ABSTRACT
A novel series of thiosemicarbazide-substituted coumarins was synthesized and the inhibitory effects against four physiologically relevant carbonic anhydrase isoforms I, II, IX and XII showed selective activities on the tumor-associated IX and XII isozymes. Molecular modeling studies on selected compounds 14a and 22a were performed. The binding modes of such compounds were determined assuming their enzymatically active structures (i.e., cinnamic acid) in the thermodynamically favored, and not previously explored, E geometry. Molecular modelling suggests multiple interactions within the enzymatic cavity and may explain the high potency and selectivity reported for the hCAs IX and XII.
Subject(s)
Carbonic Anhydrases , Neoplasms , Antigens, Neoplasm/metabolism , Carbonic Anhydrase I , Carbonic Anhydrase IX/chemistry , Carbonic Anhydrase Inhibitors/chemistry , Carbonic Anhydrase Inhibitors/pharmacology , Carbonic Anhydrases/chemistry , Coumarins/chemistry , Coumarins/pharmacology , Humans , Molecular Structure , Neoplasms/drug therapy , Semicarbazides , Structure-Activity RelationshipABSTRACT
We report for the first time a small series of compounds endowed in vitro with inhibitory properties for the human (h) expressed Carbonic Anhydrase (CAs, E.C. 4.2.1.1) enzymes of physiological interest (i.e. I, II, VA, IX and XII) and bearing the pyrazolo[1,5-a]pyrimidine (PP) scaffold at the tail section. Among the series reported, 1a-3a, 7a, 8a, 1b and 2b resulted effective ligands and with good selectivities for the hCAs II, IX or XII. In consideration of the nearly matching KI values of 7a for both the hCA II and IX (i.e. 26.4 and 23.0 nM respectively) we explored its binding mode within the CA IX mimic isoform by means of X-ray crystal experiments on the corresponding adduct.
Subject(s)
Carbonic Anhydrase Inhibitors/chemistry , Pyrazoles/chemistry , Pyrimidines/chemistry , Sulfonamides/chemistry , Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrase Inhibitors/metabolism , Carbonic Anhydrases/chemistry , Carbonic Anhydrases/metabolism , Catalytic Domain , Crystallography, X-Ray , Humans , Molecular Structure , Protein Binding , Pyrazoles/chemical synthesis , Pyrazoles/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/metabolismABSTRACT
A series of some 4-(aza substituted) methylene substituted dihydroxy coumarines were evaluated for their antioxidant and antielastase activities. Different in vitro methodologies such as total reducing power, 1,1-diphenyl-2-picryl-hydrazil (DPPH·) free radical scavenging, ABTS radical scavenging activity were used as antioxidant activity. All the tested compounds exhibited potent free radical scavenging ability and antielastase activites.