title: SAR of a series of anti-HSV-1 acridone derivatives, and a rational acridone-based design of a new anti-HSV-1 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridine series.
abstract: Herpes Simplex Virus (HSV) infections are among the most common human diseases. In this work, we assess the structural features and electronic properties of a series of ten 1-hydroxyacridone derivatives (1a-j) recently described as a new class of non-nucleoside inhibitors of Herpes Simplex Virus-1 (HSV-1). Based on these molecules, we applied rigid analogue and isosteric replacement approaches to design and synthesize nine new 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridine derivatives (2a-i). The biological and computational results of these new molecules were compared with 1-hydroxyacridones. An inhibitory profile was observed in 10-Cl substituted 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridine derivative (2f), which presents the same substituent at the analogous position of 1-hydroxyacridone derivative (1b). The structure-activity relationship (SAR) studies pointed out the 10-position next to nitrogen atom as important for the anti-HSV-1 profile in the pyrazolo-naphthyridine derivatives tested, which reinforced the promising profile for further experimental investigation. The most potent acridone and pyrazolo-naphthridine derivatives were also submitted to an in silico ADMET screening in order to determine their overall drug-score, which confirmed their potential antiviral profile.
authors.affiliation: Universidade Federal Fluminense, Instituto de Química, Departamento de Química Orgânica, Programa de Pós-Graduação em Química Orgânica, Campus do Valonguinho, 24210-150 Niterói, RJ, Brazil. alicerolim@globo.com
authors.forename: Alice M R
authors.initials: AM
authors.lastname: Bernardino
authors.forename: Helena C
authors.initials: HC
authors.lastname: Castro
authors.forename: Izabel C P P
authors.initials: IC
authors.lastname: Frugulhetti
authors.forename: Natália I V
authors.initials: NI
authors.lastname: Loureiro
authors.forename: Alexandre R
authors.initials: AR
authors.lastname: Azevedo
authors.forename: Luiz C S
authors.initials: LC
authors.lastname: Pinheiro
authors.forename: Thiago M L
authors.initials: TM
authors.lastname: Souza
authors.forename: Viveca
authors.initials: V
authors.lastname: Giongo
authors.forename: Fabiana
authors.initials: F
authors.lastname: Passamani
authors.forename: Uiaran O
authors.initials: UO
authors.lastname: Magalhães
authors.forename: Magaly G
authors.initials: MG
authors.lastname: Albuquerque
authors.forename: Lúcio M
authors.initials: LM
authors.lastname: Cabral
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Rodrigues
mesh_terms: D000166:Acridines / Q000737:chemistry* / Q000494:pharmacology; D054831:Acridones; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D018259:Herpesvirus 1, Human / Q000187:drug effects*; D006801:Humans; D009287:Naphthyridines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000166:Acridines; D054831:Acridones; D000998:Antiviral Agents; D009287:Naphthyridines; C041300:acridone