Discovery of in vitro antitubercular agents through in silico ligand-based approaches

• DOI: 10.1016/j.ejmech.2016.05.032
• Publication Date: 2016-05-23T07:17:49Z
• Authors: Daniela De Vita; Fabiana Pandolfi; Roberto Cirilli; Luigi Scipione; Roberto Di Santo; Laura Friggeri; Mattia Mori; Diego Fiorucci; Giorgio Maccari; Robert Selwyne Ar...; Claudio Zamperini; Valentina Pau; Alessandro De Logu; Silvano Tortorella; Maurizio Botta
• Keywords: Virtual screening; Pharmacology; 0301 basic medicine; 0303 health sciences; Drug Discovery3003 Pharmaceutical Science; Organic Chemistry; Antitubercular Agents; Microbial Sensitivity Tests; Mycobacterium tuberculosis; 540; Ligands; Virtual screening; anti-tubercular agents; azoles; phenyl-pyrazolopyrimidinones; 620; 3. Good health; Small Molecule Libraries; Anti-tubercular agents, Azoles, Phenyl-pyrazolopyrimidinones, Virtual screening, Drug Discovery3003, Pharmaceutical science, Organic chemistry, Pharmacology; 03 medical and health sciences; Phenyl-pyrazolopyrimidinone; Drug Discovery; Anti-tubercular agent; Anti-tubercular agents; Azoles; Phenyl-pyrazolopyrimidinones; Virtual screening; Drug Discovery3003 Pharmaceutical Science; Organic Chemistry; Pharmacology; Computer Simulation; Azole

The development of new anti-tubercular agents represents a constant challenge mostly due to the insurgency of resistance to the currently available drugs. In this study, a set of 60 molecules were selected by screening the Asinex and the ZINC collections and an in house library by means of in silico ligand-based approaches. Biological assays in Mycobacterium tuberculosis H37Ra ATCC 25177 strain highlighted (±)-1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethyl-4-(3,4-dichlorophenyl)piperazine-1-carboxylate (5i) and 3-(4-chlorophenyl)-5-(2,4-dimethylpyrimidin-5-yl)-2-methylpyrazolo[1.5-a]pyrimidin-7(4H)-one (42) as the most potent compounds, having a Minimum Inhibitory Concentration (MIC) of 4 and 2 μg/mL respectively. These molecules represent a good starting point for further optimization of effective anti-TB agents.