Fasciolosis, caused by Fasciola hepatica and Fasciola gigantica, is a very serious parasitic disease, which is responsible for heavy economic losses in sheep and cattle production in many countries of the world.
1)Besides domestic animals, other animal species and man may be infected as well.2) There are effective strategies for the control of fasciolosis which are largely based on drug (fasciolicide) use on the definitive host.3) So far the only effective drug against immature and adult flukes alike is triclabendazole (TCBZ, Fig. 1), a potent fasciolicide with a better bioavailability than that of the benzimidazole carbamates, such as albendazole. It differs structurally from the latter in having a 2-methylthio group instead of a 2-methylcarbamate group in the benzimidazole ring.
4)TCBZ appears to be highly specific for flukes, possessing 97-100% activity against all stages of Fasciola spp. The usual oral dose of TCBZ for the elimination of immature and adult forms of F. hepatica is 5-10 mg/kg for sheep and goats, and 12 mg/kg for cattle.
5)For safety and efficacy, TCBZ is the drug of choice for the treatment of human fasciolosis.6-10) Unlike nematocides, no new fasciolicides have been marketed recently and apparently no compounds are yet under development.1) Considering that fasciolosis is also a health problem in Mexico, a research project was undertaken in our laboratory with the purpose of developing new compounds with potential fasciolicidal activity. 11,12) For the design of one of the new compounds described in this paper, we use as a model pronethalol, an adrenergic blocker which was formed by replacing the 3,4-dichlorophenyl group in dichloroisoproterenol (DCI, Fig. 1) by the 2-naphtyl group.13) DCI is also an adrenergic blocker with some agonist activity thus establishing the fact that pronethalol is a bioisostere of DCI.In this paper we report the synthesis and preliminary fasciolicidal activity, in vitro and in vivo, against F. hepatica, of 5-chloro-2-methylthio-6-(1-naphthyloxy)-1H-benzimidazole (6), a TCBZ analog. In this compound, the 1-naphthyl group replaces the 3,4-dichlorophenyl group in TCBZ, a moiety change, which is analogous to that done with pronethalol-DCI.
ChemistryThe synthetic sequence in the preparation of 6 is shown in Chart 1. In the first step, 4,5-dichloro-2-nitroaniline (1) was subjected to a nucleophilic substitution reaction with 1-naphthol (2) under known conditions, 14) and the ether obtained (3) was reduced with SnCl 2 · 2H 2 O.15) The corresponding ophenylenediamine (4) formed was immediately cyclocondensed with CS 2 in an EtOH-KOH solution to give the 2-mercaptobenzimidazole (5).16) In the last step, 5 was monoalkylated with CH 3 I in acetone and KOH solution 17) to afford the title compound (6).The synthesized compounds were purified by recrystallization and their physical constants were determined. The structure of all new compounds was established by spectroscopic and spectrometric data.
PharmacologyCompound 6 was evaluated in vitro against newly excysted F. hepatica ...
