Absorption, excretion, and metabolism of Robenz, robenidine hydrochloride [1,3-bis(p-chlorobenzylideneamino)guanidine hydrochloride], in the rat

Abstract

ZULALIAN, GATTERDAMalously with the glucosyl bromide to give N-alkylation or phenyl alkylation was eliminated, for either possibility would result in a product containing a phenolic group. The absence of an aromatic hydroxyl was demonstrated by determining the uv spectra in neutral and in basic solution. Whereas the absorption maxima of 1 and 2 were shifted in the presence of sodium hydroxide, no shift occurred in the uv maxima of 5, 6, or indeed chlorpropham itself.The Michael synthesis is known to yield ß-rather than -glucosides. Confirmation of the ß configuration of compounds 3, 4, 5, and 6 was obtained by determining their specific optical rotations. These rotations, ranging from -39°to -69°, were in the range of values of the ß isomers of known substituted phenyl glucosides and their tetraacetates (-103°t o +45°) rather than in the range of the corresponding a isomers (+137°to + 212°) (Bonner et al., 1952). The susceptibility of 5 and 6 to hydrolysis by the enzyme, /3-glucosidase, also indicates ß configuration. Efforts to confirm the configuration of 3, 4, 5, and 6 by their nmr spectrum were unsuccessful. The H-l' doublet could not be observed because of signal overlap and difficulties with radiofrequency saturation.The mass spectrum of 3 showed mass peaks corresponding to those reported by Still and Mansager (1972) for a sample of acetylated chlorpropham conjugate from soybeans.ed. His procedure involved the reduction of commercially available p-nitrophenyl-/3-glucuronide, followed by reaction with isopropyl chloroformate. ACKNOWLEDGMENTThe author is indebted to Derek Horton of Ohio State University for many helpful suggestions on these syntheses and to the following PPG Industries staff for their part in this work: Kenneth Dress (uv determinations), James Gregory (synthesis of 1), Robert Pfost (mass spectra interpretation), Robert Shupe (ir and nmr determinations), Albert Strong (synthesis of 2), and Jerome Wiedmann (enzymatic hydrolysis studies).

Robenidine Analogues Are Potent Antimalarials in Drug-Resistant Plasmodium falciparum

“…That robenidine exhibited respectable in vivo antimalarial activity was somewhat surprising given that it is poorly absorbed and known to accumulate in the gastrointestinal tract. 44 The early hit compound 16 (the 4-OCF 3 analogue, ED 50 1.2 mg/kg/day) showed improved in vivo activity over robenidine (ED 50 = 1.6 mg/kg/day), while 22 (the 4-CN analogue, ED 50 = 2.7 mg/kg/day) did not. Unexpectedly, 21 (the 3-CN analogue, ED 50 = 7.1 mg/kg/day) was 6-fold less efficacious than 16 in vivo , despite being 6-fold more active than 16 in vitro .…”

“…Robenidine, 16 , 22 , and 21 were evaluated for in vivo antimalarial efficacy. That robenidine exhibited respectable in vivo antimalarial activity was somewhat surprising given that it is poorly absorbed and known to accumulate in the gastrointestinal tract . The early hit compound 16 (the 4-OCF 3 analogue, ED 50 1.2 mg/kg/day) showed improved in vivo activity over robenidine (ED 50 = 1.6 mg/kg/day), while 22 (the 4-CN analogue, ED 50 = 2.7 mg/kg/day) did not.…”

Absorption, excretion, and metabolism of 1,3-bis(p-chlorobenzylideneamino)guanidine hydrochloride (Robenz robenidine hydrochloride) in the chicken

“…Robenidine Hydrochloride--p-Chlorobenzylidene-14C. p-Chlorobenzaldehyde-carfconyZ-14C, obtained from Mallinckrodt Nuclear, was allowed to react with nonradioactive 1,3-diaminoguanidine hydrochloride as described in the previous study (Zulalian and Gatterdam, 1973). The benzylidene tracer had a specific activity of 12.7 pCi/mg and was 99.2% pure, radiochemically.…”

“…Determination of Radioactivity. Radioactivity was measured in a Packard Tri-Carb liquid scintillation spectrometer as previously described (Zulaban and Gatterdam, 1973). Radioactive spots on thin-layer chromatograms were located by means of autoradiography using Kodak Royal Pan professional grade photographic film.…”

“…Robenidine hydrochloride was metabolized by the rat to p-chlorobenzoic acid and p-chlorohippuric acid (Zulalian and Gatterdam, 1973). Since the metabolism of this compound by chickens could be different from that observed in the rat, the metabolic fate of robenidine hydrochloride was investigated in chickens and the metabolites that were found in the excreta and tissues were isolated and identified.…”