Synthesis of a new series of 3-functionalised-1-phenyl-1,2,3-triazole sulfamoylbenzamides as carbonic anhydrase I, II, IV and IX inhibitors

Abstract

The synthesis of a novel series of 3-functionalised benzenesulfonamides incorporating phenyl-1,2,3-triazole with an amide linker was achieved by using the "click-tail" approach. The new compounds, including the intermediates, were assayed as inhibitors of human carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I and II (cytosolic isoforms) and also for hCA IV and IX (transmembrane isoforms) taking acetazolamide as standard drug. Most of these compounds exhibited excellent activity against all these isoforms. hCA I was inhibited with K i s in the range of 50.8-966.8 nM, while the glaucoma associated hCA II was inhibited with K i s in the range of 6.5-760.0 nM. Isoform hCA IV was inhibited with K i s in the range of 65.3-957.5 nM, whereas the tumor associated hypoxia induced hCA IX was inhibited with K i s in the range of 30.8-815.9 nM. The structure activity relationship study for the 3-functionalised-1-phenyl-1,2,3-triazole sulfamoylbenzamides against these isoforms was also inferred from the results.

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

“…The 10 new benzoxazole-coumarin hybrids prepared herein have been evaluated in vitro as potential inhibitors of therapeutically relevant hCAs using the stopped-flow CO 2 hydration assay ( Table 1 ) using the drug acetazolamide (AAZ) as control. Two different groups of such metalloenzymes have been used: cytosolic isoforms I (off-target), II (related to glaucoma 52 ) and VII (involved in epilepsy and neuropathic pain 53 ) and membrane-bound isoforms IV (involved in rheumatoid arthritis 54 ), IX, XII (both of them overexpressed in hypoxic tumours 40 ).…”

Complexation with a Cognate Antibody Fragment Facilitates Affinity Measurements of Fluorescein-Linked Small Molecule Ligands

“…Three *M = molecular weight size marker; NR = nonreducing conditions; R = reducing conditions; size-exclusion chromatography standard peaks are obtained with bovine serum albumin (MW= 66.43 kDa) and lysozyme (MW= 14.30 kDa) [ Supporting Information, Figure S3]. different small molecule ligands, based on acetazolamide (AAZ), 4-sulfamoylbenzoic amide (SABA) and 3-sulfamoylbenzoic amide ( m -SABA), were coupled to fluorescein, in order to generate bifunctional conjugates of different affinity to CAII ( K D = 12.1 nM, 151 nM and 8.6 μM, respectively). , A diamino-PEG 2 linker was employed as spacer between the ligand and the fluorophore [Figure A]. Coating of plastic wells with a target protein of interest (e.g., CAII) should enable the capture of fluoresceinated binding molecules, followed by an antibody-based detection of the fluorescein moiety [Figure A].…”

Antibody-Inspired Affinity Measurements of Fluorescein-Linked Small Molecule Ligands

“…different small molecule ligands, based on acetazolamide (AAZ), 4sulfamoylbenzoic amide (SABA) and 3-sulfamoylbenzoic amide (m-SABA), were coupled to fluorescein, in order to generate bifunctional conjugates of different affinity to CAII (KD = 12.1 nM, 151 nM and 8.6 µM, respectively). 23,24 A diamino-PEG2 linker was employed as spacer between the ligand and the fluorophore [Figure 1A]. Coating of plastic wells with a target protein of interest (e.g., CAII) should enable the capture of fluoresceinated binding molecules, followed by an antibody-based detection of the fluorescein moiety [Figure 1A].…”