Green MW/US route from lignocellulose to FDCA-based thiadiazol scaffolds: DPP-4/COX-1 inhibition and antioxidant...

The widespread use of lignocellulosic biomass has enabled the rapid conversion of lignocellulosic biomass to 2,5-dicarboxylic acid (FDCA), derived from thiadiazol/cyclamide scaffolds, using a combination of microwave/ultrasonic (MW/US) activation and depolymerization methods for the fabrication of these products. Acid-assisted MW/US depolymerization of lignocellulosic biomass generated glucose-rich liquid products for the oxidative conversion of FDCA via the use of a polyoxometalate catalyst and the generation of a bis(1,3,4-thiadiazole) intermediate by oxidation of compound (3)). The formation of intermediate (4) occurred because of the reaction of intermediate (3)) with salicylaldehyde via the Schiff-base reaction and the subsequent microwave/ultrasound (MW/US) directed cyclocondensation of intermediate (4)) with phthalic anhydride to form macrocyclic cycloamide (6)). Theoretical calculations based on density-functional theory confirmed a multi-step mechanism for the POCl₃ activated pathway of synthesis/cyclization and identified the most reactive sites, as deduced from Fukui and charge analyses. Both compounds (4)) and (6) inhibited DPP-4 (IC₅₀ = 0.304 ± 0.012 μg/mL; sitagliptin: 0.068 ± 0.003 μg/mL), and COX-1 (IC₅₀ = 6.77 ± 0.25 μg/mL; ibuprofen: 2.18 ± 0.08 μg/mL). Compound (6) showed DPPH scavenging activity (IC₅₀ = 34.54 ± 1.40 μg/mL; quercetin: 12.11 ± 0.49 μg/mL). The overall kinetic trends predicted experimentally were confirmed using docking studies and molecular dynamic analyses, both of which provided additional support for the presence of electronegative, stabilizing hydrogen bonds and electrostatic interactions at the designated target sites.