title: Human Toll-like receptor 8-selective agonistic activities in 1-alkyl-1H-benzimidazol-2-amines.
abstract: Toll-like receptor (TLR)-8 agonists strongly induce the production of T helper 1-polarizing cytokines and may therefore serve as promising candidate vaccine adjuvants, especially for the very young and the elderly. Earlier structure-based ligand design led to the identification of 3-pentyl-quinoline-2-amine as a novel, human TLR8-specific agonist. Comprehensive structure-activity relationships in ring-contracted 1-alkyl-1H-benzimidazol-2-amines were undertaken, and the best-in-class compound, 4-methyl-1-pentyl-1H-benzo[d]imidazol-2-amine, was found to be a pure TLR8 agonist, evoking strong proinflammatory cytokine and Type II interferon responses in human PBMCs, with no attendant CD69 upregulation in natural lymphocytic subsets. The 1-alkyl-1H-benzimidazol-2-amines represent a novel, alternate chemotype with pure TLR8-agonistic activities and will likely prove useful not only in understanding TLR8 signaling but also perhaps as a candidate vaccine adjuvant.
authors.affiliation: Department of Medicinal Chemistry, University of Kansas , Lawrence, Kansas 66047, United States.
authors.forename: Mallesh
authors.initials: M
authors.lastname: Beesu
authors.forename: Subbalakshmi S
authors.initials: SS
authors.lastname: Malladi
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Fox
authors.forename: Cassandra D
authors.initials: CD
authors.lastname: Jones
authors.forename: Anshuman
authors.initials: A
authors.lastname: Dixit
authors.forename: Sunil A
authors.initials: SA
authors.lastname: David
mesh_terms: D000588:Amines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D051200:Toll-Like Receptor 8 / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D000099192:CD69 Antigens
chemical_list: D000588:Amines; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D001562:Benzimidazoles; D016207:Cytokines; D018836:Inflammation Mediators; D007371:Interferon-gamma; D037181:Lectins, C-Type; D051200:Toll-Like Receptor 8; D000099192:CD69 Antigens; C000593224:4-methyl-1-pentyl-1H-benzo(d)imidazol-2-amine; C495349:TLR8 protein, human
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