Structure−Activity Relationships for the Antileishmanial and Antitrypanosomal Activities of 1‘-Substituted 9-Anilinoacridines

Gamage, Swarna A.; Figgitt, David P.; Wojcik, S.J.; Ralph, R.K.; Ransijn, Adriana; Mauël, Jacques; Yardley, Vanessa; Snowdon, Diane; Croft, Simon L.; Denny, William A.

doi:10.1021/jm970232h

Cited by 116 publications

(52 citation statements)

References 24 publications

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“…Electron-donating groups such as SP3 oxygen are the source of electrons and could alter toxicities of molecules. 37 1-(2-Nitrophenoxy)-4-chlorobenzene (Figure 5d) is an example of these molecules. According to rule VI, a molecule is toxic if there is a phenyl ring and an electron-donating group with the distance between them being 7.3 ( 1.0 Å (Figure 5a).…”

Section: K ) 1 Mmentioning

confidence: 99%

A Novel Logic-Based Approach for Quantitative Toxicology Prediction

Amini

Muggleton

Lodhi

et al. 2007

J. Chem. Inf. Model.

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There is a pressing need for accurate in silico methods to predict the toxicity of molecules that are being introduced into the environment or are being developed into new pharmaceuticals. Predictive toxicology is in the realm of structure activity relationships (SAR), and many approaches have been used to derive such SAR. Previous work has shown that inductive logic programming (ILP) is a powerful approach that circumvents several major difficulties, such as molecular superposition, faced by some other SAR methods. The ILP approach reasons with chemical substructures within a relational framework and yields chemically understandable rules. Here, we report a general new approach, support vector inductive logic programming (SVILP), which extends the essentially qualitatiVe ILP-based SAR to quantitatiVe modeling. First, ILP is used to learn rules, the predictions of which are then used within a novel kernel to derive a support-vector generalization model. For a highly heterogeneous dataset of 576 molecules with known fathead minnow fish toxicity, the cross-validated correlation coefficients (R 2 CV ) from a chemical descriptor method (CHEM) and SVILP are 0.52 and 0.66, respectively. The ILP, CHEM, and SVILP approaches correctly predict 55, 58, and 73%, respectively, of toxic molecules. In a set of 165 unseen molecules, the R 2 values from the commercial software TOPKAT and SVILP are 0.26 and 0.57, respectively. In all calculations, SVILP showed significant improvements in comparison with the other methods. The SVILP approach has a major advantage in that it uses ILP automatically and consistently to derive rules, mostly novel, describing fragments that are toxicity alerts. The SVILP is a general machine-learning approach and has the potential of tackling many problems relevant to chemoinformatics including in silico drug design.

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Section: K ) 1 Mmentioning

confidence: 99%

A Novel Logic-Based Approach for Quantitative Toxicology Prediction

Amini

Muggleton

Lodhi

et al. 2007

J. Chem. Inf. Model.

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“…Acridines have shown efficacy against the protozoans Leishmania (9, 39), Trypanosoma brucei (15), and Trypanosoma cruzi (19) and against the flatworm bloodfluke Schistosoma mansoni (11). Bis-acridine compounds are dimeric acridine analogs, whereby two bioactive acridine heterocycles are tethered via a flexible linker.…”

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confidence: 99%

Bis-Acridines as Lead Antiparasitic Agents: Structure-Activity Analysis of a Discrete Compound Library In Vitro

Caffrey

Steverding

Swenerton

et al. 2007

Antimicrob Agents Chemother

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Parasitic diseases are of enormous public health significance in developing countries-a situation compounded by the toxicity of and resistance to many current chemotherapeutics. We investigated a focused library of 18 structurally diverse bis-acridine compounds for in vitro bioactivity against seven protozoan and one helminth parasite species and compared the bioactivities and the cytotoxicities of these compounds toward various mammalian cell lines. Structure-activity relationships demonstrated the influence of both the bisacridine linker structure and the terminal acridine heterocycle on potency and cytotoxicity. The bioactivity of polyamine-linked acridines required a minimum linker length of approximately 10 Å. Increasing linker length resulted in bioactivity against most parasites but also cytotoxicity toward mammalian cells. N alkylation, but less so N acylation, of the polyamine linker ameliorated cytotoxicity while retaining bioactivity with 50% effective concentration (EC 50 ) values similar to or better than those measured for standard drugs. Substitution of the polyamine for either an alkyl or a polyether linker maintained bioactivity and further alleviated cytotoxicity. Polyamine-linked compounds in which the terminal acridine heterocycle had been replaced with an aza-acridine also maintained acceptable therapeutic indices. The most potent compounds recorded low-to mid-nanomolar EC 50 values against Plasmodium falciparum and Trypanosoma brucei; otherwise, low-micromolar potencies were measured. Importantly, the bioactivity of the library was independent of P. falciparum resistance to chloroquine. Compound bioactivity was a function of neither the potential to bis-intercalate DNA nor the inhibition of trypanothione reductase, an important drug target in trypanosomatid parasites. Our approach illustrates the usefulness of screening focused compound libraries against multiple parasite targets. Some of the bis-acridines identified here may represent useful starting points for further lead optimization.

