title: Synthesis and pharmacological evaluation of mono-arylimidamides as antileishmanial agents.
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.
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA 30302, USA; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
authors.forename: Abdelbasset A
authors.initials: AA
authors.lastname: Farahat
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Meena
authors.initials: M
authors.lastname: Mattamana
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: April
authors.initials: A
authors.lastname: Joice
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Trupti
authors.initials: T
authors.lastname: Pandharkar
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA 30302, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Holt
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA 30302, USA.
authors.forename: Moloy
authors.initials: M
authors.lastname: Banerjee
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA 30302, USA.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Gragg
authors.affiliation: 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.
authors.forename: Laixing
authors.initials: L
authors.lastname: Hu
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA 30302, USA.
authors.forename: Arvind
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA.
authors.forename: Sihyung
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA.
authors.forename: Michael Zhuo
authors.initials: MZ
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA 30302, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Boykin
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA. Electronic address: werbovetz.1@osu.edu.
authors.forename: Karl A
authors.initials: KA
authors.lastname: Werbovetz
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005663:Furans / Q000737:chemistry; D020128:Inhibitory Concentration 50; D007893:Leishmania donovani / Q000187:drug effects* / Q000472:pathogenicity; D007894:Leishmania mexicana / Q000187:drug effects* / Q000472:pathogenicity; D007898:Leishmaniasis, Visceral / Q000188:drug therapy / Q000469:parasitology; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology; D008807:Mice, Inbred BALB C; D018512:Parasitemia / Q000188:drug therapy / Q000469:parasitology; D013329:Structure-Activity Relationship
chemical_list: D000981:Antiprotozoal Agents; D005663:Furans; C039281:furan
keywords: Arylimidamide; DB766; Drug discovery; Leishmaniasis