Molecular structure of 2-Amino-5-(1-methyl-5-nitro-2-imidazolyl)-1,3,4-thiadiazol (Megazol) and related compounds: A concerted study using X-ray crystallography,molecular mechanics,and semiempirical methods

A structural study of three nitroimidazoles was carried out using molecular mechanics, semiempirical methods, and X-ray crystallography. Structural features which might account for the high efficiency of1 (Megazol) as an antiparasitic drug and its opposite, the inactivity of its regiomers2 and3 were examined, i.e., coplanarity of the two rings, preferred conformations, and rotational barriers around the pivot bond between the two rings. For the three compounds an antiperiplanar conformation is preferred for the N(CH₃) and C-S bonds. For compounds1 and3, the rings are coplanar, with2 being somewhat twisted. The geometry obtained by molecular mechanics for compound1 is in excellent agreement with the X-ray structure, and greater confidence can be placed in this method than in semiempirical ones. Similarities observed on the LUMO positions, as well as rotational barriers lead to the conclusion that the differences in biological activity of these compounds do not rely on their ground state properties but rather on their subsequent reactions with oxygen. In addition, the calculations revealed significant structural information of a family of biological importance (nitroimidazoles) and constitute a comparative test for the MM2, AM1, and PM3 methods.