Synthesis of Some New Xanthine Derivatives and Evaluation of DPP IV Inhibitory Activities.

Dipeptidyl peptidase IV (DPP IV) inhibition prolongs incretin activity and represents an established therapeutic strategy for the management of type 2 diabetes mellitus. To investigate the underexplored combination of benzyl groups at the N7 position and a piperazine-linked arylthiazole moiety at the C8 position of the xanthine scaffold, 15 novel compounds (6a-6o) were synthesised. The synthetic route involved bromination at the C8 position of theophylline, introduction of benzyl groups at the N7 position, replacement of the bromine atom at the C8 position with piperazine, and subsequent cyclocondensation with phenacyl thiocyanate derivatives. All final compounds were characterised by 1H and 13C NMR spectroscopy, high-resolution accurate-mass mass spectrometry, and analytical HPLC. All derivatives inhibited DPP IV in the low-nanomolar range, with compounds 6c and 6b showing the highest activities, with IC50 values of 3.95 ± 0.53 and 4.04 ± 0.65 nM, respectively. NIH3T3 cytotoxicity IC50 values ranged from 28.52 to 397.63 µM, indicating substantial preliminary concentration margins relative to DPP IV inhibition. Molecular docking, 100 ns molecular dynamics simulations, interaction-fingerprint analyses and trajectory-based MM/PBSA calculations supported persistent interactions with key DPP IV active-site residues. These results identify the synthesised derivatives, particularly 6b and 6c, as promising lead structures for further optimisation.