Dinitroaniline herbicides against protozoan parasites: the case of Trypanosoma cruzi

Traub-Csekö, Yara M.; Ramalho-Ortigão, JM; Dantas, A.P.; Castro, Solange L. de; Barbosa, Helene Santos; Downing, Kenneth H.

doi:10.1016/s1471-4922(00)01834-1

Cited by 56 publications

(38 citation statements)

References 30 publications

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Yakovich

Ragone

Alfonzo

et al. 2006

Experimental Parasitology

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Previously, tubulin has been purified from Leishmania amazonensis and used to identify novel molecules with selective antimitotic activity. However, Leishmania amazonensis is pathogenic and requires a relatively expensive medium for large-scale cultivation. Herein, the purification and characterization of tubulin from the non-pathogenic Leishmania tarentolae is reported, together with the sequence of α-and β-tubulin from this organism. This protein was purified by sonication, diethylaminoethyl-Sepharose chromatography, and one assembly-disassembly cycle in 1% overall recovery based on total cellular protein. L. tarentolae tubulin was indistinguishable from the corresponding L. amazonensis protein in terms of binding affinity for dinitroaniline sulfanilamides and sensitivity to assembly inhibition by these compounds. The amino acid sequences derived from the L. tarentolae α-and β-tubulin genes were 99.6% and 99.4% identical to the corresponding amino acid sequences from the L. major Friedlin strain. These results indicate that tubulin from L. tarentolae is suitable for use in drug screening.

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Section: Introductionmentioning

confidence: 99%

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

Yakovich

Ragone

Alfonzo

et al. 2006

Experimental Parasitology

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“…Dinitroanilines (oryzalin, ethafluralin, and trifluralin) disrupt the microtubules of plants, ranging from the single-celled alga Chlamydomonas reinhardtii to higher plants such as the monocot Eleusine indica (James et al, 1993;Anthony et al, 1998;Zeng and Baird, 1999). 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).…”

mentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

Dinitroanilines Bind α-Tubulin to Disrupt Microtubules

Morrissette

Mitra

Sept

et al. 2004

MBoC

135

153

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Protozoan parasites are remarkably sensitive to dinitroanilines such as oryzalin, which disrupt plant but not animal microtubules. To explore the basis of dinitroaniline action, we isolated 49 independent resistant Toxoplasma gondii lines after chemical mutagenesis. All 23 of the lines that we examined harbored single point mutations in ␣-tubulin. These point mutations were sufficient to confer resistance when transfected into wild-type parasites. Several mutations were in the M or N loops, which coordinate protofilament interactions in the microtubule, but most of the mutations were in the core of ␣-tubulin. Docking studies predict that oryzalin binds with an average affinity of 23 nM to a site located beneath the N loop of Toxoplasma ␣-tubulin. This binding site included residues that were mutated in several resistant lines. Moreover, parallel analysis of Bos taurus ␣-tubulin indicated that oryzalin did not interact with this site and had a significantly decreased, nonspecific affinity for vertebrate ␣-tubulin. We propose that the dinitroanilines act through a novel mechanism, by disrupting M-N loop contacts. These compounds also represent the first class of drugs that act on ␣-tubulin function. INTRODUCTIONMicrotubules are polymers constructed from ␣-␤-tubulin heterodimers (Downing and Nogales, 1998a,b). These structures are rapidly assembled and disassembled to create essential components of eukaryotic cells, such as spindles and flagella. The dynamic nature of microtubules makes them susceptible to pharmacological agents. Microtubule-disrupting and microtubule-stabilizing drugs have provided great insight into tubulin and microtubule function; they also have tremendous practical use. Compounds that perturb microtubule dynamics are currently some of the most effective drugs to treat medical conditions, including cancer, gout, and helminth infection (Jordan et al., 1998). Dinitroanilines (oryzalin, ethafluralin, and trifluralin) disrupt the microtubules of plants, ranging from the single-celled alga Chlamydomonas reinhardtii to higher plants such as the monocot Eleusine indica (James et al., 1993;Anthony et al., 1998;Zeng and Baird, 1999). 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). Apicomplexans are obligate intracell...

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“…The organic layer was washed with sat. NH 4 Cl, dried over anhydrous Na 2 SO 4 , and evaporated. Purification by silica gel flash column chromatography using hexane/ethyl acetate 5:1 to 4:1 afforded 10 (2.29 g, 69%), mp = 106−107 °C.…”

Section: Dimethyl 2-bromo-5-(phenylsulfamoyl)isophthalate (10)mentioning

confidence: 99%

“…Solvent was evaporated, then the residue was extracted with EtOAc, and washed with sat. NH 4 Cl followed by brine and dried using anhydrous MgSO 4 . Purification by silica gel flash column chromatography (hexane/ethyl acetate 10:1) afforded 11 (1.99 g, 79%) as a yellow viscous liquid.…”

Section: Dimethyl 2-(di-n-butylamino)-5-(phenylsulfamoyl)isophthalatementioning

confidence: 99%

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

George

Endeshaw

Morgan

et al. 2007

Bioorganic & Medicinal Chemistry

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Dinitroanilines are of interest as antiprotozoal lead compounds because of their selective activity against the tubulin of these organisms, but concern has been raised due the potentially mutagenic nitro groups. Analogues of N 1 -phenyl-3,5-dinitro-N 4 ,N 4 -di-n-butylsulfanilamide (GB-II-150, compound 2b), a selective antimitotic agent against African trypanosomes and Leishmania, have been prepared where the nitro groups are replaced with amino, chloro, cyano, carboxylate, methyl ester, amide, and methyl ketone moieties. Dicyano compound 5 displays IC 50 values that are comparable to 2b against purified leishmanial tubulin assembly (6.6 vs. 7.4 μM), Trypanosoma brucei brucei growth in vitro (0.26 vs. 0.18 μM), L. donovani axenic amastigote growth in vitro (4.4 vs. 2.3 μM), and in vitro toxicity against Vero cells (16 vs. 9.7 μM). Computational studies provide a rationale for the antiparasitic order of activity of these analogues and further insight into the role of the substituents at the 3 and 5 positions of the sulfanilamide ring.

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Dinitroaniline herbicides against protozoan parasites: the case of Trypanosoma cruzi

Cited by 56 publications

References 30 publications

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

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

Dinitroanilines Bind α-Tubulin to Disrupt Microtubules

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

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