Molecular modeling: a tool for predicting anthelmintic activity in vivo.

The structural and electronic features of the broad-spectrum benzimidazole anthelmintic mebendazole [MBZ, methyl 5-(benzoyl)-benzimidazole-2-carbamate] have been determined using a combination of quantum mechanics, molecular graphics, and molecular modeling techniques. Using conformational analyses and quantum mechanics, we found that the three-dimensional structure and electronic features of MBZ were consistent with those previously reported for highly active broad-spectrum benzimidazole anthelmintics and that in vivo drug efficacy against Hymenolepis diminuta depends upon the orientation of the benzoyl group at position 5 on the heterocyclic ring system, the magnitude of the molecular dipole moment, and the percentage of polar surface area. The chemotherapeutic actions of MBZ on H. diminuta in vivo were accompanied by marked changes in worm weight and chemical composition. Tapeworms recovered from rats that had received a therapeutically effective dose of MBZ 24 h earlier were significantly smaller and contained much less glycogen (as a percentage of the wet weight) than worms from untreated controls. In MBZ-treated worms, protein concentrations rose at a rate sufficient to offset the decline in glycogen concentration. Glycogen/protein ratios in MBZ-treated worms were considerably lower than the corresponding control values. Differences in the absolute amounts of glycogen between control and drug-treated worms were even more profound. Administration of a curative dose of MBZ to the rat host produced in H. diminuta another change, the onset of which coincided with the gross alterations in worm weight and chemical composition.(ABSTRACT TRUNCATED AT 250 WORDS)