Azaterphenyl diamidines as antileishmanial agents

Hu, Linping; Arafa, Reem K.; Ismail, Mohamed A.; Wenzler, Tanja; Brun, Reto; Munde, Manoj; Wilson, W. David; Nzimiro, Sandra; Samyesudhas, Serene; Werbovetz, Karl A.; Boykin, David W.

doi:10.1016/j.bmcl.2007.10.091

Cited by 28 publications

(44 citation statements)

References 27 publications

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“…Since AIAs contain amidine functional groups, the ultrastructural effects caused by the lead AIA DB766 were compared with those caused by the diamidine DB1111 in Leishmania donovani axenic amastigotes. While DB1111 caused dilation of the L. donovani mitochondrion, as observed previously (16), no changes in mitochondrial morphology were observed upon DB766 treatment. Instead, other ultrastructural alterations were noted in other organelles, including an increased number of vesicles in the flagellar pocket, damage to the flagellar membrane, and increased cytoplasmic vacuolization (data not shown).…”

Section: Resultssupporting

confidence: 83%

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Studies on the Antileishmanial Mechanism of Action of the Arylimidamide DB766: Azole Interactions and Role of CYP5122A1

Pandharkar

Zhu

Mathur

et al. 2014

Antimicrob Agents Chemother

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c Arylimidamides (AIAs) are inspired by diamidine antimicrobials but show superior activity against intracellular parasites. The AIA DB766 {2,5-bis[2-(2-i-propoxy)-4-(2-pyridylimino)aminophenyl]furan hydrochloride} displays outstanding potency against intracellular Leishmania parasites and is effective in murine and hamster models of visceral leishmaniasis when given orally, but its mechanism of action is unknown. In this study, through the use of continuous DB766 pressure, we raised Leishmania donovani axenic amastigotes that displayed 12-fold resistance to this compound. These DB766-resistant (DB766R) parasites were 2-fold more sensitive to miltefosine than wild-type organisms and were hypersensitive to the sterol 14␣-demethylase (CYP51) inhibitors ketoconazole and posaconazole (2,000-fold more sensitive and over 12,000-fold more sensitive than the wild type, respectively). Western blot analysis of DB766R parasites indicated that while expression of CYP51 is slightly increased in these organisms, expression of CYP5122A1, a recently identified cytochrome P450 associated with ergosterol metabolism in Leishmania, is dramatically reduced in DB766R parasites. In vitro susceptibility assays demonstrated that CYP5122A1 halfknockout L. donovani promastigotes were significantly less susceptible to DB766 and more susceptible to ketoconazole than their wild-type counterparts, consistent with observations in DB766R parasites. Further, DB766-posaconazole combinations displayed synergistic activity in both axenic and intracellular L. donovani amastigotes. Taken together, these studies implicate CYP5122A1 in the antileishmanial action of the AIAs and suggest that DB766-azole combinations are potential candidates for the development of synergistic antileishmanial therapy.

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Section: Resultssupporting

confidence: 83%

“…Drugs and reagents. The CellTiter reagent was obtained from Promega (Madison, WI), miltefosine was purchased from Cayman Chemical Company (Ann Arbor, MI), and DB1111, DB766, DB745, and DB1852 were synthesized according to known methods (5,8,16). All other reagents were purchased from Sigma-Aldrich (St. Louis, MO), unless otherwise indicated.…”

Section: Methodsmentioning

confidence: 99%

Studies on the Antileishmanial Mechanism of Action of the Arylimidamide DB766: Azole Interactions and Role of CYP5122A1

Pandharkar

Zhu

Mathur

et al. 2014

Antimicrob Agents Chemother

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“…This type of damage has been reported with other diamidines (3,5,9,10,12) and reversed amidines (24). Significantly, the flow cytometry studies corroborated the TEM results showing that DB1362 targeted the mitochondrion-kinetoplast complex.…”

Section: Discussionsupporting

confidence: 85%

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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“…Another class of compounds, aromatic diamidines (AD) and their analogues, target the minor groove of DNA and has been tested against pathogenic microorganisms [Hu et al 2008]. The effect of several AD analogues was demonstrated against T. cruzi , and among them, significant in vitro activity was found for arylimidamides (AIAs), including DB889, DB786, DB702 and DB766 [Silva et al 2007].…”

Section: New Drugs For Treating Chagas Disease: New Hopes In Need Of mentioning

confidence: 99%

Clinical aspects of Chagas disease and implications for novel therapies

Menezes

Costa

Gollob

et al. 2011

Drug Development Research

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The interaction between the protozoan parasite Trypanosoma cruzi and the human host dates back 9000 years, as demonstrated by molecular analysis of material obtained from Andean mummies indicating the presence of the parasite’s kinetoplast DNA in populations from Chile and Peru. This long-established interaction, which persists today, demonstrates that T. cruzi has established a very well adapted relationship with the human host. From a host-parasite relationship point-of-view this is desirable, however, such a high degree of adaptation is perhaps the foundation for many of the unknowns that surround this disease. Unveiling of the immunological mechanisms that underlie the establishment of pathology, identification of parasite-associated factors that determine strain-differential tissue tropism, discovery of host genetic elements that influence the development of different clinical forms of the disease, and understanding environmental factors that may influence the host-parasite interactions, are some of the key questions remaining to be answered. The response to these questions will aid in addressing some of the current challenges in Chagas disease: fulfilling the need for efficient diagnosis, developing effective prophylactic measures, discovering effective therapeutics, and finding methods to control disease progression.

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Azaterphenyl diamidines as antileishmanial agents

Cited by 28 publications

References 27 publications

Studies on the Antileishmanial Mechanism of Action of the Arylimidamide DB766: Azole Interactions and Role of CYP5122A1

Studies on the Antileishmanial Mechanism of Action of the Arylimidamide DB766: Azole Interactions and Role of CYP5122A1

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

Clinical aspects of Chagas disease and implications for novel therapies

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