Brian W. Clare

Carbonic anhydrase inhibitors – Part 57: Quantum chemical QSAR of a group of 1,3,4-thiadiazole- and 1,3,4-thiadiazoline disulfonamides with carbonic anhydrase inhibitory properties

Quantum chemical QSAR expressions for 20 1,3,4-thiadiazole disulfonamide and 20 1,3,4-thiadiazoline disulfonamide inhibitors of carbonic anhydrase, for the isozymes CA I, CA II and CA IV have been developed on the basis of AM1 calculations. As in many previous studies, charges on the atoms of the sulfonamide moiety are of central importance, as is also the electric field in the neighborhood of the primary sulfonamide group. Also as in previous studies, the polarizability of the molecule is implicated in an anisotropic manner. A new feature is correlation with the solvation energy of the molecule, calculated by the COSMO continuum model.

Iron chelators of the pyridoxal isonicotinoyl hydrazone class Part II. Formation constants with iron(III) and iron(II)

Formation constants for the iron(III) complexes of the orally effective iron chelator pyridoxal isonicotinoyl hydrazone (PIH) and three analogues: pyridoxal benzoyl hydrazone (PBH), 3-hydroxy- isonicotinaldehyde isonicotinoyl hydrazone (IIH) and salicylaldehyde isonicotinoyl hydrazone (SIH), have been determined by a combination of spectrophotometry and potentiometry. All four ligands bind iron(III) strongly giving, at physiological pH 7.4, values of pM (−log[uncomplexed metal]) between 27.7 and 50, comparable to or greater than those for transferrin (25.6) and desferrioxamine B (28.6). The complexation of Fe(II) by PIH has also been studied and has been found to be appreciable but very much weaker than that for Fe(III).

Carbonic anhydrase inhibitors. Part 61. Quantum chemical QSAR of a group of benzenedisulfonamides

The synthesis of a large group of benzenesulfonamides containing both a primary and secondary sulfonamide moiety is described. These compounds are powerful inhibitors of several isozymes of the enzyme carbonic anhydrase. Separate QSARs are given for inhibition of three of these isozymes, using descriptors mainly derived from molecular orbital calculations by the semiempirical AM1 method. Activity was found to depend on electrostatic potential-based charges on the atoms of both sulfonamide groups, HOMO and LUMO energies, dipole moments, and lipophilicities. These results are compared with those from other studies.

Carbonic anhydrase inhibitors. Part 24. A quantitative structure-activity relationship study of positively charged sulfonamide inhibitors

Summary A quantitative structure-activity relationship (QSAR) study is presented for 28 carbonic anhydrase inhibitors (CAIs), derivatives of tri-, tetra- and penta-substituted 1-(2-sulfonamido-1,3,4-thiadiazol-5-yl)pyridinium perchlorates. Several of these derivatives are new compounds and their synthesis and properties are also reported. The conclusion of the study is that activity is greatly modulated by electronic effects on the pyridinium ring. The most significant effects were enhancement of activity with increased positive charge on this ring, weakening of activity with increasing HOMO energy, and a dependence on anisotropic polarizability which may be attributable to London forces.

Iron chelators of the pyridoxal isonicotinoyl hydrazone class Part I. Ionisation characteristics of the ligands and their relevance to biological properties

The orally effective iron chelator, pyridoxal isonicotinoyl hydrazone (PIH), and five analogues, pyridoxal benzoyl hydrazone (PBH), pyridoxal p-methoxybenzoyl hydrazone ((PpMBH), pyridoxal m-fluorobenzoyl hydrazone (PmFBH), 3-hydroxy- isonicotinaldehyde isonicotinoyl hydrazone (IIH) and salicylaldehyde isonicotinoyl hydrazone (SIH) were synthesised and characterised and their acid dissociation constants measured by glass electrode potentiometry and UV—Vis spectrophotometry. Analysis of the data showed that at physiological pH all of the ligands are predominantly (av. 80%) in the form of the neutral molecule, allowing passage through cell membranes and access to intracellular iron pools. The results are discussed in the context of the development of an orally effective iron chelator for clinical use.

