Microtubule inhibitors: structure-activity analyses suggest rational models to identify potentially active compounds

Abstract

Trifluralin, a dinitroaniline microtubule inhibitor currently in use as an herbicide, has been shown to inhibit the proliferation of Plasmodium falciparum, Trypanosoma brucei, and several species of Leishmania, in vitro. As a topical formulation, trifluralin is also effective in vivo (in BALB/c mice) against Leishmania major and Leishmania mexicana. Although trifluralin and other dinitroaniline herbicides show significant activity as antiparasitic compounds, disputed indications of potential carcinogenicity will probably limit advanced development of these substances. However, researchers have suggested that the activity of trifluralin is due to an impurity or contaminant, not to trifluralin itself. We have pursued this lead and identified the structure of the active impurity. This compound, chloralin, is 100 times more active than trifluralin. On the basis of its structure, we developed a rational structure-activity model for chloralin. Using this model, we have successfully predicted and tested active analogs in a Leishmania promastigote assay; thus, we have identified the putative mechanism of action of this class of drugs in Leishmania species. Potentially, this will allow the design of noncarcinogenic, active drugs.

High-performance liquid chromatographic method for determination of amino acids by precolumn derivatization with 4-chloro-3,5-dinitrobenzotrifluoride

“…The CNBF derivatization was rapid at moderate temperature, along with the resultant derivatives being very stable and of high ultraviolet and fluorescent absorption [41][42][43][44][45][46][47]. There were not any multiple derivatives and by-products except CNBF hydrolysis compound in the reaction, while excess reagent and its hydrolysis compound could not disturb the separation.…”

Residue determination of glyphosate in environmental water samples with high-performance liquid chromatography and UV detection after derivatization with 4-chloro-3,5-dinitrobenzotrifluoride

“…Thus for sensitive determination of glyphosate, many derivatization agents have been developed including 4-chloro-7-nitrobenzofurazan (NBD-Cl) [20], 2,2-dihydroxy-1h-indene-1,3-(2h)-dione (Ninhydrin) [21][22][23], lfluoro-2,4-dinitrobenzene (DNP) [24], 9-fluorenylmethyl chloroformate (FMOC-Cl) [25][26][27][28][29][30][31][32][33][34], o-phthalaldehyde-mercaptoethanol (OPA-MERC) [35,36], p-toluenesulphonyl chloride (TsCl) [37,38]. 4-Chloro-3,5-dinitrobenzotrifluoride (CNBF) is an important fine chemical, which has been known to react with primary or secondary amines in presence of base to produce stable N-substituted-2,6-dinitro-4-(trifluoromethyl)-benzamine derivatives which are satisfactory ultraviolet absorption [39][40][41][42][43].…”

Determination of biogenic amines in beer with pre-column derivatization by high performance liquid chromatography

“…Therefore, many derivatization agents is usually applied for their analysis such as 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC) [40], N-(2-acridonyl)-maleimide (MIAC) [48], benzoyl chloride [38], bis [2-ethylhexyl] sulphosuccinate (AOT) [41], dabsyl chloride (Dbs-Cl) [21,36,37], dansyl chloride (Dns-Cl) [43,44,46], 3,5-dinitrobenzoyl chloride (DNBZ-Cl) [35], 9-fluorenylmethyl chloroformate (FMOC) [51], 9-fluorenylmethyloxy carbonyl chloride (Fmoc-Cl) [45], N-(9-fluorenylmethoxycarbonyloxy) succinimide (Fmoc-Osu) [39], N-hydroxysuccinimidyl fluorescein-o-acetate (SIFA) [49], 8-phenyl-(4-oxy-acetic acid N-hydroxysuccinimideester)-4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene (TMPAB-OSu) [42], and o-phthalaldehyde (OPA) [47]. 4-Chloro-3,5-dinitrobenzotrifluoride (CNBF) is an important fine chemical, which has been known to react with primary or secondary amines in presence of base to produce stable N-substituted-2,6-dinitro-4-(trifluoromethyl)-benzamine derivatives which are satisfactory ultraviolet absorption [50][51][52][53][54]. The levels of biogenic amines in American, Bulgarian, Brazilian and European beers have been reported [17,39,55,56].…”