2. Academic Validation
  3. Synthesis and pharmacological evaluation of mono-arylimidamides as antileishmanial agents

Synthesis and pharmacological evaluation of mono-arylimidamides as antileishmanial agents

  • Bioorg Med Chem Lett. 2016 May 15;26(10):2551-2556. doi: 10.1016/j.bmcl.2016.03.082.
Xiaohua Zhu 1,  Abdelbasset A Farahat 2,  Meena Mattamana 1,  April Joice 1,  Trupti Pandharkar 1,  Elizabeth Holt 3,  Moloy Banerjee 3,  Jamie L Gragg 3,  Laixing Hu 4,  Arvind Kumar 3,  Sihyung Yang 5,  Michael Zhuo Wang 5,  David W Boykin 3,  Karl A Werbovetz 6
Affiliations

Affiliations

  • 1 Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
  • 2 Department of Chemistry, Georgia State University, Atlanta, GA 30302, USA; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
  • 3 Department of Chemistry, Georgia State University, Atlanta, GA 30302, USA.
  • 4 Department of Chemistry, Georgia State University, Atlanta, GA 30302, USA; Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 5 Department of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA.
  • 6 Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA. Electronic address: werbovetz.1@osu.edu.
PMID: 27048943 DOI: 10.1016/j.bmcl.2016.03.082
Abstract

Arylimidamide (AIA) compounds containing two pyridylimidamide terminal groups (bis-AIAs) possess outstanding in vitro antileishmanial activity, and the frontrunner bis-AIA DB766 (2,5-bis[2-(2-isopropoxy)-4-(2-pyridylimino)aminophenyl]furan) is active in visceral leishmaniasis models when given orally. Eighteen compounds containing a single pyridylimidamide terminal group (mono-AIAs) were synthesized and evaluated for their antileishmanial potential. Six of these compounds exhibited sub-micromolar potency against both intracellular Leishmania donovani and Leishmania amazonensis amastigotes, and three of these compounds also displayed selectivity indexes of 25 or greater for the parasites compared to a J774 macrophage cell line. When given orally at a dose of 100mg/kg/day for five days, compound 1b (N-(3-isopropoxy-4-(5-phenylfuran-2-yl)phenyl)picolinimidamide methanesulfonate) reduced liver parasitemia by 46% in L. donovani-infected mice. Mono-AIAs are thus a new class of candidate molecules for antileishmanial drug development.

Keywords

Arylimidamide; DB766; Drug discovery; Leishmaniasis.

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