title: Discovery and preliminary structure-activity relationship of the marine natural product manzamines as herpes simplex virus type-1 inhibitors.
abstract: Herpes simplex virus type-1 (HSV-1) is a member of alpha-herpesviridae family and is known to cause contagious human infections. The marine habitat is a rich source of structurally unique bioactive secondary metabolites. A small library of marine natural product classes 1-10 has been screened to discover a new hit entity active against HSV-1. Manzamine A showed potent activity against HSV-1 via targeting the viral gene ICP0. Manzamine A is a β-carboline alkaloid isolated from the Indo-Pacific sponge Acanthostrongylophora species. Currently, acyclovir is the drug of choice for HSV-1 infections. Compared with 50 µM acyclovir, manzamine A at 1 µM concentration produced potent repressive effects on viral replication and release of infectious viruses in SIRC cells in recent studies. The potent anti-HSV-1 activity of manzamine A prompted a preliminary structure-activity relationship study by testing targeted manzamines. These included 8-hydroxymanzamine A (11), to test the effect of the C-8 hydroxy substitution at the β-carboline moiety; manzamine E (12), to assess the importance of substitution at the azacyclooctane ring; and ircinal A (13), to determine whether the β-carboline ring is required for the activity. Manzamine A was chemically transformed to its salt forms, manzamine A monohydrochloride (14) and manzamine A monotartrate (15), to test whether improving water solubility and hydrophilicity will positively affect the activity. Compounds were tested for activity against HSV-1 using fluorescent microscopy and plaque assay. The results showed the reduced anti-HSV-1 activity of 11, suggesting that C-8 hydroxy substitution might adversely affect the activity. Similarly, manzamines 12 and 13 showed no activity against HSV-1, indicating the preference of the unsubstituted azacylcooctane and β-carboline rings to the activity. Anti-HSV-1 activity was significantly improved for the manzamine A salts 14 and 15, suggesting that improving the overall water solubility as salt forms can significantly enhance the activity. Manzamines have significant potential for future development as anti-HSV-1 entity.
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, USA.
authors.forename: Jayavardhana R
authors.initials: JR
authors.lastname: Palem
authors.affiliation: Department of Pharmaceutical, Social and Administrative Sciences, D'Youville College School of Pharmacy, Buffalo, NY 14201, USA.
authors.forename: Mudit
authors.initials: M
authors.lastname: Mudit
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland Eastern Shore School of Pharmacy, Princess Anne, MD 21853, USA.
authors.forename: Shao-Chung V
authors.initials: SV
authors.lastname: Hsia
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, USA, Tel.: +1-318-342-1725, Fax: +1-318-342-1737.
authors.forename: Khalid A El
authors.initials: KAE
authors.lastname: Sayed
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001688:Biological Products / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology*; D002243:Carbolines / Q000494:pharmacology; D002460:Cell Line; D003315:Cornea; D004353:Drug Evaluation, Preclinical; D018259:Herpesvirus 1, Human / Q000187:drug effects*; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D011817:Rabbits; D013329:Structure-Activity Relationship; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D001688:Biological Products; D002227:Carbazoles; D002243:Carbolines; C078290:manzamine A; C086783:8-hydroxymanzamine A