Synthesis, biological evaluation, molecular docking and structure-activity relationship of caffeine derivatives

Abstract A series of 8-(hetero)aryl caffeine was synthesized by C-H bond activation reaction using Pd-NHCs complexes as a catalyst. The derivatives were screened for their antioxidant, antimicrobials, and enzyme inhibitory activities. Furthermore, done their in-silico study. The 4a, 4b, 4e, 4f, 4g and 4n showed significant Total Antioxidant Capacity (TAC) of 64.03, 50.87, 70.02, 98.14, 71.81, 45.48 and 44.28 µg AAE/mg, respectively. The 4a, 4b, 4d, 4e, 6h, 4i, 4j, 4k and 4l were found active against Staphylococcus aureus at a minimum inhibitory concentration of 25, 12.5, 12.5, 12.5, 12.5, 6.25, 6.25, 12.5, 6.25 and 6.25 µg/ml, respectively. Some derivatives displayed activity against Escherichia coli, Bacillus subtilus, Klebsiella pneumonae and Pseudomonas auregenosa. A good activity was exhibited against Alternaria solani among five fungal strains. All the compounds (4a-4n) showed excellent protein kinase inhibitory activity except 4e, 4g and 4n. Additionally, derivatives showed α-Amylase enzyme inhibition potential (IC50 = 1.49 ± 0.317 to 7.44 ± 0.156 µg/ml) compared to standard Acarbose (IC50 = 4.34 ± 0.333 µg/ml). The 4b, 4d, 4j, 4m and 4n compounds displayed good α-Glucosidase inhibitory potential. Molecular modelling was done for protein kinase, α-Amylase, and α-Glucosidase enzymes. The results of these activities proved the caffeine derivatives to be bioactive.