Microtubule inhibitors: structure-activity analyses suggest rational models to identify potentially active compounds (original) (raw)
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Molecular and Biochemical Parasitology, 2006
Microtubules play important roles in cell division, motility and structural integrity of malarial parasites. Some microtubule inhibitors disrupt parasite development at very low concentrations, but most of them also kill mammalian cells. However, the dinitroaniline family of herbicides, which bind specifically to plant tubulin, have inhibitory activity on plant cells but are relatively non-toxic to human cells. Certain dinitroanilines are also inhibitory to various protozoal parasites including Plasmodium. Here we demonstrate that the dinitroanilines trifluralin and oryzalin inhibited progression of erythrocytic Plasmodium falciparum through schizogony, blocked mitotic division, and caused accumulation of abnormal microtubular structures. Moreover, radiolabelled trifluralin interacted with purified, recombinant parasite tubulins but to a much lesser extent with bovine tubulins. The phosphorothioamidate herbicide amiprophos-methyl, which has the same herbicidal mechanism as dinitroanilines, also had antimalarial activity and a similar action on schizogony. These data suggest that P. falciparum tubulin contains a dinitroaniline/phosphorothioamidate-binding site that is not conserved in humans and might be a target for new antimalarial drugs.
Proceedings of The National Academy of Sciences, 1993
Leishmaniasis is a major tropical disease for which current chemotherapies, pentavalent antimonials, are inadequate and cause severe side effects. It has been reported that trifluralin, a microtubule-disrupting herbicide, is inhibitory to Leishmania amazonensis. In this study, the in vitro effect of trifluralin on different species of trypanosomatid protozoans was determined. In addition to L. amazonensis, trifluralin is effective against Leishmania major and Leishmania tropica, which cause cutaneous infections, Leishmania donovani, which causes visceral disease, Leishmania panamensis, which may cause mucocutaneous infection, and Trypanosoma brucei, an important human and veterinary pathogen. Moreover, most encouragingly, trifluralin is effective in vivo as a topical ointment against L. major and Leishmania mexicana murine cutaneous leishmaniasis. Thus, trifluralin is a promising lead drug for several related, prevalent tropical diseases: leishmaniasis, trypanosomiasis of animals, and, possibly, African trypanosomiasis in humans.
Dinitroaniline herbicides against protozoan parasites: the case of Trypanosoma cruzi
Trends in Parasitology, 2001
The drugs presently in use against Chagas disease are very toxic, inducing a great number of side effects. Alternative treatments are necessary, not only for Chagas disease but also for other diseases caused by protozoan parasites where current drugs pose toxicity problems. The plant microtubule inhibitor trifluralin has previously been tested with success against Leishmania, Trypanosoma brucei and several other protozoan parasites. Trypanosoma cruzi, the causative agent of Chagas disease, is also sensitive to the drug. This sensitivity has been correlated with the deduced amino acid sequences of α αand β β-tubulin of T. cruzi as compared with plant, mammal and other parasite sequences.
ABSTRACT Purpose: In the present study, antitubercular activities and in silico physicochemical toxicities and bioactivity profile of some 3-chloro-6-arylpyridazines (3a-d) and 6-aryl-4,5-dihydropyridazine-3(2H)-thiones (4a-d) are studied. Approach: The compounds (3a-d) and (4a-d) were evaluated as antitubercular agents against Mycobacterium tuberculosis H37Rv by screening through in vitro Microplate Alamar Blue Assay (MABA) method. Findings: In silico physicochemical parameter revealed that the entire compounds follow Lipinski’s rule-of-5 to become a “drug like” molecule. ADME (absorption, distribution, metabolism and excretions) profile prediction has shown that all the compounds can be absorbed through human intestine (HIA+), Caco-2 cell (Caco-2+) and can cross blood brain barrier (BBB+), they all are non-substrate and non-inhibitor of p-glycoprotein. Compounds 4a-d are inhibitor of human microsomal enzyme like CYP 450 1A2, CYP 450 2C19 and CYP 450 3A4. Research limitations/implications: Compounds 4a-4d are better ligand for enzyme inhibition than 3a-d compounds. The MIC of compounds 4a-d and 3a is 6.25 μg/ml. They are potent than compound 3b-d with MIC 12.5 μg/ml. Originality: Toxicity prediction indicated that compounds 3a-3d and 4a-d are non-carcinogenic and non-mutagenic. Bioactivity prediction for compounds 3a-3d and 4a-d indicated better ligand as enzyme inhibitor in comparison to standard.
Synthesis, Structural Determination, and Pharmacology of Putative Dinitroaniline Antimalarials
A series of novel, homologous compounds possessing the general formula N 1-N n-bis(2,6-dinitro-4-trifluormethylphenyl)-1,n-diamino alkanes (where n = 4, 6, 10 or 12), were designed to probe inter-and intra-binding site dimensions in malarial parasite (Plasmodium) tubulin. Various crystal structures, including chloralin and trifluralin, an isopropyl dimer, and 2,6-dinitro-4-trifluoromethyl-phenylamine, were determined. Dinitroanilines, when soluble, were evaluated both in culture and in vivo. Trifluralin was up to 2-fold more active than chloralin against cultured parasites. The isopropyl dimer was water soluble (> 5 mM) and revealed activity superior to that of chloralin in culture. The effects of selected dinitroanilines upon the mitotic microtubular structures of Plasmodium, the putative target of these dinitroanilines, were also determined. Electronic properties of the molecules were calculated using DFT (B3LYP/6-31 + G* level) to ascertain whether incorporation of such a pharmacophore could allow both QSAR and rational development of more selectively toxic antiparasitic agents.
The biochemistry of compounds with anti-microtubule activity in plant cells
Pharmacology & Therapeutics, 1991
The experimental use of anti-microtubule compounds has revealed essential functions of microtubules in plant cytoskeletal arrays, including the pre-prophase band, the mitotic and meiotic spindles, the phragmoplast, and the cortical array. The most commonly used plant microtubule depolymerization compounds are colchicine, and several synthetic herbicides belonging to three different chemical classes, the dinitroanilines, phosphoric amides, and N-phenyl carbamates. Taxol, a secondary plant product, is the only drug found to promote the polymerization of plant microtubules. This paper summarizes our current understanding of the biochemical interactions of colchicine, anti-microtubule herbicides, and taxol with plant tubulin and microtubules. CONTENTS 223 223 225 225
Characterization, Modes of Action and Effects of Trifluralin: A Review
Herbicides - Current Research and Case Studies in Use, 2013
Herbicides may be classified according to different criteria related to their properties, characteristics, use, efficiency, permanence in the environment and mechanism of action. As for their chemical features, herbicides may be classified as carbamates, amides, diphenyl ethers, amino phosphates, and dinitroanilines, among others .