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

Abstract

We have carried out the design, synthesis, and evaluation of a small library of 2-aminobenzoxazole-appended coumarins as novel inhibitors of tumour-related CAs IX and XII. Substituents on C-3 and/or C-4 positions of the coumarin scaffold, and on the benzoxazole moiety, together with the length of the linker connecting both units were modified to obtain useful structure-activity relationships. CA inhibition studies revealed a good selectivity towards tumour-associated CAs IX and XII ( K i within the mid-nanomolar range in most of the cases) in comparison with CAs I, II, IV, and VII ( K i > 10 µM); CA IX was found to be slightly more sensitive towards structural changes. Docking calculations suggested that the coumarin scaffold might act as a prodrug, binding to the CAs in its hydrolysed form, which is in turn obtained due to the esterase activity of CAs. An increase of the tether length and of the substituents steric hindrance was found to be detrimental to in vitro antiproliferative activities. Incorporation of a chlorine atom on C-3 of the coumarin moiety achieved the strongest antiproliferative agent, with activities within the low micromolar range for the panel of tumour cell lines tested.

Coumarins inhibit η-class carbonic anhydrase from Plasmodium falciparum

“…Modifications leading to effective inhibitors should thus consider substitution patterns in positions 6, 7 and 8 of the coumarin. This situation was in fact observed also for the inhibition of the human CA isoforms hCA I-XIV already in the first studies in which coumarins were reported as CAIs 1 , 2 .…”

“…Comarins were discovered relatively recently to act as inhibitors of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1) 1 . Unlike all other inhibitor classes investigated at that time, surprisingly, these compounds were shown to not coordinate to the metal ion from the α-CA active sites (the human isoforms hCA I – XIV were initially investigated for their interaction with these compounds 1 , 2 ) but to bind at the entrance of the active site cavity. In addition, the coumarin lactone ring was found hydrolysed to the corresponding 2-hydroxycinnamic acids (either in cis - or trans geometry) making these compounds the first reported class of pro-drug CA inhibitors (CAIs).…”

“…In addition, the coumarin lactone ring was found hydrolysed to the corresponding 2-hydroxycinnamic acids (either in cis - or trans geometry) making these compounds the first reported class of pro-drug CA inhibitors (CAIs). Thus, a rather large number of drug design studies were performed over the last decade 2–4 using both natural products as well as synthetic coumarins as starting point, which established the fact that coumarjns are among the most effective and isoform-selective CAIs known to date 1–4 . Indeed, derivatives with selectivity for all human isoforms have been reported so far, although the largest number of studies and derivatives investigated to date were designed for targeting the transmembrane, cancer-associated isoforms hCA IX and XII, which are validated antitumor/antimetastatic drug targets 5 , 6 .…”

Squaramide-Tethered Sulfonamides and Coumarins: Synthesis, Inhibition of Tumor-Associated CAs IX and XII and Docking Simulations

“…Previously reported methodology was used [ 77 ]. For sulfonamides, deprotonated species were considered.…”

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

“…22 , 23 Recent studies have shown the role of CA inhibitors (CAIs) as a therapeutic hit for other diseases like neuropathic pain, 24 cerebral ischemia, 25 and tumor. 26 The unexpected and novel application of CAIs in synaptic transformation and attentional gating of memory is quite appreciating in the treatment of Alzheimer’s disease. 27 …”