Coumarin-Based Dual Inhibitors of Human Carbonic Anhydrases and Monoamine Oxidases Featuring Amino Acyl and (Pseudo)-Dipeptidyl Appendages: In Vitro and Computational Studies

Abstract

The involvement of human carbonic anhydrase (hCA) IX/XII in the pathogenesis and progression of many types of cancer is well acknowledged, and more recently human monoamine oxidases (hMAOs) A and B have been found important contributors to tumor development and aggressiveness. With a view of an enzymatic dual-blockade approach, in this investigation, new coumarin-based amino acyl and (pseudo)-dipeptidyl derivatives were synthesized and firstly evaluated in vitro for inhibitory activity and selectivity against membrane-bound and cytosolic hCAs (hCA IX/XII over hCA I/II), as well as the hMAOs, to estimate their potential as anticancer agents. De novo design of peptide-coumarin conjugates was subsequently carried out and involved the combination of the widely explored coumarin nucleus with the unique biophysical and structural properties of native or modified peptides. All compounds displayed nanomolar inhibitory activities towards membrane-anchored hCAs, whilst they were unable to block the ubiquitous CA I and II isoforms. Structural features pertinent to potent and selective CA inhibitory activity are discussed, and modeling studies were found to support the biological data. Lower potency inhibition of the hMAOs was observed, with most compounds showing preferential inhibition of hMAO-A. The binding of the most potent ligands (6 and 16) to the hydrophobic active site of hMAO-A was investigated in an attempt to explain selectivity on the molecular level. Calculated Ligand Efficiency values indicate that compound 6 has the potential to serve as a lead compound for developing innovative anticancer agents based on the dual inhibition strategy. This information may help design new coumarin-based peptide molecules with diverse bioactivities.