title: Inhibition of human carbonic anhydrase isozymes I, II, IX and XII with a new series of sulfonamides incorporating aroylhydrazone-, [1,2,4]triazolo[3,4-b][1,3,4]thiadiazinyl- or 2-(cyanophenylmethylene)-1,3,4-thiadiazol-3(2H)-yl moieties.
abstract: A series of benzenesulfonamides incorporating aroylhydrazone, piperidinyl, sulfone, [1,2,4]triazolo[3,4-b][1,3,4]thiadiazinyl- or 2-(cyanophenyl-methylene)-1,3,4-thiadiazol-3(2H)-yl moieties was investigated as inhibitors of four α-carbonic anhydrases (CAs, EC 4.2.1.1), the human (h) isoforms hCA I, II (cytosolic, offtarget enzymes) and hCA IX and XII (transmembrane, tumor-associated isoforms). Low nanomolar activity was observed against hCA II (KIs of 0.56-17.1 nM) with these sulfonamides, whereas the slow cytosolic isoform hCA I was less inhibited by these compounds (KIs of 86.4 nM-32.8 µM). Most of these sulfonamides significantly inhibited CA IX, with KIs in the range of 4.5-47.0 nM, although some of the derivatives incorporating bulkier bicyclic moieties, as well as 2-thienyl fragments, showed a weaker activity against this isoform (KIs in the range 50.1-553 nM). All the investigated compounds also inhibited CA XII with KIs in the range 0.85-376 nM. The best inhibitors were those incorporating bulky [1,2,4]triazolo[3,4-b][1,3,4]thiadiazinyl moieties and 1,3,4-thiadiazol-3(2H)-yl groups.
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, Salman bin Abdulaziz University , Alkharj , Saudi Arabia .
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Alafeefy
authors.forename: Hatem A
authors.initials: HA
authors.lastname: Abdel-Aziz
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.forename: Abdul-Malek S
authors.initials: AM
authors.lastname: Al-Tamimi
authors.forename: Amani S
authors.initials: AS
authors.lastname: Awaad
authors.forename: Menshawy A
authors.initials: MA
authors.lastname: Mohamed
authors.forename: Clemente
authors.initials: C
authors.lastname: Capasso
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000951:Antigens, Neoplasm / Q000737:chemistry*; D024401:Carbonic Anhydrase I / Q000737:chemistry*; D024402:Carbonic Anhydrase II / Q000737:chemistry*; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D002256:Carbonic Anhydrases / Q000737:chemistry*; D057075:Enzyme Assays; D006801:Humans; D006835:Hydrazones / Q000737:chemistry; D007700:Kinetics; D010880:Piperidines / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry*; D013450:Sulfones / Q000737:chemistry; D013830:Thiadiazoles / Q000737:chemistry
chemical_list: D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; D006835:Hydrazones; D010880:Piperidines; D011994:Recombinant Proteins; D013449:Sulfonamides; D013450:Sulfones; D013830:Thiadiazoles; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C477378:carbonic anhydrase XII
keywords: Cancer-associated isoform; carbonic anhydrase; enzyme inhibitor; sulfonamide