Studies in Enteric Anthelmintics: Activity Profile of Prodrug of a Bisbenzimidazole [1] A. M. Khan, Suman Gupta, and J. C. Katiyar Parasitology Division Sudhir K. Singh, V. L. Sharma, Satyavan Sharma, and A. P. Bhaduri Medicinal Chemistry Division Central Drug Research Institute, Lucknow 226001, India Z. Naturforsch. 46c, 673-677 (1991); received February 13/May 8, 1991 Prodrug, Anthelmintic Activity, Bisbenzimidazole, Comparative Efficacy The comparative anthelmintic activity of a possible prodrug, 2,2'-dicarbomethoxyamino- 5,5'-dibenzimidazolyl methanol (2) with its parent compound 2,2'-dicarbomethoxyamino-5,5'- dibenzimidazolyl ketone (1) and the reference drug mebendazole (3a) is reported. At a dose of 25 mg/kg, compound 2 was 100% effective against Ancylostoma ceylanicum in hamsters. Com pound 2 also exhibited a similar order of activity against Syphacia obvelata, Hymenolepis nana and H. diminuta at a dose of 100 mg/kg. The drug exhibited lethal effects against metamorphic forms of A. ceylanicum at a dose of 100 mg/kg. However the trichostrongylids, Nippostrongy- lus brasiliensis remained unaffected up to a dose of 250 mg/kg of 2. Both 1 and 3 a exhibited inferior activity than 2 except against adult A. ceylanicum. The activity of 1 and 2 has been explained on the basis of their ability to resist systemic hydrolysis resulting in higher concen tration of the active drug in biophase. Introduction Despite extensive work carried out towards design and synthesis of ideal benzimidazole- 2-carbamate anthelmintics, it has not been possi ble to eliminate some of the basic limitations asso ciated with this class of drugs [2-4], The major limitations with benzimidazole drugs are their poor absorption through the gastrointestinal tract and irratic pharmacophoric behaviour in biophase [5]. Further, benzimidazole-2-carbamate mole cules are extremely sensitive to even minor struc tural changes and, therefore, skeletal modifica tions play a detrimental role in successful drug design [6]. In an effort to obtain a benzimidazole anthelmintic which is devoid of the inherent limi tations as discussed above, a series of methyl 5(6)- substituted benzimidazole-2-carbamates were syn thesized in this laboratory [7-11] of which methyl 5(6)-[a-hydroxy-a-phenyl]methylbenzimidazole-2- carbamate (3 b), an active metabolite of mebend azole (3 a), was found to display excellent anthel mintic activity against a variety of intestinal and tissue-dwelling helminths [12]. Reprint requests to Dr. Satyavan Sharma. Verlag der Zeitschrift für Naturforschung, D-7400 Tübingen 0939-5075/91/0700-0673 $01.30/0 In a further probe in this direction, 2,2'-dicarbo- methoxyamino-5,5'-dibenzimidazolyl methanol (2) was synthesized as a possible prodrug of 2,2'-dicarbomethoxyamino-5,5'-dibenzimidazolyl ketone (1), a compound synthesized in this labora tory and found to possess high order of activity against different luminal and tissue-dwelling hel minths [13]. The basis for synthesizing 2 also lies in the fact that this molecule is expected to be highly sensitive to biological oxidoredox reactions by virtue of two electron-deficient rings attached to secondary alcohol. The present communication is, therefore, con cerned with the synthesis and anthelmintic activity of 2 against different helminth parasites in experi mental animals. o H H 2 1 - 3 : R = NHCOOCHj