Quinoline

Quinoline ranks among the most historically and currently productive scaffolds in medicinal chemistry, appearing in natural products including quinine and camptothecin. Quinoline-containing compounds have gained particular prominence as kinase inhibitors in oncology drug discovery, with several FDA-approved quinoline-based small molecules now utilised in clinical settings, reflecting their significance across multiple cancer signalling pathways. The ring system presents a single nitrogen atom with hydrogen-bond acceptor capacity, a planar aromatic surface suited to π-stacking and intercalative interactions with nucleic acids and protein binding pockets, and multiple substitution positions that allow extensive exploration of structure-activity relationships via cross-coupling, and electrophilic aromatic substitution routes. The well explored Skraup synthesis allows creation of quinoline rings with unique substitution patterns to explore structure-activity relationships. These properties have sustained quinoline as a productive scaffold across anti-infective, antimalarial, cardiovascular, and oncology programmes, with the electron-deficient ring facilitating binding to diverse target classes including kinases, ATP synthases, and nuclear receptors. The fused bicyclic system also confers metabolic stability advantages in certain substitution patterns, and the broad synthetic accessibility of quinoline building blocks bearing amines, halides, carboxylic acids, and sulfonamides makes them well suited to rapid analogue synthesis in lead optimisation campaigns.

Examples of Quinoline-containing compounds in the clinic include Bedaquiline (Sirturo, Janssen), a first-in-class diarylquinoline antibiotic approved in December 2012 for the treatment of multidrug-resistant tuberculosis, representing the first novel class of antituberculosis agents in over 40 years and acting through selective inhibition of the proton pump subunit of mycobacterial ATP synthase. Pitavastatin (Livalo, Kowa) a synthetic HMG-CoA reductase inhibitor built around a trisubstituted quinoline core, approved in 2010 for the treatment of hypercholesterolaemia, where the quinoline ring provides improved pharmacokinetics and potent LDL-cholesterol-lowering efficacy at low doses, with minimal cytochrome P450 3A4-mediated metabolism and consequently low drug-drug interaction potential.

Our range of Quinolines features novel substitutions and the incorporation of synthetically tractable functional groups such as boronic acids and esters, amines, carboxylic acids, ketones, hydroxyls and halogens to enable expedient synthetic strategies. The full range can be found using the substructure feature of our Search tools.