title: 2-Guanidino-quinazolines as a novel class of translation inhibitors.
abstract: A variety of structurally unrelated organic compounds has been reported to have antibacterial activity. Among these, certain small-molecule translation inhibitors have attracted a great deal of attention, due to their relatively high selectivity against prokaryotes, and an appropriate therapeutic index with minor "off target" effects. However, ribosomes are being considered as poorly druggable biological targets, thereby making some routine computational-based approaches to rational drug design and its development rather ineffective. Taking this into account, diversity-oriented biological screening can reasonably be considered as the most advantageous strategy. Thus, using a high-throughput screening (HTS) platform, we applied a unique biological assay for in vitro evaluation of thousands of organic molecules, especially targeted against bacterial ribosomes and translation. As a result, we have identified a series of structurally diverse small-molecule compounds that induce a reporter strain sensitive to translation and DNA biosynthesis inhibitors. In a cell free system, several molecules were found to strongly inhibit protein biosynthesis. Among them, compounds bearing a 2-guanidino-quinazoline core demonstrated the most promising antibacterial activity. With regard to the preliminary structure-activity relationship (SAR) study, we revealed that relatively small substituents at positions 4, 6 and 8 of the quinazoline ring significantly enhance the target activity whereas modification of the guanidine group leads to decrease or loss of antibacterial potency. This novel class of translation inhibitors can properly be regarded as a promising starting point for the development of novel antibacterial therapeutic or screening tools.
authors.affiliation: Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, 119992, Russia.
authors.forename: E S
authors.initials: ES
authors.lastname: Komarova Andreyanova
authors.affiliation: A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119992, Russia; Skolkovo Institute of Science and Technology, Skolkovo, 143026, Russia; Chemistry Dept., Lomonosov Moscow State University, Moscow, 119991, Russia.
authors.forename: I A
authors.initials: IA
authors.lastname: Osterman
authors.affiliation: A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119992, Russia; Skolkovo Institute of Science and Technology, Skolkovo, 143026, Russia; Chemistry Dept., Lomonosov Moscow State University, Moscow, 119991, Russia.
authors.forename: P I
authors.initials: PI
authors.lastname: Pletnev
authors.affiliation: Chemistry Dept., Lomonosov Moscow State University, Moscow, 119991, Russia; Moscow Institute of Physics and Technology (State University), Moscow Region, 117303, Russia; National University of Science and Technology (MISiS), Moscow, 119049, Russia.
authors.forename: Y A
authors.initials: YA
authors.lastname: Ivanenkov
authors.affiliation: Chemistry Dept., Lomonosov Moscow State University, Moscow, 119991, Russia; National University of Science and Technology (MISiS), Moscow, 119049, Russia.
authors.forename: A G
authors.initials: AG
authors.lastname: Majouga
authors.affiliation: A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119992, Russia; Chemistry Dept., Lomonosov Moscow State University, Moscow, 119991, Russia.
authors.forename: A A
authors.initials: AA
authors.lastname: Bogdanov
authors.affiliation: A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119992, Russia; Skolkovo Institute of Science and Technology, Skolkovo, 143026, Russia; Chemistry Dept., Lomonosov Moscow State University, Moscow, 119991, Russia. Electronic address: petya@genebee.msu.ru.
authors.forename: P V
authors.initials: PV
authors.lastname: Sergiev
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects / Q000472:pathogenicity; D015195:Drug Design; D006801:Humans; D007239:Infections / Q000188:drug therapy / Q000382:microbiology; D014176:Protein Biosynthesis / Q000187:drug effects*; D011500:Protein Synthesis Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D011500:Protein Synthesis Inhibitors; D011799:Quinazolines; D054852:Small Molecule Libraries
keywords: Antibacterial; Bacteria; Protein synthesis; Quinazoline; Reporter strain; Screening; Translation