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

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.

Synthesis, Biological Evaluation, and In Silico Studies of Novel Coumarin-Based 4H,5H-pyrano[3,2-c]chromenes as Potent β-Glucuronidase and Carbonic Anhydrase Inhibitors

“…The molecular docking studies are facilitated to understand the mechanism behind the selective potency and inhibition tendency of these three compounds against hCA II. Previously reported coumarin derivatives as hCA II inhibitors revealed the interaction of substituents with active site residues and non-involvement of the coumarin ring due to steric hindrance, − thus exhibiting an innovative mechanistic approach where the coumarin ring could not enter deep into the active pocket of the enzyme due to bulkiness and rigidity, which therefore could not be hydrolyzed due to the esterase activity of CA II. The attachment of the molecule at the entrance of the cavity of the enzyme blocks and deshapes the active site, so the natural substrate could not enter into the enzyme pocket.…”

“… 52 , 53 Earlier studies from the literature revealed that some of the coumarin derivatives could not access the enzyme cavity of CA due to bulkiness, which therefore could not be hydrolyzed by the esterase activity of the enzyme. 54 − 57 …”

“…Some of the first- and second-generation pharmacophores like sulfamides, sulfamates, and sulfonamides, still utilized in medical treatment as CAIs, are zinc binders exhibiting various complications. − Contrary to the above-mentioned compounds, coumarins and thiocoumarins are contrived as CAIs for selective inhibition of hCA isoforms, exploring an inhibition pathway not vulnerable to Zn 2+ (Figure S1). , Coumarin compounds are hydrolyzed by the esterase activity of CA and proposed to bind with the entrance of the active site of hCA, the region that is quite variable in various isoforms, where the interaction of coumarin substrates with amino acids leads to higher selectivity toward various isoforms. , Earlier studies from the literature revealed that some of the coumarin derivatives could not access the enzyme cavity of CA due to bulkiness, which therefore could not be hydrolyzed by the esterase activity of the enzyme. − …”

Synthesis and Kinetic Study of Novel Coumarin- Based Mutual Prodrug of 5-fluorouracil and 5-ethynyluracil

“…In the past four decades, great attention has been directed to the design and synthesis of coumarinbased prodrugs in an attempt to enhance the therapeutic efficacy of many drugs [14]. This type of prodrug is utilized for alcohol-and amine-containing compounds to improve their lipophilicity [15] and minimize their metabolic inactivation [16].…”

Recent Trends in Enzyme Inhibition and Activation in Drug Design

“…Two compounds exhibited potent inhibitory activity against hCA IX, showing better or equal potency that acetazolamide used as a reference drug. For the study of the binding mode of this class coumarins/dihydrocoumarins within the active site of hCA IX and XII computational methods were used, validating hCA IX and XII as anti-tumor targets [19].…”