Synthesis and biological activities of curcumin-pyrrole hybrids

Natural plant-derived compounds are widely used as therapeutics in various human pathophysiological disorders. Among them, curcumin has attracted significant interest in medicinal chemistry due to its extensive biological properties, including antioxidant, anti-inflammatory, antidiabetic, anticancer, antimicrobial, and neuroprotective activities. While the phenolic hydroxyl groups are essential for its antioxidant profile, the central β-diketone moiety significantly limits its therapeutic application due to poor bioavailability and rapid metabolism. Although several attempts to mask this group with heterocyclic rings are described in the literature, the integration of a pyrrole scaffold into the curcumin skeleton remains largely unexplored. Herein, we report an unprecedented synthetic route to a novel series of curcumin-pyrrole hybrids. This study presents the in silico drug-likeness, molecular modelling and molecular dynamics (MD) results, alongside the biological evaluation of these newly synthesized entities as inhibitors of lipoxygenase (LOX) and lipid peroxidation. Curcumin was found earlier to present 38% LOX inhibition and 78% lipid peroxidation at 100 μM. The hybridization strategy offered interesting results, identifying compound 3a as a potent inhibitor of lipid peroxidation and lipoxygenase (2.78 μM and 63%), while 3c emerged as a promising lead compound for further structural modifications (1.98 μM LOX inhibition). Hybrids 3k and 3x are also potent LOX inhibitors (3.14 μM and 3.28 μM). In general, the tested curcumin hybrids present high anti-lipid peroxidation activity (59.6-100%) with the exception of 3c (49%). All compounds were characterized as drug-like according to the MDDR-like criterion, and the in silico ADMET properties of 3a and 3c further support their potential as candidates for drug development. From the MD analysis compounds 3a and 3n were found to follow similar pattern. Although, they are not found to be equipotent. These findings open a new chemical space in curcumin-based drug design, providing a previously unreported class of stable and bioactive derivatives.