title: Synthesis and anti-tubercular activity of N(2)-arylbenzo[g]isoquinoline-5,10-dione-3-iminium bromides.
abstract: Tuberculosis has remained a challenge for medicinal chemists worldwide. In the framework of a collaborative program to identify and evaluate novel antitubercular candidate compounds, the biological properties of benzo[g]isoquinoline-5,10-diones have been found to be very promising. In this paper we have further expanded the library by incorporation of an amidinium moiety into the benzo[g]isoquinoline-5,10-dione scaffold. The presence of this functional group also increased the solubility of the quinones in polar solvents. To this purpose N(2)-arylbenzo[g]isoquinoline-5,10-dione-3-iminium bromides were synthesized in a straightforward way by means of a reaction of anilines with 2-(bromomethyl)-3-(cyanomethyl)-1,4-dimethoxynaphthalene. Following the biological evaluation, N(2)-(4-chlorophenyl)-5,10-dioxobenzo[g]isoquinoline-3(2H)-iminium bromide (MIC = 1.16 μM, CC50 = 28.51 μM, SI = 24.58) was selected as the most promising representative. Apart from the nano-molar anti-mycobacterial activity, the compound was able to target intracellular residing Mycobacterium tuberculosis and the susceptibility of a multi-drug-resistant strain towards the compound was confirmed.
authors.affiliation: Organic Synthesis, Faculty of Sciences, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium. Kourosch.AbbaspourTehrani@uantwerpen.be.
authors.forename: G
authors.initials: G
authors.lastname: Rotthier
authors.affiliation: Laboratory of Microbiology, Parasitology and Hygiene (LMPH), S7, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium and Scientific Service Immunology, O.D. Communicable & Infectious Diseases, Scientific Institute of Public Health (Site Ukkel), Engelandstraat 642, B-1180 Ukkel, Belgium.
authors.forename: D
authors.initials: D
authors.lastname: Cappoen
authors.affiliation: Institute of Chemistry, Vietnam Academy of Sciences and Technology, 18-Hoang Quoc Viet, Cau Giay, Ha Noi, Vietnam.
authors.forename: Quang Trung
authors.initials: QT
authors.lastname: Nguyen
authors.affiliation: Institute of Chemistry, Vietnam Academy of Sciences and Technology, 18-Hoang Quoc Viet, Cau Giay, Ha Noi, Vietnam.
authors.forename: Tuyet Anh
authors.initials: TA
authors.lastname: Dang Thi
authors.affiliation: Program Tuberculosis and Mycobacteria, Service Bacterial Diseases, O.D. Communicable & Infectious Diseases, Scientific Institute of Public Health (Site Ukkel), Engelandstraat 642, B-1180 Ukkel, Belgium.
authors.forename: V
authors.initials: V
authors.lastname: Mathys
authors.affiliation: Institute of Chemistry, Vietnam Academy of Sciences and Technology, 18-Hoang Quoc Viet, Cau Giay, Ha Noi, Vietnam.
authors.forename: Van Tuyen
authors.initials: VT
authors.lastname: Nguyen
authors.affiliation: Scientific Service Immunology, O.D. Communicable & Infectious Diseases, Scientific Institute of Public Health (Site Ukkel), Engelandstraat 642, B-1180 Ukkel, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Huygen
authors.affiliation: Laboratory of Microbiology, Parasitology and Hygiene (LMPH), S7, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Maes
authors.affiliation: Laboratory of Microbiology, Parasitology and Hygiene (LMPH), S7, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Cos
authors.affiliation: Organic Synthesis, Faculty of Sciences, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium. Kourosch.AbbaspourTehrani@uantwerpen.be.
authors.forename: K
authors.initials: K
authors.lastname: Abbaspour Tehrani
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006842:Hydrocarbons, Brominated / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D013329:Structure-Activity Relationship; D018088:Tuberculosis, Multidrug-Resistant
chemical_list: D000995:Antitubercular Agents; D006842:Hydrocarbons, Brominated; D007546:Isoquinolines