Searching for New Leads for Tuberculosis: Design, Synthesis, and Biological Evaluation of Novel 2-Quinolin-4-yloxyacetamides.

In this study, a new series of more than 60 quinoline derivatives has been synthesized and evaluated against Mycobacterium tuberculosis (H37Rv). Apart from the SAR exploration around the initial hits, the optimization process focused on the improvement of the physicochemical properties, cytotoxicity, and metabolic stability of the series. The best compounds obtained exhibited MIC values in the low micromolar range, excellent intracellular antimycobacterial activity, and an improved physicochemical profile without cytotoxic effects. Further investigation revealed that the amide bond was the source for the poor blood stability observed, while some of the compounds exhibited hERG affinity. Compound 83 which contains a benzoxazole ring instead of the amide group was found to be a good alternative, with good blood stability and no hERG affinity, providing new opportunities for the series. Overall, the obtained results suggest that further optimization of solubility and microsomal stability of the series could provide a strong lead for a new anti-TB drug development program.

[1]  Y. Av‐Gay,et al.  Development of an Intracellular Screen for New Compounds Able To Inhibit Mycobacterium tuberculosis Growth in Human Macrophages , 2015, Antimicrobial Agents and Chemotherapy.

[2]  A. Kestranek,et al.  Chemiluminescent Nitrogen Detection (CLND) to Measure Kinetic Aqueous Solubility , 2013, Current protocols in chemical biology.

[3]  Diptesh Sil,et al.  Toll-like receptor-8 agonistic activities in C2, C4, and C8 modified thiazolo[4,5-c]quinolines. , 2013, Organic & biomolecular chemistry.

[4]  Alfonso Mendoza,et al.  Fueling Open-Source Drug Discovery: 177 Small-Molecule Leads against Tuberculosis , 2013, ChemMedChem.

[5]  Bin Zhang,et al.  Copper-catalyzed highly regioselective 2-aryloxylation of 2,x-dihalopyridines , 2013 .

[6]  J. Gut,et al.  The design, synthesis, in silico ADME profiling, antiplasmodial and antimycobacterial evaluation of new arylamino quinoline derivatives. , 2012, European journal of medicinal chemistry.

[7]  J. Vidal,et al.  Design, synthesis, and in vitro activity of novel 2'-O-substituted 15-membered azalides. , 2012, Journal of medicinal chemistry.

[8]  C. Kunin,et al.  Susceptibility of Mycobacterium tuberculosis to sulfamethoxazole, trimethoprim and their combination over a 12 year period in Taiwan. , 2012, The Journal of antimicrobial chemotherapy.

[9]  F. Marra,et al.  Fluoroquinolones for the Treatment of Pulmonary Tuberculosis , 2012, Drugs.

[10]  David Barros,et al.  4‐Substituted Thioquinolines and Thiazoloquinolines: Potent, Selective, and Tween‐80 in vitro Dependent Families of Antitubercular Agents with Moderate in vivo Activity , 2011, ChemMedChem.

[11]  Darren V S Green,et al.  Getting physical in drug discovery II: the impact of chromatographic hydrophobicity measurements and aromaticity. , 2011, Drug discovery today.

[12]  Yuquan Wei,et al.  Synthesis and biological activity of novel barbituric and thiobarbituric acid derivatives against non-alcoholic fatty liver disease. , 2011, European journal of medicinal chemistry.

[13]  A. V. Adhikari,et al.  Design and synthesis of some new quinoline-3-carbohydrazone derivatives as potential antimycobacterial agents. , 2010, Bioorganic & medicinal chemistry letters.

[14]  Lynn Rasmussen,et al.  Antituberculosis activity of the molecular libraries screening center network library. , 2009, Tuberculosis.

[15]  Annamaria Lilienkampf,et al.  Structure-activity relationships for a series of quinoline-based compounds active against replicating and nonreplicating Mycobacterium tuberculosis. , 2009, Journal of medicinal chemistry.

[16]  N. Peet,et al.  Survey of Solvents for the Conrad–Limpach Synthesis of 4-Hydroxyquinolones , 2009, Synthetic communications.

[17]  J. Vors,et al.  Trifluoromethyl Ethers: Synthesis and Properties of an Unusual Substituent , 2009 .

[18]  Evan W. Orenstein,et al.  Treatment outcomes among patients with multidrug-resistant tuberculosis: systematic review and meta-analysis. , 2009, The Lancet. Infectious diseases.

[19]  Dirk Bald,et al.  Diarylquinolines target subunit c of mycobacterial ATP synthase. , 2007, Nature chemical biology.

[20]  L. A. Basso,et al.  The resumption of consumption -- a review on tuberculosis. , 2006, Memorias do Instituto Oswaldo Cruz.

[21]  Alimuddin Zumla,et al.  Treatment of tuberculosis: present status and future prospects. , 2005, Bulletin of the World Health Organization.

[22]  R. Chaisson,et al.  Tuberculosis drug resistance: a global threat. , 2003, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[23]  H. Waterbeemd,et al.  Pharmacokinetics and Metabolism in Drug Design: Smith: Pharmacokinetics , 2001 .

[24]  A. Hagler,et al.  The generation of possible crystal structures of primary amides , 1983, Proceedings of the Royal Society of London. A. Mathematical and Physical Sciences.

[25]  E. M. Ayerst,et al.  Refinement of the crystal structure of oxamide , 1954 .