Multitargeting approaches involving carbonic anhydrase inhibitors: hybrid drugs against a variety of disorders

Abstract

Carbonic anhydrases (CAs, EC 4.2.1.1) are enzymes involved in a multitude of diseases, and their inhibitors are in clinical use as drugs for the management of glaucoma, epilepsy, obesity, and tumours. In the last decade, multitargeting approaches have been proposed by hybridisation of CA inhibitors (CAIs) of sulphonamide, coumarin, and sulphocoumarin types with NO donors, CO donors, prostaglandin analogs, β-adrenergic blockers, non-steroidal anti-inflammatory drugs, and a variety of anticancer agents (cytotoxic drugs, kinase/telomerase inhibitors, P-gp and thioredoxin inhibitors). Many of the obtained hybrids showed enhanced efficacy compared to the parent drugs, making multitargeting an effective and innovative approach for various pharmacological applications.

2-Aminobenzoxazole-appended coumarins as potent and selective inhibitors of tumour-associated carbonic anhydrases

“…Coumarins are considered as a privileged structure in medicinal chemistry 21 , exhibiting a plethora of bioactivities 22 , such as antioxidant 23 , anti-inflammatory 24 , antimicrobial 25 , anti-Alzheimer’s 26 , 27 , or antiproliferative 28 , 29 properties. Conjugation of coumarins with a second pharmacophore is currently gaining attention to access multitarget drugs 30 . Many of such activities are the result of the inhibition of key enzymes by coumarin-containing derivatives 20 , 31–38 , either natural or synthetic; this is due to their peculiar planar structure and to the possibility of establishing strong non-covalent interactions involving the lactone moiety (hydrogen bonding, dipole-dipole) and the aromatic scaffold (π-π and cation-π interactions) 21 .…”

Targeting carbonic anhydrase IX and XII isoforms with small molecule inhibitors and monoclonal antibodies

“…These include the use of cytotoxins (monomethyl auristatin, tubulysin B, the maytansinoids, mertansine), antimalarial agents (artemisinin and dihydroartemisinin), EGFR antagonists, inhibitors of 15-lipoxygenase-cyclooxygenase 2, telomerase inhibitors, P-glycoprotein inhibitors, thioredoxin inhibitors, adenosine A2A receptor antagonists, pyrophosphatase/phosphodiesterase-3 inhibitors and others extensively reviewed by Supuran C.T. 126 , 212 …”

Discovery of 2,4-thiazolidinedione-tethered coumarins as novel selective inhibitors for carbonic anhydrase IX and XII isoforms

“…Coumarin I is a naturally-derived, privileged heterocyclic scaffold and molecules containing it show numerous biological properties such as inhibition of CK2, EGFR and PI3K-AKT-mTOR signalling. Moreover, coumarins are known to have anticoagulation, monoamine oxidase inhibition, anti-infective, antioxidant, anti-inflammatory and anticancer activities [ 14 , 18–20 ]. Coumarins are recently discovered as a novel class of h CAIs with inhibitory mechanism different from the sulfonamide-based inhibitors.…”