title: Synthetically modified L-histidine-rich peptidomimetics exhibit potent activity against Cryptococcus neoformans.
abstract: We describe the synthesis and antimicrobial evaluation of structurally new peptidomimetics, rich in synthetically modified L-histidine. Two series of tripeptidomimetics were synthesized by varying lipophilicity at the C-2 position of L-histidine and at the N- and C-terminus. The data indicates that peptides (5f, 6f, 9f and 10f) possessing highly lipophilic adamantan-1-yl group displayed strong inhibition of Cryptococcus neoformans. Peptide 6f is the most potent of all with IC50 and MFC values of 0.60 and 0.63 μg/mL, respectively, compared to the commercial drug amphotericin B (IC50=0.69 and MFC=1.25 μg/mL). The selectivity of these peptides to microbial pathogen was examined by a tryptophan fluorescence quenching study and transmission electron microscopy. These studies indicate that the peptides plausibly interact with the mimic membrane of pathogen by direct insertion, and results in disruption of membrane of pathogen.
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160 062, India.
authors.forename: Amit
authors.initials: A
authors.lastname: Mahindra
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160 062, India.
authors.forename: Nitin
authors.initials: N
authors.lastname: Bagra
authors.affiliation: Center for Nanoscience and Nanotechnology, Panjab University, Sector 14, Chandigarh 160 014, India.
authors.forename: Nishima
authors.initials: N
authors.lastname: Wangoo
authors.affiliation: Center for Nanoscience and Nanotechnology, Panjab University, Sector 14, Chandigarh 160 014, India.
authors.forename: Rohan
authors.initials: R
authors.lastname: Jain
authors.affiliation: National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS 38677, USA.
authors.forename: Shabana I
authors.initials: SI
authors.lastname: Khan
authors.affiliation: National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS 38677, USA.
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Jacob
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160 062, India. Electronic address: rahuljain@niper.ac.in.
authors.forename: Rahul
authors.initials: R
authors.lastname: Jain
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003455:Cryptococcus neoformans / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006639:Histidine / Q000737:chemistry*; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D057786:Peptidomimetics; D006639:Histidine
keywords: Alkylation; Antifungal peptides; C. neoformans; Ecofriendly peptide synthesis; Microwave