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Large-scale High-throughput Screening Revealed 5'-(carbonylamino)-2,3'- bithiophene-4'-carboxylate as Novel Template for Antibacterial Agents

Author(s):

Yan A. Ivanenkov, Renat S. Yamidanov, Ilya A. Osterman, Petr V. Sergiev, Vladimir A. Aladinskiy, Anastasia V. Aladinskaya, Victor A. Terentiev, Mark S. Veselov, Andrey A. Ayginin, Dmitry A. Skvortsov, Katerina S. Komarova, Bogdan A. Zagribelnyy*, Alexey Kh. Baimiev, Kseniya Yu. Shvetc, Andrey Kh. Baimiev, Alina A. Sofronova, Alexey E. Machulkin, Rostislav A. Petrov, Liana F. Zainullina, Marina A. Maximova, Zulfiya R. Zileeva, Yulia V. Vakhitova, Dmitry S. Bezrukov, Maria M. Puchinina and Olga A. Dontsova   Pages 1 - 9 ( 9 )

Abstract:


Herein, we present the results of high-throughput screening (HTS) campaign, that has been performed utilizing our HTS platform based on unique double-reporter system - pDualrep2. A large-scale small molecule library was designed and tested. As a result, 5'-(carbonylamino)-2,3'-bithiophene-4'-carboxylate derivates were observed as novel class of antibacterials with promising potency. One of the he most active compounds showed a minimal inhibitory concentration (MIC) value of 1.8 µg/mL and induced weak SOS response. Additional investigation displayed that the hit slightly inhibited prokaryotic translational machinery at a concentration of 16.7 µg/mL. Another hit with MIC value of 1.2 µg/mL exhibited high activity against S. aureus. Cytotoxic studies demonstrated a relatively good selectivity index for the most active compounds within the series towards a small panel of eukaryotic cells. The follow-up screening of several derivatives of the discovered scaffold elucidated the key structural features important for exhibiting antibacterial activity.

Keywords:

Antibiotics, Antibacterial, HTS, `3`-Bithiophene, MIC

Affiliation:

Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Oktyabrya Prospekt 71, 450054, Ufa, Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Oktyabrya Prospekt 71, 450054, Ufa, Lomonosov Moscow State University, Chemistry Dept, Leninskie gory, Building 1/3, GSP-1, Moscow, 119991, Lomonosov Moscow State University, Department of Chemistry and A.N. Belozersky Institute of Physico-Chemical Biology, Moscow, Moscow Institute of Physics and Technology (State University), 9 Institutskiy lane, Dolgoprudny City, Moscow Region, 141700, Moscow Institute of Physics and Technology (State University), 9 Institutskiy lane, Dolgoprudny City, Moscow Region, 141700, Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Oktyabrya Prospekt 71, 450054, Ufa, Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Oktyabrya Prospekt 71, 450054, Ufa, Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Oktyabrya Prospekt 71, 450054, Ufa, Lomonosov Moscow State University, Department of Chemistry and A.N. Belozersky Institute of Physico-Chemical Biology, Moscow, Lomonosov Moscow State University, Department of Chemistry and A.N. Belozersky Institute of Physico-Chemical Biology, Moscow, Lomonosov Moscow State University, Chemistry Dept, Leninskie gory, Building 1/3, GSP-1, Moscow, 119991, Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Oktyabrya Prospekt 71, 450054, Ufa, Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Oktyabrya Prospekt 71, 450054, Ufa, Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Oktyabrya Prospekt 71, 450054, Ufa, Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, Moscow, Lomonosov Moscow State University, Chemistry Dept, Leninskie gory, Building 1/3, GSP-1, Moscow, 119991, Lomonosov Moscow State University, Chemistry Dept, Leninskie gory, Building 1/3, GSP-1, Moscow, 119991, Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Oktyabrya Prospekt 71, 450054, Ufa, Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Oktyabrya Prospekt 71, 450054, Ufa, Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Oktyabrya Prospekt 71, 450054, Ufa, Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Oktyabrya Prospekt 71, 450054, Ufa, Lomonosov Moscow State University, Chemistry Dept, Leninskie gory, Building 1/3, GSP-1, Moscow, 119991, Moscow Institute of Physics and Technology (State University), 9 Institutskiy lane, Dolgoprudny City, Moscow Region, 141700, Lomonosov Moscow State University, Chemistry Dept, Leninskie gory, Building 1/3, GSP-1, Moscow, 119991



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