Old World cutaneous leishmaniasis is caused by infection with Leishmania major and Leishmania tropica. Pentamidine and related dications exhibit broad spectrum antiprotozoal activity. Based on the previously reported efficacy of these compounds against related organisms, 18 structural analogs of pentamidine were evaluated for in vitro antileishmanial activity, using pentamidine as the standard reference drug for comparison. Furan analogs and reversed amidine compounds were examined for activity against L. major and L. tropica promastigotes. The most active compounds against both Leishmania species were in the reversed amidine series. DB745 and DB746 exhibited the highest activity against L. major and DB745 was the most active compound against L. tropica. Both of these compounds exhibited 50% inhibitory concentrations (IC50) below 1 nM for L. major. Ten reversed amidines were also tested for their ability to inhibit growth in an axenic amastigote model. Nine of 10 reversed amidine analogs were active at concentrations below 1 nM. These results justify further study of dicationic compounds as potential new agents for treating cutaneous leishmaniasis.
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June 2008
THERAPEUTICS-DIAGNOSTICS|
June 01 2008
Inhibition by Dications of In Vitro Growth of Leishmania major and Leishmania tropica: Causative Agents of Old World Cutaneous Leishmaniasis
Alexa C. Rosypal;
Alexa C. Rosypal
School of Medicine, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599. tidwell@med.unc.edu
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Karl A. Werbovetz;
Karl A. Werbovetz
School of Medicine, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599. tidwell@med.unc.edu
* College of Pharmacy, Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, Ohio 43210
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Manar Salem;
Manar Salem
School of Medicine, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599. tidwell@med.unc.edu
* College of Pharmacy, Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, Ohio 43210
† Current address: Faculty of Pharmacy, Tanta University, Egypt
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Chad E. Stephens;
Chad E. Stephens
School of Medicine, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599. tidwell@med.unc.edu
‡ Department of Chemistry, Georgia State University, Atlanta, Georgia 30302
∥ To whom correspondence should be addressed
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Arvind Kumar;
Arvind Kumar
School of Medicine, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599. tidwell@med.unc.edu
‡ Department of Chemistry, Georgia State University, Atlanta, Georgia 30302
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David W. Boykin;
David W. Boykin
School of Medicine, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599. tidwell@med.unc.edu
‡ Department of Chemistry, Georgia State University, Atlanta, Georgia 30302
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James E. Hall;
James E. Hall
School of Medicine, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599. tidwell@med.unc.edu
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Richard R. Tidwell
Richard R. Tidwell
School of Medicine, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599. tidwell@med.unc.edu
§ Current address: Augusta State University, 2500 Walton Way, Augusta, Georgia 30904
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J Parasitol (2008) 94 (3): 743–749.
Citation
Alexa C. Rosypal, Karl A. Werbovetz, Manar Salem, Chad E. Stephens, Arvind Kumar, David W. Boykin, James E. Hall, Richard R. Tidwell; Inhibition by Dications of In Vitro Growth of Leishmania major and Leishmania tropica: Causative Agents of Old World Cutaneous Leishmaniasis. J Parasitol 1 June 2008; 94 (3): 743–749. doi: https://doi.org/10.1645/GE-1387.1
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