Molecular modeling: a tool for predicting anthelmintic activity in vivo

Abstract

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)

Effects of benzimidazole anthelmintics as microtubule-active drugs on the synthesis and transport of surface glycoconjugates in Hymenolepis microstoma , Echinostoma caproni , and Schistosoma mansoni

“…Overall, it is not clear which cellular injuries contribute most ecaciously to the killing of the worms. An inhibition of tegumental absorption of glucose by Moniezia expansa and a signi®-cant reduction in, or even depletion of, glycogen in H. diminuta have been reported to ensue from benzimidazole treatment (Rahman and Bryant 1977;Ahmad and Nizami 1987;Lipkowitz and McCracken 1993), but this has not been seen in other parasites (Lacey 1988). According to the present observations, glycogen remained stored in appreciable amounts in drug-treated H. microstoma and E. caproni until the death of the worms.…”

Tautomerism in drugs with benzimidazole carbamate moiety: an electronic structure analysis

“…Our group reported the detailed electronic structure studies, conformational and tautomeric preferences on aminoguanidine, biguanide, guanylthiourea, sulfonylurea, and guanylurea derivatives, which are therapeutically important [33][34][35][36][37][38][39][40][41]. Lipkowitz and McCracken performed semi-empirical (MNDO) studies on albendazole, oxibendazole, etc., to understand the conformational tautomerism in these molecules [42][43][44][45]. They suggested that the conformer B is the most stable molecular model, but did not consider structure C in the study.…”

Synthesis, spectroscopic, thermal analyses, and anti-cancer studies of metalloantibiotic complexes of Ca(II), Zn(II), Pt(II), Pd(II), and Au(III) with albendazole drug

“…Benzimidazole is essential structural block of organic compounds used as DOI: 10.1134/S1070363215070270 antimicrobial agents against most microorganisms [14][15][16][17][18][19]. It is important in synthesis of anti-fungal [20], anti-tubercular [21], anti-oxidant [22], anti-allergic [23], antiparasitic [24] and herbicidal [25], anthelmintic [26], nematodes, hidatidosis, and teniasis [27] agents and many other biologically active compounds [28][29][30]. Cu(II) complexes of benzimidazoles demonstrated antibacterial activity against S. epidermidis [31] and fungi [32][33][34][35][36].…”