Theoretical conformational analysis, electronic structure and molecular modelling studies in dihydropteroate synthase in hibition by multisubstituted s

Theoretical conformational analysis (MNDO) has been performed for six selected 4-aminoaryl multisubstituted aryl sulphones (4'-NH2; 2',4'-Cl2; 2',4',6'-Cl3; 2'-OH, 4'-O-; 2'-Cl, 4'-O-; 2'-CH3,4'-O-) which are competitive inhibitors, with respect to the substrate 4-aminobenzoate, of the dihydropteroate synthase. These derivatives show multiple conformational energy minima mainly due to the torsional freedom of the sulphur-carbon bond (θ2) of the substituted aryl ring. The other sulphur-carbon torsional angle considered (θ1), lying on the biofunctional common moiety 4-NH2C6H4SO2, is quite rigid, with the aryl ring perpendicular to the C1-S-C1' plane (θ1=90 °). The most stable conformera for all the derivatives considered are θ1=90 ° and θ2=90 ° (butterfly conformation) and θ1=90 ° and θ2=60 °. The highly active derivatives are, in general, less flexible and the inhibitory potency of the six sulphones considered is rationalized in terms of the electronic features of their common moiety, which do not significantly change among the different conformera of the same derivative. Finally, a good matching was obtained by computer superposition between the substrate 4-NH2C6H4COO- and the biofunctional common moiety 4-NH2C6H4SO2 of the sulphones. © 1991.