학술논문
Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold- Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa
Document Type
Author
Cotman, Andrej Emanuel; Durcik, Martina; Tiz, Davide Benedetto; Fulgheri, Federica; Secci, Daniela; Sterle, Masa; Mozina, Stefan; Skok, Ziga; Zidar, Nace; Zega, Anamarija; Ilas, Janez; Masic, Lucija Peterlin; Tomasic, Tihomir; Hughes, Diarmaid, 1956; Huseby, Douglas L.; Cao, Sha; Garoff, Linnea; Fernandez, Talia Berruga; Giachou, Paraskevi; Crone, Lisa; Simoff, Ivailo; Svensson, Richard; Birnir, Bryndis; Korol, Sergiy; Jin, Zhe; Vicente, Francisca; Ramos, Maria C.; de la Cruz, Mercedes; Glinghammar, Bjorn; Lenhammar, Lena; Henderson, Sara R.; Mundy, Julia E. A.; Maxwell, Anthony; Stevenson, Clare E. M.; Lawson, David M.; Janssen, Guido V.; Sterk, Geert Jan; Kikelj, Danijel
Source
Journal of Medicinal Chemistry. 66(2):1380-1425
Subject
Language
English
ISSN
0022-2623
1520-4804
1520-4804
Abstract
We have developed compounds with a promising activity against Acinetobacter baumannii and Pseudomonas aerugi-nosa, which are both on the WHO priority list of antibiotic -resistant bacteria. Starting from DNA gyrase inhibitor 1, we identified compound 27, featuring a 10-fold improved aqueous solubility, a 10-fold improved inhibition of topoisomerase IV from A. baumannii and P. aeruginosa, a 10-fold decreased inhibition of human topoisomerase II alpha, and no cross-resistance to novobiocin. Cocrystal structures of 1 in complex with Escherichia coli GyrB24 and (S)-27 in complex with A. baumannii GyrB23 and P. aeruginosa GyrB24 revealed their binding to the ATP-binding pocket of the GyrB subunit. In further optimization steps, solubility, plasma free fraction, and other ADME properties of 27 were improved by fine-tuning of lipophilicity. In particular, analogs of 27 with retained anti-Gram-negative activity and improved plasma free fraction were identified. The series was found to be nongenotoxic, nonmutagenic, devoid of mitochondrial toxicity, and possessed no ion channel liabilities.