Synthesis of xanthene derivatives, molecular docking and molecular dynamics simulations, drug similarity analysis, ADMET prediction, and assessment of carbonic anhydrase inhibitory activity

Abstract A series of xanthene derivatives ( 3 a – n ) was synthesized using microwave-assisted catalysis with trifluoroacetic acid (TFA) in an aqueous medium, achieving high yields within 10 min. The structural features of these compounds were comprehensively characterized by FT-IR, 1 H-NMR, 13 C-NMR, and mass spectrometry (MS). The inhibitory effects of the synthesized xanthene derivatives on human carbonic anhydrase isoenzymes (hCA I and hCA II) were assessed in vitro. Notably, compounds 3 c and 3 n demonstrated significant inhibition of these isoenzymes, with compound 3 c exhibiting a K i value of 3.619 µM for hCA I and compound 3 n showing a K i value of 0.178 µM for hCA II. In silico analyses further supported the strong inhibitory activity of compounds 3 c and 3 n against hCA I and hCA II. Drug-likeness and ADMET properties were evaluated according to Lipinski’s rules and computational prediction tools. Molecular docking studies indicated that both compounds formed strong interactions with their target receptors (2CAB and 1CA2) via active-site residues, including His94, His96, and His119. The binding affinities of 3 c and 3 n exceeded that of the reference inhibitor, acetazolamide (AAZ). Additionally, 100 ns molecular dynamics simulations confirmed the structural stability of the resulting complexes, as assessed by RMSD and RMSF analyses.