An analysis of the 63 possible isomers of C60H36 containing a three-fold axis. A new structure for C60H20

Abstract The structures and stabilities of all 63 isomers of C60H36, in which pairs of hydrogen atoms occupy the hex-hex edges of the truncated icosahedron and in which there is at least one three-fold axis, have been calculated. The two most stable structures, of Tand Dad symmetry, are based on C18H18 crowns and have been described previously. A statistical analysis of the heats of formation as a function of the 12 types of polyhedral face which may be present in each structure shows that C6H4 (or C6 which are equivalent in this case), 1,2,3-CA, 1,2-C5H2 and C5H rings are particularly stabilising, whereas C6H6 and C5H5 rings are particularly destabilising. Extension of this analysis shows enhanced stability is achieved by the edge sharing of C6 and 1,2,3-C5H3 rings. These indications of stabilising features have led to postulation of structures of other C60Hn molecules. One of these, a D5d belt structure of C60H20, is slightly more stable than any found previously.

Carbonic anhydrase inhibitors. Part 47 : Quantum chemical quantitative structure-activity relationships for a group of sulfanilamide Schiff base inhibitors of carbonic anhydrase

A series of sulfanilamide Schiff base inhibitors of CA I and CA II have been studied by the semi-empirical AM1 method. The charges on the atoms of the sulfonamide group, and the dipole moment, have been calculated by four methods: a standard vacuum calculation, a solution calculation by the COSMO method, a solution calculation with, in addition, the charges and dipole moments calculated by fitting to the calculated electrostatic potential, and a calculation by the older CNDO method. The data were subjected to a classical multiple regression analysis with care to avoid the possibility of chance correlation or collinearity. The ACE technique was also used to allow for nonlinearity. A number of statistically significant equations were derived, which were mostly consistent with previous studies. While the ESP-based charges gave the best equations, the improvement was not sufficient to convincingly exclude the other methods. This is the first study which evidenced by means of QSAR calculations isozyme-specific features of the two isozymes CA I and CA II, in their interaction with sulfonamide inhibitors.

Carbonic anhydrase inhibitors. Part 41. Quantitative structure-activity correlations involving kinetic rate constants of 20 sulfonamide inhibitors from a non-congeneric series

A quantitative structure-activity relationship study is presented for 20 sulfonamide inhibitors of carbonic anhydrase. These drugs do not form a classical congeneric series, in that the only common factor is the sulfonamide group, which is attached to a variety of substituted aromatic and hetero-aromatic nuclei. The important factors were local factors such as Mulliken charge on atoms of the sulfonamide group, and global factors such as the size and shape of the molecule, its calculated frontier orbital energies, and its lipophilicity. Good correlations were obtained with the equilibrium constant and the kinetic association rate constant, but not with the kinetic dissociation rate constant.

Structures and Stabilities of hydrofullerenes. Completion of Crown Structures at C60H18 and C60H24.

Abstract The calculation of the stabilities of different isomers of C60Hn has been extended from n = 12 to n = 24. Each structure in a first series of molecules was obtained by addition of a pair of hydrogen atoms onto the most stable structure for C60Hn-2. This series culminates in C60H24, consisting of a crown composed of 18 linked CH groups plus three CH-CH groups remaining from the original C60H12 structure. A second series of structures was similarly obtained based on C60H18, in which all hydrogen atoms are part of the C18H[in18 crown. The most stable molecules are C60H12 (first series) and C60H22 (second series).

Structures and stabilities of hydrofullerenes C60Hn

Abstract The stabilities of the different isomers of C60Hn have been calculated using the AM1 hamiltonian and the program mopac 6.0 . The most stable isomer of C60H2 has the two CH groups forming an edge between two hexagonal faces (the hex-hex edges) of the truncated icosahedral structure of C60. Successive pairs of hydrogen atoms add to successive hex-hex edges, the centres of which are arranged in an octahedral manner about the truncated icosahedron.