Testing tuberculosis drug efficacy in a zebrafish high-throughput translational medicine screen

Analytical BioSciencesAnimal science

Carbamoyl Triazoles, Known Serine Protease Inhibitors, Are a Potent New Class of Antimalarials.

Screening of the GSK corporate collection, some 1.9 million compounds, against Plasmodium falciparum (Pf), revealed almost 14000 active hits that are now known as the Tres Cantos Antimalarial Set (TCAMS). Followup work by Calderon et al. clustered and computationally filtered the TCAMS through a variety of criteria and reported 47 series containing a total of 522 compounds. From this enhanced set, we identified the carbamoyl triazole TCMDC-134379 (1), a known serine protease inhibitor, as an excellent starting point for SAR profiling. Lead optimization of 1 led to several molecules with improved antimalarial potency, metabolic stabilities in mouse and human liver microsomes, along with acceptable cytotoxicity profiles. Analogue 44 displayed potent in vitro activity (IC50 = 10 nM) and oral activity in a SCID mouse model of Pf infection with an ED50 of 100 and ED90 of between 100 and 150 mg kg(-1), respectively. The results presented encourage further investigations to identify the target of these highly active compounds

Carbamoyl Triazoles, Known Serine Protease Inhibitors, Are a Potent New Class of Antimalarials

Screening of the GSK corporate collection, some 1.9 million compounds, against Plasmodium falciparum (<i>Pf</i>), revealed almost 14000 active hits that are now known as the Tres Cantos Antimalarial Set (TCAMS). Followup work by Calderon et al. clustered and computationally filtered the TCAMS through a variety of criteria and reported 47 series containing a total of 522 compounds. From this enhanced set, we identified the carbamoyl triazole TCMDC-134379 (<b>1</b>), a known serine protease inhibitor, as an excellent starting point for SAR profiling. Lead optimization of <b>1</b> led to several molecules with improved antimalarial potency, metabolic stabilities in mouse and human liver microsomes, along with acceptable cytotoxicity profiles. Analogue <b>44</b> displayed potent in vitro activity (IC₅₀ = 10 nM) and oral activity in a SCID mouse model of <i>Pf</i> infection with an ED₅₀ of 100 and ED₉₀ of between 100 and 150 mg kg⁻¹, respectively. The results presented encourage further investigations to identify the target of these highly active compounds

Carbamoyl Triazoles, Known Serine Protease Inhibitors, Are a Potent New Class of Antimalarials

Screening of the GSK corporate collection, some 1.9 million compounds, against Plasmodium falciparum (<i>Pf</i>), revealed almost 14000 active hits that are now known as the Tres Cantos Antimalarial Set (TCAMS). Followup work by Calderon et al. clustered and computationally filtered the TCAMS through a variety of criteria and reported 47 series containing a total of 522 compounds. From this enhanced set, we identified the carbamoyl triazole TCMDC-134379 (<b>1</b>), a known serine protease inhibitor, as an excellent starting point for SAR profiling. Lead optimization of <b>1</b> led to several molecules with improved antimalarial potency, metabolic stabilities in mouse and human liver microsomes, along with acceptable cytotoxicity profiles. Analogue <b>44</b> displayed potent in vitro activity (IC₅₀ = 10 nM) and oral activity in a SCID mouse model of <i>Pf</i> infection with an ED₅₀ of 100 and ED₉₀ of between 100 and 150 mg kg⁻¹, respectively. The results presented encourage further investigations to identify the target of these highly active compounds

Encoded library technology as a source of hits for the discovery and lead optimization of a potent and selective class of bactericidal direct inhibitors of mycobacterium tuberculosis inha

Tuberculosis (TB) is one of the world's oldest and deadliest diseases, killing a person every 20 s. InhA, the enoyl-ACP reductase from Mycobacterium tuberculosis, is the target of the frontline antitubercular drug isoniazid (INH). Compounds that directly target InhA and do not require activation by mycobacterial catalase peroxidase KatG are promising candidates for treating infections caused by INH resistant strains. The application of the encoded library technology (ELT) to the discovery of direct InhA inhibitors yielded compound 7 endowed with good enzymatic potency but with low antitubercular potency. This work reports the hit identification, the selected strategy for potency optimization, the structure-activity relationships of a hundred analogues synthesized, and the results of the in vivo efficacy studies performed with the lead compound 65. © 2014 American Chemical Society.Peer Reviewe