Antiparasitic activity of aromatic diamidines and their patented literature

Soeiro, Maria de Nazaré Correia; Souza, Elen Mello de; Boykin, David W.

doi:10.1517/13543776.17.8.927

Cited by 10 publications

(7 citation statements)

References 90 publications

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“…AD and their congeners present broadspectrum activity against pathogenic microorganisms, and some of them have veterinary and human clinical uses {e.g., pentamidine isethionate [1,5-bis(4-amidino-phenoxy)pentane] (Pentacarinat; Rhodia)} (45,57,72). However, these compounds often cause considerable side effects and require parenteral routes of administration, which stimulates the synthesis and screening of new analogs and prodrugs to overcome these limitations (19,34,56,59).…”

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confidence: 99%

Arylimidamide DB766, a Potential Chemotherapeutic Candidate for Chagas' Disease Treatment

Batista

Oliveira

et al. 2010

Antimicrob Agents Chemother

195

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Chagas' disease, a neglected tropical illness for which current therapy is unsatisfactory, is caused by the intracellular parasite Trypanosoma cruzi. The goal of this work is to investigate the in vitro and in vivo effects of the arylimidamide (AIA) DB766 against T. cruzi. This arylimidamide exhibits strong trypanocidal activity and excellent selectivity for bloodstream trypomastigotes and intracellular amastigotes (Y strain), giving IC 50 s (drug concentrations that reduce 50% of the number of the treated parasites) of 60 and 25 nM, respectively. DB766 also exerts striking effects upon different parasite stocks, including those naturally resistant to benznidazole, and displays higher activity in vitro than the reference drugs. By fluorescent and transmission electron microscopy analyses, we found that this AIA localizes in DNA-enriched compartments and induces considerable damage to the mitochondria. DB766 effectively reduces the parasite load in the blood and cardiac tissue and presents efficacy similar to that of benznidazole in mouse models of T. cruzi infection employing the Y and Colombian strains, using oral and intraperitoneal doses of up to 100 mg/kg/day that were given after the establishment of parasite infection. This AIA ameliorates electrocardiographic alterations, reduces hepatic and heart lesions induced by the infection, and provides 90 to 100% protection against mortality, which is similar to that provided by benznidazole. Our data clearly show the trypanocidal efficacy of DB766, suggesting that this AIA may represent a new lead compound candidate to Chagas' disease treatment.

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confidence: 99%

Arylimidamide DB766, a Potential Chemotherapeutic Candidate for Chagas' Disease Treatment

Batista

Oliveira

et al. 2010

Antimicrob Agents Chemother

195

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“…To overcome these limitations, new aromatic dications and their prodrugs have been synthesized and screened both in vitro and in vivo against different pathogens (2,26). Recent studies have shown good in vitro and in vivo activity for diamidines such as furamidine (DB75), its N-phenyl-substituted analogue (DB569), and reversed amidines (5,7,8,23,24) against T. cruzi.…”

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confidence: 99%

In Vitro and In Vivo Studies of the Trypanocidal Activity of a Diarylthiophene Diamidine against Trypanosoma cruzi

Silva

Batista

et al. 2008

Antimicrob Agents Chemother

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Aromatic diamidines are DNA minor groove-binding ligands that display excellent antimicrobial activity against fungi, bacteria, and protozoa. Due to the currently unsatisfactory chemotherapy for Chagas' disease and in view of our previous reports regarding the effect of diamidines and analogues against both in vitro and in vivo Trypanosoma cruzi infection, this study evaluated the effects of a diarylthiophene diamidine (DB1362) against both amastigotes and bloodstream trypomastigotes of T. cruzi, the etiological agent of Chagas' disease. The data show the potent in vitro activity of DB1362 against both parasite forms that are relevant for mammalian infection at doses which do not exhibit cytotoxicity. Ultrastructural analysis and flow cytometry studies show striking alterations in the nuclei and mitochondria of the bloodstream parasites. In vivo studies were performed at two different drug concentrations (25 and 50 mg/kg/day) using a 2-day or a 10-day regimen. The best results were obtained when acutely infected mice were treated with two doses at the lower concentration, resulting in 100% survival, compared to the infected and untreated mice. Although it did not display higher efficacy than benznidazole, DB1362 reduced both cardiac parasitism and inflammation, and in addition, it protected against the cardiac alterations (determined by measurements) common in T. cruzi infection. These results support further investigation of diamidines and related compounds as potential agents against Chagas' disease.

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“…Supplementary crystallographic data have been deposited with the Cambridge Crystallographic Data Centre, CCDC nos. 1031758 (1), 1031757 (2), 1031756 (3), 1031755 (4), 1031753 (5a), 1031754 (5b), 1031752 (6), 1031750 (7), 1031749 (8), 1031748 (9), 1031747 (10). Copies of the data may be obtained free of charge from The Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk or www: http://www.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

“…[1][2][3][4][5][6][7] Due to the similarity of the amidine group to the guanidine group of L-arginine, amidines can interact with the L-arginine binding site of NO synthase. 8 Several benzamidine derivatives are potent competitive inhibitors of trypsin-and trypsin-like enzymes and serineproteases.…”

Section: Introductionmentioning

confidence: 99%

Hydrogen Bonding Networks and Solid-State Conversions in Benzamidinium Salts

Kamali

Aljohani

McArdle

et al. 2015

Crystal Growth & Design

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Ten benzamidinium salts of carboxylic acids, amides and sulfonamides have been crystallized from solution. Single-crystal X-ray analyses revealed various hydrogen bonding motifs which are discussed in terms of supramolecular synthons and graph sets. Benzamidinium hydrogen maleate (5a) crystallizes as large needles of up to > 3 cm length. Attempts to influence the crystal habit and size through a change of solvent and the presence of additives yielded a second polymorph (5b). The formation of the benzamidinium salts by mechanochemical reaction was also investigated. Grinding of benzamidine with nicotinic acid, salicylic acid, paminobenzoic acid, cyanuric acid, pimelic acid, saccharin and sulfathiazole with mortar and pestle or using a ball-mill gave compounds identical to those obtained by crystallization from solution. Time-dependent X-ray powder patterns of a stoichiometric benzamidine/cyanuric acid mixture suggested that the mechanochemical salt formation occured via the amorphous state. Ball-milling of benzamidine with sulfamerazine generated amorphous benzamidinium sulfamerazinate that was stable towards crystallization for at least two weeks, when stored at 25 % relative humidity.2

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Antiparasitic activity of aromatic diamidines and their patented literature

Cited by 10 publications

References 90 publications

Arylimidamide DB766, a Potential Chemotherapeutic Candidate for Chagas' Disease Treatment

Arylimidamide DB766, a Potential Chemotherapeutic Candidate for Chagas' Disease Treatment

In Vitro and In Vivo Studies of the Trypanocidal Activity of a Diarylthiophene Diamidine against Trypanosoma cruzi

Hydrogen Bonding Networks and Solid-State Conversions in Benzamidinium Salts

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