Antibiotic resistance represents a significant threat worldwide. There is an urgent need to discover structurally innovative antibacterial agents for which no pre-existing resistance is known. With the aim to speed up the drug discovery process and to reduce the limitations of target-based high-through put screenings (HTS) we described the synthesis and biological evaluation of a novel series of 1,5-diphenylpyrroles active against a wide panel of ESKAPE bacteria. In particular, a subsequent structure-activity relationship (SAR) study revealed that the modification of the functional groups can switch the selectivity and the antimicrobial activity from mycobacteria to Gram positive and Gram negative bacteria [1,2]. The new compounds show high activity against both wild type and drug-resistant Gram positive and Gram negative bacteria at concentrations similar than levofloxacin. Microbiology studies revealed that the plausible target of this class of compounds is the bacterial DNA gyrase, with the pyrrole derivatives displaying similar inhibitory activity to levofloxacin against the wild type enzyme and retaining activity against the fluoroquinolone-resistant enzyme. References: [1] Bhakta, S.; Manetti, F.; Castagnolo, D. et al (2016) Design and Synthesis of 1-((1,5-Bis(4-chlorophenyl)-2-methyl-1H-pyrrol-3-yl)methyl)-4-methylpiperazine (BM212) and N-Adamantan-2-yl-N′-((E)-3,7-dimethylocta-2,6-dienyl)ethane-1,2-diamine (SQ109) Pyrrole Hybrid Derivatives: Discovery of Potent Antitubercular Agents Effective against Multidrug-Resistant Mycobacteria. J. Med. Chem.59:2780-2793. [2] Masci, D.; Hind, C.; K. Islam, M.; Toscani, A.; Clifford, M.; Coluccia, A.; Conforti, I.; Touitou, M.; Wei, X.; Memdouh, S.; La Regina, G.; Silvestri, R; Sutton, M.; Castagnolo, D. (2019) Switching on the activity of 1,5-diaryl-pyrrole derivatives against drug-resistant ESKAPE bacteria: structure-activity relationships and mode of action studies. Eur. J. Med. Chem. 178:500-514.
Switching on the activity of 1,5-diaryl-pyrrole derivatives against drug-resistant ESKAPE bacteria / Masci, Domiziana; Sutton, Mark; Castagnolo, Daniele. - (2019). (Intervento presentato al convegno 3rd International StaPa Retreat tenutosi a Rome).
Switching on the activity of 1,5-diaryl-pyrrole derivatives against drug-resistant ESKAPE bacteria
Masci Domiziana;
2019
Abstract
Antibiotic resistance represents a significant threat worldwide. There is an urgent need to discover structurally innovative antibacterial agents for which no pre-existing resistance is known. With the aim to speed up the drug discovery process and to reduce the limitations of target-based high-through put screenings (HTS) we described the synthesis and biological evaluation of a novel series of 1,5-diphenylpyrroles active against a wide panel of ESKAPE bacteria. In particular, a subsequent structure-activity relationship (SAR) study revealed that the modification of the functional groups can switch the selectivity and the antimicrobial activity from mycobacteria to Gram positive and Gram negative bacteria [1,2]. The new compounds show high activity against both wild type and drug-resistant Gram positive and Gram negative bacteria at concentrations similar than levofloxacin. Microbiology studies revealed that the plausible target of this class of compounds is the bacterial DNA gyrase, with the pyrrole derivatives displaying similar inhibitory activity to levofloxacin against the wild type enzyme and retaining activity against the fluoroquinolone-resistant enzyme. References: [1] Bhakta, S.; Manetti, F.; Castagnolo, D. et al (2016) Design and Synthesis of 1-((1,5-Bis(4-chlorophenyl)-2-methyl-1H-pyrrol-3-yl)methyl)-4-methylpiperazine (BM212) and N-Adamantan-2-yl-N′-((E)-3,7-dimethylocta-2,6-dienyl)ethane-1,2-diamine (SQ109) Pyrrole Hybrid Derivatives: Discovery of Potent Antitubercular Agents Effective against Multidrug-Resistant Mycobacteria. J. Med. Chem.59:2780-2793. [2] Masci, D.; Hind, C.; K. Islam, M.; Toscani, A.; Clifford, M.; Coluccia, A.; Conforti, I.; Touitou, M.; Wei, X.; Memdouh, S.; La Regina, G.; Silvestri, R; Sutton, M.; Castagnolo, D. (2019) Switching on the activity of 1,5-diaryl-pyrrole derivatives against drug-resistant ESKAPE bacteria: structure-activity relationships and mode of action studies. Eur. J. Med. Chem. 178:500-514.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
