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.

6‐Aminocoumarin oxime‐ether/sulfonamides as selective hCA IX and XII inhibitors: Synthesis, evaluation, and molecular dynamics studies

“…[ 25 ] Agamennone et al reported coumarin‐linked amino acyl pseudo‐dipeptide derivative VI showing good activity against hCA IX and hCA XII with K i of 260.5 and 9.5 nM. [ 26 ] Arrighi et al reported coumarin‐sulfonamides VII tethered by squaramide and alkyl chains as hCA IX and XII inhibitors with K i values 19.2 and 7.23 nM, respectively. [ 27 ] In our previous work, we explored the coumarin linked with various active moieties like sulfonamides and oxime ethers through piperazine, of which compounds VIII and IX showed good inhibition against hCA IX and hCA XII with K i of 4.1 and 9.4 µM, respectively.…”

A Multitarget Approach against Neuroinflammation: Alkyl Substituted Coumarins as Inhibitors of Enzymes Involved in Neurodegeneration

“…Thus, this approach is the first to comprehensively investigate the potential neuroprotective activities of the "pleiotropic" coumarin scaffold involving not only carbonic anhydrase inhibition, after the demonstration of the dual inhibitory activity (MAOs and Cas) exerted by other substituted coumarins [55] (Figure 1).…”

Designing Next-Generation Drug-like Molecules for Medicinal Applications

“…The synthetic compounds exhibited a nanomolar inhibition efficacy. Computational studies shed light on the interesting features required for the inhibitory profiles as well as the isoform selectivity [ 16 ].…”