5-(Sulfamoyl)thien-2-yl 1,3-oxazole inhibitors of carbonic anhydrase II with hydrophilic periphery

Abstract

Hydrophilic derivatives of an earlier described series of carbonic anhydrase inhibitors have been designed, prepared and profiled against a panel of carbonic anhydrase isoforms, including the glaucoma-related hCA II. For all hydrophilic derivatives, computational prediction of intraocular permeability routes showed the predominance of conjunctival rather than corneal absorption. The potentially reactive primary or secondary amine periphery of these compounds makes them suitable candidates for bioconjugation to polymeric drug carriers. As was shown previously, the most active hCA II inhibitor is efficacious in alleviating intraocular pressure in normotensive rabbits with efficacy matching that of dorzolamide.

Keywords: Glaucoma; bioconjugation; hydrophilicity; intraocular delivery; intraocular pressure.

Graphical abstract

Figure 1.

Clinically used antiglaucoma carbonic anhydrase inhibitors.

Figure 2.

Earlier reported potent hCAII inhibitors 5(6)a–c and their modified hydrophilic thiophene analogues 7 designed and investigated in this work.

Scheme 1.

Synthesis of hydrophilic sulphonamides 7a–e investigated in this work.

Figure 3.

Binding poses of 5c (A) and 7a (B) in the hCAII active site.

Figure 4.

RMSD changes observed for the complexes ‘acetazolamide – hCA II’ (A) and ‘compound 7a – hCA II’ (B) during a 120 ns molecular dynamics simulation.

Figure 5.

Percentage change in IOP (y axis) over time (x axis) after administration of compound 7a (two independent experiments), negative control phosphate buffered saline (PBS) and positive control dorzolamide (DRZ) in albino rabbits (n = 6).