Identification and optimization of a new series of anti-tubercular quinazolinones.
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.
Sanofi R&D, TSU Infectious Disease, 1541, Avenue Marcel Merieux, 69280 Marcy l'Etoile, France. Electronic address: cedric.couturier@sanofi.com.
Cédric
C
Couturier
Sanofi R&D, TSU Infectious Disease, 1541, Avenue Marcel Merieux, 69280 Marcy l'Etoile, France.
Christine
C
Lair
Sanofi R&D, TSU Infectious Disease, 1541, Avenue Marcel Merieux, 69280 Marcy l'Etoile, France.
Alain
A
Pellet
Global Alliance for TB Drug Development, New York, NY 10005, United States.
Anna
A
Upton
Global Alliance for TB Drug Development, New York, NY 10005, United States.
Takushi
T
Kaneko
Sanofi R&D, Lead Generation and Candidate Realization, 195, route d'Espagne BP 13669, 31036 Toulouse Cedex 1, France.
Corinne
C
Perron
Sanofi R&D, Lead Generation and Candidate Realization, 195, route d'Espagne BP 13669, 31036 Toulouse Cedex 1, France.
Eric
E
Cogo
Sanofi R&D, Lead Generation and Candidate Realization, 195, route d'Espagne BP 13669, 31036 Toulouse Cedex 1, France.
Jérome
J
Menegotto
Sanofi Deutschland GmbH, Lead Generation and Candidate Realization, Industriepark Hoechst, 65926 Frankfurt am Main, Germany.
Armin
A
Bauer
Sanofi Deutschland GmbH, Lead Generation and Candidate Realization, Industriepark Hoechst, 65926 Frankfurt am Main, Germany.
Bodo
B
Scheiper
Sanofi R&D, TSU Infectious Disease, 1541, Avenue Marcel Merieux, 69280 Marcy l'Etoile, France.
Sophie
S
Lagrange
Sanofi R&D, TSU Infectious Disease, 1541, Avenue Marcel Merieux, 69280 Marcy l'Etoile, France.
Eric
E
Bacqué
D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D020102:Mycobacterium smegmatis / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D052999:Quinazolinones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000995:Antitubercular Agents; D052999:Quinazolinones
Antitubercular drugs; High throughput screening; Lead optimization; Tuberculosis