title: Carbonic anhydrase inhibitors: synthesis and inhibition of the human carbonic anhydrase isoforms I, II, VII, IX and XII with benzene sulfonamides incorporating 4,5,6,7-tetrabromophthalimide moiety.
abstract: A series of 4,5,6,7-tetrabromo-1,3-dioxoisoindolin-2-yl benzenesulfonamide derivatives (compounds 1-8) was synthesized by reaction of benzene sulfonamide derivatives with 4,5,6,7-tetrabromophthalic anhydride moiety. These new sulfonamides were investigated as inhibitors of the zinc metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) and more specifically against the human (h) cytosolic isoforms hCA I, II and VII and the transmembrane tumor-associated isoform hCA IX and XII. The new compounds were good hCA I inhibitors (Kis in the range of 143 to >10,000nM), but were moderately effective, as hCA II inhibitors (Kis of 47-190nM) and poor hCA VII inhibitors (Kis in the range of 54-175nM) compared to acetazolamide. The tumor-associated hCA IX was effectively inhibited with Kis ranging between 8.5 and 234nM and hCA XII with inhibition constants in the range of 6.1-197nM with high selectivity ratio. The structure-activity relationship (SAR) with this series of sulfonamides is straightforward, with the main features leading to good activity for each isoforms being established. The high sequence hCA alignment homology and molecular docking study of compounds was performed to rationalize the SAR reported over here.
authors: Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, Ranchi 835215, India. kalyansethi@gmail.com
authors: Kalyan K
authors: KK
authors: Sethi
authors: Daniella
authors: D
authors: Vullo
authors: Saurabh M
authors: SM
authors: Verma
authors: Muhammet
authors: M
authors: Tanç
authors: Fabrizio
authors: F
authors: Carta
authors: Claudiu T
authors: CT
authors: Supuran
mesh_terms: D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000737:chemistry; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008954:Models, Biological; D015394:Molecular Structure; D010797:Phthalimides / Q000737:chemistry; D020033:Protein Isoforms / Q000737:chemistry / Q000145:classification; D013329:Structure-Activity Relationship
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D010797:Phthalimides; D020033:Protein Isoforms; C056577:N-bromophthalimide; D002256:Carbonic Anhydrases
keywords: 4,5,6,7-Tetrabromo-1,3-dioxoisoindolin-2-yl benzenesulfonamide; ASN; AZM; BRZ; BZA; Benzenesulfonamide; CA; CAI; CLX; CNS; COX; DCP; DMSO; DZA; Docking; EZA; FT-IR; Fourier transform infrared; GLN; HIF; HIS; Human carbonic anhydrase inhibitors; IND; MZA; NMR; PDB; RMSD; SAR; SLP; Structure–activity relationship; THR; TLC; TPM; TRP; UV; VHL; VLX; XP; ZNS; Zn; acetazolamide; asparagine; benzolamide; brinzolamide; carbonic anhydrase; carbonic anhydrase inhibitor; celecoxib; central nervous system; cyclo-oxygenase enzyme; dibromophenamide; dimethyl sulfoxide; dorzolamide; ethoxzolamide; extra precision; glutamine; hCA; histidine; human carbonic anhydrase; hypoxia inducible factor; indisulam; mM; methazolamide; milimolar; nM; nanomolar; nuclear magnetic resonance; protein data bank; root mean square deviation; structure–activity relationship; sulpiride; thin layer chromatography; threonine; topiramate; tryptophan; ultraviolet; valdecoxib; von Hippel–Lindas protein; zinc; zonisamide