Identification and optimization of a new series of anti-tubercular quinazolinones
Abstract
A high throughput phenotypic screening against Mycobacterium smegmatis led us to the discovery of a new class of bacteriostatic, highly hydrophobic antitubercular quinazolinones that potently inhibited the in vitro growth of either extracellular or intramacrophagic M. tuberculosis (Mtb), via modulation of an unidentified but yet novel target. Optimization of the initial hit compound culminated in the identification of potent but poorly soluble Mtb growth inhibitors, three of which were progressed to in vivo efficacy studies. Despite nanomolar in vitro potency and attractive PK properties, none of these compounds was convincingly potent in our in vivo mouse tuberculosis models. This lack of efficacy may be linked to the poor drug-likeness of the test molecules and/or to the properties of the target.
Graphical abstract
A high throughput phenotypic screening against Mycobacterium smegmatis led us to the discovery of a new class of bacteriostatic, highly hydrophobic antitubercular quinazolinones that potently inhibited the in vitro growth of either extracellular or intramacrophagic M. tuberculosis (Mtb), via modulation of an unidentified but yet novel target. Optimization of the initial hit compound culminated in the identification of potent but poorly soluble Mtb growth inhibitors, three of which were progressed to in vivo efficacy studies. Despite nanomolar in vitro potency and attractive PK properties, none of these compounds was convincingly potent in our in vivo mouse tuberculosis models. This lack of efficacy may be linked to the poor drug-likeness of the test molecules and/or to the properties of the target.
Keywords
- Tuberculosis;
- High throughput screening;
- Antitubercular drugs;
- Lead optimization
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Corrected proofs are Articles in Press that contain the authors' corrections. Final citation details, e.g., volume and/or issue number, publication year and page numbers, still need to be added and the text might change before final publication.
Although corrected proofs do not have all bibliographic details available yet, they can already be cited using the year of online publication and the DOI , as follows: author(s), article title, Publication (year), DOI. Please consult the journal's reference style for the exact appearance of these elements, abbreviation of journal names and use of punctuation.
