title: Synthesis and Biological Evaluation of Novel 2-Aminonicotinamide Derivatives as Antifungal Agents.
abstract: Based on the structures of the reported compounds G884 [N-(3-(pentan-2-yloxy)phenyl)nicotinamide], E1210 [3-(3-(4-((pyridin-2-yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine], and 10 b [2-amino-N-((5-(3-fluorophenoxy)thiophen-2-yl)methyl)nicotinamide], which inhibit the biosynthesis of glycosylphosphatidylinositol (GPI)-anchored proteins in fungi, a series of novel 2-aminonicotinamide derivatives were designed, synthesized, and evaluated for in vitro antifungal activity. Most of these compounds were found to exhibit potent in vitro antifungal activity against Candida albicans, with MIC80values ranging from 0.0313 to 4.0 μg mL-1. In particular, compounds 11 g [2-amino-N-((5-(((2-fluorophenyl)amino)methyl)thiophen-2-yl)methyl)nicotinamide] and 11 h [2-amino-N-((5-(((3-fluorophenyl)amino)methyl)thiophen-2-yl)methyl)nicotinamide] displayed excellent activity against C. albicans, with MIC80values of 0.0313 μg mL-1, and exhibited broad-spectrum antifungal activity against fluconazole-resistant C. albicans, C. parapsilosis, C. glabrata, and Cryptococcus neoformans, with a MIC80range of 0.0313-2.0 μg mL-1. Further studies by electron microscopy and laser confocal microscopy indicated that compound 11 g targets the cell wall and decreases GPI anchor content on the cell surface of C. albicans.
authors.affiliation: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China.
authors.forename: Tingjunhong
authors.initials: T
authors.lastname: Ni
authors.affiliation: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Li
authors.affiliation: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Xie
authors.affiliation: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China.|School of Pharmacy, Fujian University of Traditional Chinese Medicine, 1 Qiuyang Road, Fuzhou, 350112, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, Tongji University School of Medicine, 1239 Siping Road, Shanghai, 200092, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, Tongji University School of Medicine, 1239 Siping Road, Shanghai, 200092, China.
authors.forename: Maomao
authors.initials: M
authors.lastname: An
authors.affiliation: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China.
authors.forename: Chengxu
authors.initials: C
authors.lastname: Zang
authors.affiliation: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Cai
authors.affiliation: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China.|School of Pharmacy, Fujian University of Traditional Chinese Medicine, 1 Qiuyang Road, Fuzhou, 350112, China.
authors.forename: Dazhi
authors.initials: D
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China.
authors.forename: Yuanying
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D000631:Aminopyridines / Q000737:chemistry*; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002175:Candida / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects; D003455:Cryptococcus neoformans / Q000187:drug effects; D025141:Drug Resistance, Fungal / Q000187:drug effects; D007555:Isoxazoles / Q000737:chemistry*; D008826:Microbial Sensitivity Tests; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C570438:APX001A; D000631:Aminopyridines; D000935:Antifungal Agents; D007555:Isoxazoles; D009536:Niacinamide
keywords: 2-aminonicotinamide; antifungal agents; glycosylphosphatidylinositol; structure-activity relationships; synthesis