title: Differential characterization using readily accessible NMR experiments of novel N- and O-alkylated quinolin-4-ol, 1,5-naphthyridin-4-ol and quinazolin-4-ol derivatives with antimycobacterial activity.
abstract: During the construction of bioactive molecules, regioselective alkylation of heterocyclic, N/O ambident nucleophiles is a frequently encountered synthetic transformation. In this framework, specific attention is required to unambiguously determine the structures of obtained reaction products. As part of our project on quinoloxyacetamide based antimycobacterial agents, a series of N- or O- alkylated quinolin-4-ol, 1,5-naphthyridin-4-ol and quinazolin-4-ol derivatives were prepared during the course of which we observed unexpected selectivity issues. After finding that no consistent procedure existed in the literature for assigning regioisomers of this type, we applied three readily accessible NMR experiment types (13C NMR, HSQC/HMBC and NOE) to resolve any uncertainties regarding the obtained regioisomeric structures. Furthermore, the antimycobacterial activity of all final compounds was evaluated with the best compound 23 showing potent antitubercular activity (MIC = 1.25 μM) without cytotoxic effects.
authors: Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universitieitsplein 1, B-2610, Wilrijk, Belgium.
authors: Eleni
authors: E
authors: Pitta
authors: Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universitieitsplein 1, B-2610, Wilrijk, Belgium.
authors: Olga
authors: O
authors: Balabon
authors: Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universitieitsplein 1, B-2610, Wilrijk, Belgium.
authors: Maciej K
authors: MK
authors: Rogacki
authors: Diseases of the Developing World (DDW), Tres Cantos Medicines Development Campus (TCMDC), GlaxoSmithKline, Severo Ochoa 2, 28760, Tres Cantos Madrid, Spain.
authors: Jesús
authors: J
authors: Gómez
authors: Diseases of the Developing World (DDW), Tres Cantos Medicines Development Campus (TCMDC), GlaxoSmithKline, Severo Ochoa 2, 28760, Tres Cantos Madrid, Spain.
authors: Fraser
authors: F
authors: Cunningham
authors: Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universitieitsplein 1, B-2610, Wilrijk, Belgium.
authors: Jurgen
authors: J
authors: Joosens
authors: Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universitieitsplein 1, B-2610, Wilrijk, Belgium.
authors: Koen
authors: K
authors: Augustyns
authors: Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universitieitsplein 1, B-2610, Wilrijk, Belgium. Electronic address: pieter.vanderveken@uantwerpen.be.
authors: Pieter
authors: P
authors: van der Veken
authors: Diseases of the Developing World (DDW), Tres Cantos Medicines Development Campus (TCMDC), GlaxoSmithKline, Severo Ochoa 2, 28760, Tres Cantos Madrid, Spain. Electronic address: robert.h.bates@gsk.com.
authors: Robert
authors: R
authors: Bates
mesh_terms: D000478:Alkylation; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D000995:Antitubercular Agents / Q000737:chemistry; D002470:Cell Survival / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D015394:Molecular Structure; D009159:Mycobacteriaceae / Q000187:drug effects*; D009287:Naphthyridines / Q000737:chemistry / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D009287:Naphthyridines; D011799:Quinazolines
keywords: Alkylation; NMR; Naphthyridinol; Quinazolinol; Quinolinol; Regioselectivity; Tuberculosis