Extending the Inhibition Profiles of Coumarin-Based Compounds Against Human Carbonic Anhydrases: Synthesis, Biological, and In Silico Evaluation.

Kartsev Kartsev,Kazaks Kazaks,Petrou Petrou,Supuran Supuran,Leitans Leitans,Bua Bua,Frasinyuk Frasinyuk,Geronikaki Geronikaki,Tars Tars,Nocentini Nocentini,Lichitsky Lichitsky

doi:10.3390/molecules24193580

Abstract

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the fundamental reaction of CO2 hydration in all living organisms and are actively involved in the regulation of a plethora of pathological and physiological conditions. A set of new coumarin/ dihydrocoumarin derivatives was here synthesized, characterized, and tested as human CA inhibitors. Their inhibitory activity was evaluated against the cytosolic human isoforms hCA I and II and the transmembrane hCA IX and hCA XII. Two compounds showed potent inhibitory activity against hCA IX, being more active or equipotent with the reference drug acetazolamide. Computational procedures were used to investigate the binding mode of this class of compounds within the active site of hCA IX and XII that are validated as anti-tumor targets.

Highlights

Coumarins are naturally occurring compounds and their richest sources are higher plants of Rutaceae and Umbelliferae types [1]
X-ray crystallography studies were conducted, which showed that coumarins acts as prodrug - at least in human CAs being hydrolyzed to the active species 2-hydroxycinnamic acids by the CA esterase activity [33]
The binding of the coumarin active species occurs in regions of the CA active site that most significantly differ among the various human isoforms known to date, furnishing the explanation for the high isoform-selective inhibitory profile shown by such a class of compounds [33]

Summary

Introduction

Coumarins are naturally occurring compounds and their richest sources are higher plants of Rutaceae and Umbelliferae types [1]. CAs are ubiquitous metalloenzymes in all life kingdoms [8,9] They catalyze the reversible hydration of CO2 with formation of bicarbonate and protons, efficiently converting two neutral molecules in a weak base (bicarbonate) and a very strong acid (H+ ion). For this reason, in most organisms investigated so far, these enzymes are involved in pH regulation as well as several crucial metabolic pathways.

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Results

Conclusion