THEORETICAL-ANALYSIS OF THE STRUCTURAL AND CHEMICAL-REACTIVITY PROPERTIES OF THE SCHISTOSOMICIDAL DRUG NIRIDAZOLE

A theoretical quantum mechanical analysis of the structural, conformat ional and reactivity properties of the schistosomicidal drug niridazol e is presented. The computations are carried out in the CNDO/2 approxi mation including full molecular geometry optimization and modellizatio n of the solvent effect. The change in molecular properties when the m olecule approaches a macromolecular receptor is simulated with decreas ing values for the dielectric constant of the medium. In addition, the reactivity properties of niridazole are analyzed within the frontier orbital approximation. The structural analysis of the optimized geomet ries reveals a planar structure for the nitro group and the thiazole r ing whereas the imidazolidinone ring is found to be non planar. The co nformational analysis shows that the flexibility of the molecule, meas ured by the barriers to rotation of the imidazolidinone ring against t he thiazole ring, increases greatly when the molecule approaches to a macromolecular receptor, Our reactivity results are in agreement with the experimental data and they support the hypothesis that the metabol ic activation of niridazole in the schistosome involves a nucleophilic attack, The nitro group and some selected positions on the thiazole r ing are the preferred points for this attack.