Synthesis of Parthenin Analogues via Palladium-Catalyzed Heck Coupling Reaction, Their Toxicity Analysis, and In Silico Molecular Docking Studies

Parthenin (1) is the phytotoxin present in abundantly available Parthenium hysterophorus L., which is a highly invasive species in many countries. Various Heck analogues of parthenin were prepared by reaction with aryl halides. This method tolerates the wide functionalities present in the aryl iodides, including halides, methyl, trifluoromethyl, hydroxy, methoxy, cyano, carboxylic acid, nitro, and amino groups. Good yields (54–90%) were observed for all the Heck products (3a-3r) of parthenin. All the compounds were evaluated for drug-likeness, ADME attributes, and toxicity assessment, which revealed that only three derivatives (3e, 3f, and 3 l, containing -F, -Cl, and -CN functional groups, respectively, on the substituted aryl ring) met all standards, including Lipinski’s rule & toxicity evaluation. In contrast, the parent compound 1 satisfied only Lipinski’s rule. ADME and toxicity predictions were performed through ADMETlab 3.0 and ProTox, while molecular docking with receptor proteins was conducted using the CB-Dock 2 tool. Molecular docking studies of selected analogues, viz. 3e, 3f, and 3 l against top receptor proteins, namely AP-1 and Cox-2 (−7.4 to −9.9 kcal/mol), found comparable to the reference drug dexamethasone (−7.9 to −10 kcal/mol). Due to their strong binding affinity toward the targeted proteins, the synthesized analogues may serve as promising candidates for the development of anti-diabetic, anti-inflammatory, and antioxidant agents, as they showed noteworthy interaction with the key receptor proteins involved in these pathways.