Antifilarial benzimidazoles

Antiemetic drugs, 27 (1990) 297 Antifilarial benzimidazoles, 25 (1988) 233 Antifolates as anticancer agents, 25 (1988)... 

Benzimidazoles have been identified as antifilarial agents [1-5] based on an extensive series of studies in jirds (a kind of gerbil) and cats. The mechanism of action of benzimidazoles has been extensively studied in many laboratories and, in general, three possible modes of action have been suggested for these drugs. 

Table 4.1. ANTIFILARIAL ACTIVITY OF MEBENDAZOLE, FLUBENDAZOLE AND NEW CLASS OF BENZIMIDAZOLE CARBAMATES...

Hoechst laboratories synthesized a large variety of 2-phenyl-5-substituted benzimidazoles of which HOE-33258 (32) was found to possess high micro- and macrofilaricidal activity against L. carinii in cotton rats at a subcutaneous dose of 4-8 mg/kg given for 5 days [37]. Despite the strong antifilarial activity exhibited by 32, it was not pursued further due to its strong binding with the hosTs DNA [38]. 

The marked anthelmintic activity associated with 5-aminobenzimidazoles like cambendazole (5), prompted the synthesis of various 5(6)-substituted aminobenzimi-dazole-2-carbamates (54). These, however, showed poor anthelmintic activity, except for the benzimidazoles (55), which carry a piperazin-l-yl residue at the 5-position [47,66,89-91]. Of these, the 5(6)-(4-substituted piperazin-l-yl)benzimidazoles (55) exhibited highly antifilarial activity, the most notable being the Hoechst compound HOE-33258 (32) and 55a,b. 

The antifilarial methyl-[5-(a-ainino-4-fluorobenzyl)benzimidazol-2-yl]carbainate (MAFBC) and four metabolites (e.g., flubendazole and decarbamoylated-MAFBC) were extracted fi om plasma and separated on a Cjg column (A = 291 nm) using a 70/30 - 45/55 (at 10.25 min hold 2.75 min) ->30/70 (at 17.56 min hold 3 min) water (50 mM phosphate to pH 4.0 with H3P04)/(75/25 methanol/acetonitrile) gradient [55,7]. Good peak shapes and resolution were obtained. The calibration range used was 10-500ng/mL and quantitation limits of lOng/mL (parent) and 20-1000 ng/mL for the metabolites (analyte dependent) were reported. 

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