Synthesis and pharmacological evaluation of mono-arylimidamides as antileishmanial agents

Xiaohua Zhu; Abdelbasset A Farahat; Meena Mattamana; April Joice; Trupti Pandharkar; Elizabeth Holt; Moloy Banerjee; Jamie L Gragg; Laixing Hu; Arvind Kumar; Sihyung Yang; Michael Zhuo Wang; David W Boykin; Karl A Werbovetz

doi:10.1016/j.bmcl.2016.03.082

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. Epub 2016 Mar 25.

Authors

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.

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.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Animals
Antiprotozoal Agents / chemical synthesis
Antiprotozoal Agents / chemistry*
Antiprotozoal Agents / pharmacology*
Chemistry Techniques, Synthetic
Drug Evaluation, Preclinical / methods
Furans / chemistry
Inhibitory Concentration 50
Leishmania donovani / drug effects*
Leishmania donovani / pathogenicity
Leishmania mexicana / drug effects*
Leishmania mexicana / pathogenicity
Leishmaniasis, Visceral / drug therapy
Leishmaniasis, Visceral / parasitology
Macrophages / drug effects
Macrophages / parasitology
Mice, Inbred BALB C
Parasitemia / drug therapy
Parasitemia / parasitology
Structure-Activity Relationship

Substances

Antiprotozoal Agents
Furans
furan