Bisguanidine, Bis(2-aminoimidazoline), and Polyamine Derivatives as Potent and Selective Chemotherapeutic Agents against <i>Trypanosoma brucei rhodesiense</i>. Synthesis and in Vitro Evaluation

In this paper we report the synthesis of three families of new amidine-based aromatic derivatives as potential DNA minor groove binding agents for the treatment of cancer. The preparation of mono-guanidine, mono-2-aminoimidazoline and asymmetric diphenyl guanidine/2-aminoimidazoline derivatives (compounds 1a,b,c to 8a,b,c) is presented. The affinity of these substrates and of a family of mono-and bis-isoureas (previously prepared in Rozas' laboratory) for DNA was evaluated by means of DNA thermal denaturation measurements. In particular, compounds 2c, 5c, 6c, 7c, and 8c were found to bind strongly both to natural DNA and to Adenine-Thymine oligonucleotides, showing a preference for the Adenine-Thymine base pairs sequences.Abbreviations: HB, hydrogen bond; ΔT m , increment in DNA denaturation temperature; AT, Adenine-Thymine pairs; MES, 2-(N-morpholino)ethanesulfonic acid; P/D, ratio between base pairs and ligand (drug);

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“…19 It is also worth mentioning that, the unreacted starting diamines could be recovered from the column eluting with a more polar solvent system.…”

Section: Methodsmentioning

confidence: 99%

Asymmetrical Diaromatic Guanidinium/2-Aminoimidazolinium Derivatives: Synthesis and DNA Affinity

et al. 2009

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“…4 Even though the recent inclusion of the combination therapy Nifurtimox-eflornithine as simplified stage 2 treatment for T. b. gambiense sleeping sickness improves the therapeutic arsenal against late-stage HAT, the discovery of new orally active drugs that are able to cure the acute and CNS stages of HAT remains a priority in tropical medicine. 1 In previous reports, we have shown that 4,4'-bis(imidazolinylamino)diphenylamine dihydrochloride (1, Chart 1) displayed excellent antitrypanosomal 6 and antiplasmodial 7 ‡ Abbreviations: BBB: blood-brain barrier; CNS: central nervous system; DMF: N,Ndimethylformamide; DIPEA: N,N-diisopropylethylamine; EtOAc: ethyl acetate; Et 2 O: diethyl ether; HAT: human African trypanosomiasis; LY: lucifer yellow; Ns (nosyl): 2-nitrobenzenesulfonamide. activity in vitro.…”

Section: Introductionmentioning

confidence: 95%

Synthesis and Antiprotozoal Activity of N-Alkoxy Analogues of the Trypanocidal Lead Compound 4,4′-Bis(imidazolinylamino)diphenylamine with Improved Human Blood−Brain Barrier Permeability

et al. 2010

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“…The screening of compound libraries to discover new hit and lead compounds against protozoan parasites has been used very efficiently by our group for the past few years. Very potent antiprotozoal compounds, active in vitro and in vivo against Trypanosoma brucei rhodesiense and Plasmodium falciparum, were identified by our group (16,17,38). These lead compounds were discovered by screening against T. brucei and P. falciparum a small library (Ͻ100 molecules) of dicationic compounds structurally related to known antiparasitic drugs (e.g., pentamidine, diminazene) but primarily synthesized by us for different medicinal targets.…”

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confidence: 99%

Antiprotozoal Activity of 1-Phenethyl-4-Aminopiperidine Derivatives

Dardonville

Fernandez-Fernandez

Gibbons

et al. 2009

Antimicrob Agents Chemother

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A series of 44 4-aminopiperidine derivatives was screened in vitro against four protozoan parasites (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum). This screening identified 29 molecules selectively active against bloodstream-form T. b. rhodesiense trypomastigotes, with 50% inhibitory concentrations (IC 50 ) ranging from 0.12 to 10 M, and 33 compounds active against the chloroquine-and pyrimethamine-resistant K1 strain of P. falciparum (IC 50 range, 0.17 to 5 M). In addition, seven compounds displayed activity against intracellular T. cruzi amastigotes in the same range as the reference drug benznidazole (IC 50 , 1.97 M) but were also cytotoxic to L-6 cells, showing little selectivity for T. cruzi. None of the molecules tested showed interesting antileishmanial activity against axenic amastigotes of L. donovani. To our knowledge, this is the first report of the antitrypanosomal activity of molecules bearing the 4-aminopiperidine skeleton.Tropical diseases due to parasitic protozoa cause great mortality and disability in the less developed world. Malaria and kinetoplastid diseases such as human African trypanosomiasis (HAT, or sleeping sickness), Chagas' disease, and leishmaniases are among the main neglected parasitic diseases, affecting hundreds of millions of people worldwide (http://www.dndi.org /index.php/diseases.html?idsϭ2). However, the low income of the affected populations does not make it financially attractive for pharmaceutical companies to invest in the development of new drugs against these diseases. The number of antiprotozoal drugs available is limited, and they are old, toxic, and losing efficacy due to the emergence of resistant parasites. New drugs are thus urgently needed (37).The landscape of drug discovery and development for new antiparasitic drugs has changed in the past few years thanks to financial backing from not-for-profit organizations and the involvement of public-private partnerships. The collaboration of various pharmaceutical companies with the Special Programme for Research and Training in Tropical Diseases (TDR), giving access to their compound libraries to help scientists search for new antiparasitic drugs, is a good example of the pragmatic approach required for the development of new medicaments for those neglected diseases (15,32,40). The screening of compound libraries to discover new hit and lead compounds against protozoan parasites has been used very efficiently by our group for the past few years. Very potent antiprotozoal compounds, active in vitro and in vivo against Trypanosoma brucei rhodesiense and Plasmodium falciparum, were identified by our group (16,17,38). These lead compounds were discovered by screening against T. brucei and P. falciparum a small library (Ͻ100 molecules) of dicationic compounds structurally related to known antiparasitic drugs (e.g., pentamidine, diminazene) but primarily synthesized by us for different medicinal targets.Following this successful approach, we have now selected from our i...

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Bisguanidine, Bis(2-aminoimidazoline), and Polyamine Derivatives as Potent and Selective Chemotherapeutic Agents against Trypanosoma brucei rhodesiense. Synthesis and in Vitro Evaluation

Cited by 50 publications

References 47 publications

Asymmetrical Diaromatic Guanidinium/2-Aminoimidazolinium Derivatives: Synthesis and DNA Affinity

Asymmetrical Diaromatic Guanidinium/2-Aminoimidazolinium Derivatives: Synthesis and DNA Affinity

Synthesis and Antiprotozoal Activity of N-Alkoxy Analogues of the Trypanocidal Lead Compound 4,4′-Bis(imidazolinylamino)diphenylamine with Improved Human Blood−Brain Barrier Permeability

Antiprotozoal Activity of 1-Phenethyl-4-Aminopiperidine Derivatives

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