. Building on this, novel sugar-conjugated Knoevenagel condensate curcumin derivatives were successfully synthesised, through O-glycosylation with galactose, glucose, and mannose, and evaluated for their antimalarial potential. Assessments revealed the influence of sugar moieties on bioactivity. Generally, sugar-conjugated compounds, which demonstrated enhanced aqueous solubility, showed enhancements in absorption, distribution, metabolism, excretion and toxicity (ADMET) profiles and density functional theory (DFT) results, along with better cytotoxicity profiles and favourable haemin (HMN) binding. Notably, the acetylated glucosyl derivative 2a-Glc exhibited significantly strong GSK-3β inhibition (-10.48 kcal mol-1) and evidently the most potent antiplasmodial compound with an EC50 of 1.53 ± 0.10 µM (3D7). Overall, the study demonstrated bioactivity improvements attributable to curcumin's structural derivatisation, with the acetylated glycoside 2a-Glc showing the greatest antimalarial potential based on in silico profiles, Plasmodium falciparum lactate dehydrogenase (pLDH) assays, HMN binding, and GSK-3β inhibition. This strategy highlighted refined synthesis strategies, in silico modelling, and biological evaluations in drug discovery, offering valuable insights into the benefits of exploring curcumin derivatives and glycosylation for developing promising bioactive compounds with antimalarial efficacy.