Aromatic/ Heterocyclic Sulfonamides Containing Chromone Moieties and Their Transition Metal Complexes: Synthesis, Structural Elucidation and Evaluation of Biological Activities

Abstract

Carbonic anhydrases (CA E.C. 4.2.1.1) are zinc containing metalloenzymes found in both prokaryotes and eukaryotes where they perform important physiological functions. CA has at least 16 different isozymes many of which are important drug targets. Sulfonamides and its metal derivatives are well established inhibitors of CA. The task of developing a new class of chromone containing sulfonamide CA inhibitors was taken up in this research/thesis. Consequently cobalt (II), nickel (II) and copper (II) transition metal complexes were also synthesized and tested as inhibitors of CA. An assortment of structurally diverse aromatic/heterocyclic sulfonamides containing chromone moieties were synthesized by condensation of various substituted and un-substituted 4-oxo-4H-1-benzopyran-3-carboxaldehydes with different aminobenzenesulfonamides. Compounds L1, L4, L7 and L10 were prepared by reacting 4-oxo-4H-1-benzopyran-3-carboxaldehyde (C10H6O3) and substituted 4- oxo-4H-1-benzopyran-3-carboxaldehydes (R1R2-C10H4O3, R1 = F, Br; R2 = H, Br) with 4-aminobenzenesulfonamide (4-ABS). Compounds L2, L5, L8 and L11 were prepared by reacting above chromone-3-carboxaldehydes with 3- aminobenzenesulfonamide (3-ABS). Similarly compounds L3, L6, L9 and L12 were obtained by reaction with 2-aminobenzenesulfonamide (2-ABS). Compounds L13- L17 were prepared by reaction of 4-oxo-4H-1-benzopyran-3-carboxaldehyde and 4- oxo-6-fluoro -4H-1-benzopyran-3-carboxaldehydes with N-(heteroaryl)substituted sulfonamides. In case of reactions with 3-ABS and 4-ABS, enamine products of type and 4-[{(2-ethoxy-6-(un)substituted-4-oxo-chroman)3-ylidene}methylamino] xv benzenesulfonamides were obtained. However, on reaction with 2-ABS, a benzothiadiazine product containing chromone moiety at 3-position resulted due to cyclization. Only 4-oxo-6,8-dibromo-4H-1-benzopyran-3-carboxaldehyde proved to be the only exception giving an enamine product, 2-[{(2-ethoxy-6,8-dibromo-4-oxo- chroman)3-ylidene}methylamino]benzenesulfonamide. Stable, non electrolyte, non polymeric metal complexes were obtained in good yields by reacting Co (II), Ni (II) and Cu (II) acetates with above compounds under basic conditions. Molecular structure of all fifty three compounds (both ligands and their complexes) was ascertained by means of IR, 1H-NMR, 13C-NMR, MS and elemental (C, H, N) analysis. The metal content of the metal complexes was determined by AAS. In case where suitable crystals were available, single crystal X-ray diffraction was carried out. In view of CA inhibitory role of sulfonamides and their metal complexes, CA inhibitions activity of all the compounds and their metal complexes was evaluated against bovine cytosolic enzyme containing CA-I and CA-II. All compounds containing free sulfonamide group showed excellent CAI activity (IC50values are in the range 4.31 to 29.12 μmoles). Compounds containing substituted sulfonamide group were found to be inactive as CAIs. Among metal complexes copper complexes were most active followed by some nickel complexes; cobalt complexes were not very active as CAIs. DPPH radical scavenging activity for all the compounds was also evaluated. Only compounds L12 and L14 showed moderate activity (67 and 41 % inhibition respectively). None of the other compounds showed outstanding radical scavenging activity.