Second generation of Benzothiazoles as inhibitors of Girasa B (E. coli) Design, synthesis and biological evaluation

PARRAVICINI, OSCAR; ENRIZ, RICARDO D.; ANTONELLA BONVILLANI; GUTIERREZ LUCAS JOEL

San Luis

Congreso; XLVIII Reunión Anual de la Sociedad Argentina de Biofísica; 2019

Second generation of Benzothiazoles as inhibitors of Girasa B (E. coli):Design, synthesis and biological evaluationBonvillani Aa, Kikelj Db, Parravicini Oa, Enriz Ra, Gutiérrez Laa - Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis; InstitutoMultidisciplinario de Investigaciones Biológicas (IMIBIO-SL-CONICET).b - University of Ljubljana, Faculty of PharmacyThe growing appearance of pathogenic bacteria resistant to antibacterial drugs inacquired infections is a serious threat to global health, because the available therapieswill no longer be effective in treating these infections (1). Although the rate of bacterialresistance on the medications currently used is on the rise, no new antibacterial drugsappear on the market. Bacterial topoisomerases are enzymes that catalyze changes inDNA topology and are very attractive targets for antibacterial drug discovery (2). DNAgyrase is a tetrameric A2B2 type protein consisting of two GyrA subunits and two GyrBsubunits, while topoisomerase IV is composed of two ParC and two ParE subunits (C2E2)that are homologous to GyrA and GyrB, respectively. The GyrA and ParC subunits areinvolved in DNA transit, while the GyrB and ParE subunits hydrolyze the ATP to obtain theenergy necessary for the functioning of the GyrA subunits. At present there are no drugsthat inhibit topoisomerase function due to competencies with ATP, this makes the GyrBsubunit a new and attractive target for the generation of new and potent antibacterialcompounds. This work presents a new series of compounds derived from benzothiazolesdesigned through the use of molecular modeling tools. We employed techniques ofdocking, molecular dynamics and calculations QTAIM (Quantum Theory of Atoms InMolecules) which allowed us to explain the different activities of the compounds, as wellas the characterization of a new sub-site found in the active site of GyrB. The maininteractions observed in this sub-site are those with Ile94, Gly102 and Lys103. Thefinding of this sub-site allowed us to increase the number of ligand-receptor interactionsby improving IC50 values from 58 nM to 20 nM.References1). Silver, S. L. Clin. Microb. Rev. 2011, 24, 71−109.2). Gellert, M.; Mizuuchi, K.; O?Dea, M. H.; Nash, H. A Proc. Natl. Acad. Sci. U. S. A. 1976,73, 3872−3876.