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“…This resistance occurred in 5 to 70% of patients in some areas of endemicity (28, 36). There is, therefore, a great and urgent need for the development of new, effective, and safe drugs for the treatment of leishmaniasis.A number of investigations to explore potential antileishmanial drugs have been carried out during the last 2 decades (2,6,15,21,22,25,30,33,38). We have previously reported that chalcones have potent antileishmanial and antimalarial activities and might be developed into a new class of antileishmanial drugs (7-10, 39).…”

mentioning

confidence: 99%

Inhibition of Fumarate Reductase in Leishmania major and L. donovani by Chalcones

Chen

Zhai

Christensen

et al. 2001

Antimicrob Agents Chemother

200

130

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Our previous studies have shown that chalcones exhibit potent antileishmanial and antimalarial activities in vitro and in vivo. Preliminary studies showed that these compounds destroyed the ultrastructure of Leishmania parasite mitochondria and inhibited the respiration and the activity of mitochondrial dehydrogenases of Leishmania parasites. The present study was designed to further investigate the mechanism of action of chalcones, focusing on the parasite respiratory chain. The data show that licochalcone A inhibited the activity of fumarate reductase (FRD) in the permeabilized Leishmania major promastigote and in the parasite mitochondria, and it also inhibited solubilized FRD and a purified FRD from L. donovani. Two other chalcones, 2,4-dimethoxy-4-allyloxychalcone (24m4ac) and 2,4-dimethoxy-4-butoxychalcone (24mbc), also exhibited inhibitory effects on the activity of solubilized FRD in L. major promastigotes. Although licochalcone A inhibited the activities of succinate dehydrogenase (SDH), NADH dehydrogenase (NDH), and succinate-and NADHcytochrome c reductases in the parasite mitochondria, the 50% inhibitory concentrations (IC 50 ) of licochalcone A for these enzymes were at least 20 times higher than that for FRD. The IC 50 of licochalcone A for SDH and NDH in human peripheral blood mononuclear cells were at least 70 times higher than that for FRD. These findings indicate that FRD, one of the enzymes of the parasite respiratory chain, might be the specific target for the chalcones tested. Since FRD exists in the Leishmania parasite and does not exist in mammalian cells, it could be an excellent target for antiprotozoal drugs.Leishmaniasis is a major and increasing public health problem, particularly in Africa, Asia, and Latin America (23, 37). Some 350 million people are at risk of infection with Leishmania spp., and more than 12 million people are infected with different species of the parasite. Each year, there are 1.5 million new cases, and 500,000 of these are visceral leishmaniasis, which is nearly always fatal if left untreated (23). Treatment of leishmaniasis is unsatisfactory in that the existing drugs require repeated parenteral administration, and none of them are effective in all cases or are totally free of side effects (1, 26, 37). Furthermore, large-scale clinical resistance to antimonials, the first-line antileishmanial drugs, has been reported recently. This resistance occurred in 5 to 70% of patients in some areas of endemicity (28, 36). There is, therefore, a great and urgent need for the development of new, effective, and safe drugs for the treatment of leishmaniasis.A number of investigations to explore potential antileishmanial drugs have been carried out during the last 2 decades (2,6,15,21,22,25,30,33,38). We have previously reported that chalcones have potent antileishmanial and antimalarial activities and might be developed into a new class of antileishmanial drugs (7-10, 39). Attempting to elucidate the antileishmanial mechanism of action of the chalcones, we have previously fou...

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Structure−Activity Relationships for the Antileishmanial and Antitrypanosomal Activities of 1‘-Substituted 9-Anilinoacridines

Cited by 116 publications

References 24 publications

A Novel Logic-Based Approach for Quantitative Toxicology Prediction

A Novel Logic-Based Approach for Quantitative Toxicology Prediction

Bis-Acridines as Lead Antiparasitic Agents: Structure-Activity Analysis of a Discrete Compound Library In Vitro

Inhibition of Fumarate Reductase in Leishmania major and L. donovani by Chalcones

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