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
  • 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: [email protected].
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.