Inhibition of Leishmanias But Not Host Macrophages by the Antitubulin Herbicide Trifluralin

Abstract

The dinitroaniline herbicide trifluralin (alpha, alpha, alpha-trifluoro-2,6-dinitro-N, N-dipropyl-p-toluidine), at micromolar concentrations, selectively inhibited both proliferation and differentiation of the parasitic protozoan Leishmania mexicana amazonensis. In vitro, radioactive trifluralin showed specific binding to leishmania tubulin but not to mammalian tubulin. Because herbicides such as trifluralin are economical and are considered safe for man and domesticated animals, they may serve as useful sources of potential antiparasitic agents.

Leishmania tarentolae: Purification and characterization of tubulin and its suitability for antileishmanial drug screening

“…Dinitroaniline herbicides have shown activity versus both Leishmania and trypanosomes (Chan and Fong, 1990;Chan et al, 1991;Chan et al, 1993a;Chan et al, 1993b;Traub-Cseko et al, 2001), and tubulin has been implicated as the target of these compounds (Chan and Fong, 1990;Chan et al, 1991;Traub-Cseko et al, 2001). N 1 -phenyl-3,5-dinitro-N 4 ,N 4 -di-n-propylsulfanilamide (GB-II-5) (Werbovetz et al, 2003) and N 1 -phenyl-3,5-dinitro-N 4 ,N 4 -di-n-butylsulfanilamide (GB-II-150) (Bhattacharya et al, 2004) are derivatives of the dinitroaniline herbicide oryzalin that have displayed potent antimitotic effects on kinetoplastid parasites (see Figure 1 for structures).…”

Dinitroanilines Bind α-Tubulin to Disrupt Microtubules

“…It is therefore ideally suited for genetic analysis of recessive mutations that would be masked in a diploid organism, particularly one with redundant gene family members. These genetic qualities allowed the isolation of a large number of tubulin mutations that are partially recessive to wild-type tubulin.It is well established that dinitroanilines selectively inhibit the microtubules of plants and protozoa and do not act on fungal or vertebrate tubulins (Chan and Fong, 1990;Chan et al, 1991;James et al, 1993;Gu et al, 1995;Edlind et al, 1996;Stokkermans et al, 1996;Anthony et al, 1998Armson et al, 1999;Zeng and Baird, 1999; Makioka et al, 2000a,b;Traub-Cseko et al, 2001). Dinitroaniline disruption of plant microtubules has been exploited to develop these compounds as components of a variety of preemergence herbicides.…”

“…Dinitroanilines also disrupt the microtubules of protozoa, including both free-living species such as Tetrahymena and protozoan parasites such as Trypanosoma spp., Leishmania spp., Entamoeba spp., Plasmodium falciparum, Cryptosporidium parvum, and Toxoplasma gondii (Chan and Fong, 1990;Chan et al, 1991;Gu et al, 1995;Edlind et al, 1996;Stokkermans et al, 1996;Armson et al, 1999; Makioka et al, 2000a,b;Traub-Cseko et al, 2001). Remarkably, the activity of dinitroanilines is restricted to plants and protozoa; these compounds are ineffective against vertebrate or fungal microtubules (Chan and Fong, 1990;Hugdahl and Morejohn, 1993;Murthy et al, 1994;Edlind et al, 1996).T. gondii is a member of the Apicomplexa, a phylum of parasites that includes several medically and agriculturally significant pathogens (Black and Boothroyd, 2000).…”

Synthesis, biological evaluation, and molecular modeling of 3,5-substituted-N1-phenyl-N4,N4-di-n-butylsulfanilamides as antikinetoplastid antimicrotubule agents

“…The reaction mixture was then filtered through celite and evaporated to afford 3 (850 mg, 98%) as a colorless solid, mp = 85−86 °C. 1 …”

“…The crude product was then purified by column chromatography using hexanes/EtOAc (10:1) to afford 4 (51 mg, 23%) as a colorless solid, mp = 90−91 °C. 1 …”