Discovery of bioactive molecules from CuAAC click-chemistry-based combinatorial libraries

Evaluating the Contribution of Transition-State Destabilization to Changes in the Residence Time of Triazole-Based InhA Inhibitors

“…25,37,38 Although the alkyl diphenyl ethers have high affinity for InhA and antibacterial activity towards M. tuberculosis , these compounds display relatively high ClogP values (6–7). Replacement of the hydrophobic alkyl substituent with a triazole moiety is expected to result in an improvement in ClogP and an improved clogD, and some of our triazole diphenyl ethers even have ClogP values as low as 2.2 (Table 1).…”

Design, combinatorial synthesis and biological evaluations of novel 3-amino-1′-((1-aryl-1 H -1,2,3-triazol-5-yl)methyl)-2′-oxospiro[benzo[ a ] pyrano[2,3- c ]phenazine-1,3′-indoline]-2-carbonitrile antitumor hybrid molecules

“…Click chemistry, mainly the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), offers a robust approach to construct 1,2,3-triazole moieties, which are attractive connecting units because they are stable to metabolic degradation and capable of hydrogen bonding, which can well bind biomolecular targets and improve compounds' solubility [25]. The rapid construction and screening of focused combinatorial fragment libraries using CuAAC click chemistry is a highly efficient way for establishing structure-activity relationship (SAR) and for discovering bioactive molecules [26,27].…”

Small Molecule Microarray Based Discovery of PARP14 Inhibitors

“…Previously,w ea nd others used Cu I -catalyzed azide-alkyne cycloaddition (CuAAC) for the rapid synthesis and screening of bidentate inhibitors against different enzymes. [13,14] While this method is as tep forward compared to traditional compound synthesis/screening strategies,i ti st ime-consuming, resource-intensive,a nd often complicated by the risk of compound impurities.S mall molecule microarrays (SMMs) are miniaturized assemblies of compounds immobilized across a2 .5 7.5 cm glass slide,o nw hich thousands of protein-ligand interactions may be simultaneously measured. [15,16] Over the years,b yi mproving key aspects related to immobilization, [16b] on-chip quantitative binding measurements,a nd dual-color fluorescence screening, [9,16a,d] we have successfully used this technology for rapid screening and identification of small molecule inhibitors against avariety of targets.…”

“…[16b] With the nearly quantitative yield of atypical CuAACc oupling,w ee xpected most if not all of the 1120 bidentate inhibitors to be successfully assembled on the microarray.Anadditional advantage of this strategy was that purification of immobilized compounds could be done en masse by simple washes of the resulting microarray to remove contaminating CuAACr eagents/copper catalysts,a s well as excessive azides,a ll of which are known to cause severe interference during screening with compounds synthesized from solution-phase CuAACm ethods. [13,14] As shown in Figure 1B and Scheme S1, W1-20 were synthesized from five different ligands known to bind to the nicotinamide-binding pocket of PA RP1 (WH-1 to WH-5), and they were expected to bind well to other PA RP proteins. TheT zm oiety was attached to these ligands through four different linkers derived from aspartic/glutamic acids at-tached to amine-containing terminal alkynes (L1 to L4).…”