A two stage click-based library of protein tyrosine phosphatase inhibitors

Abstract

Protein tyrosine phosphatases (PTPs) are important regulators of signal transduction pathways. Potent and selective PTP inhibitors are useful for probing these pathways and also may serve as drugs for the treatment of a variety of diseases including type 2 diabetes and infection by the bacterium Yersinia pestis. In this report Cu(I)-catalyzed 'click' cycloaddition reactions between azides and alkynes were employed to generate two sequential libraries of PTP inhibitors. In the first round library methyl 4-azidobenzoylformate was reacted with 56 mono-and diynes. After hydrolysis of the methyl esters, the resulting α-ketocarboxylic acids were assayed in crude form against the Yersinia PTP and PTP1B. Four compounds were selected for further evaluation, and one compound was chosen as the lead for generation of the second round library. This lead compound was modified by conversion of an alcohol into an azide group, and the resulting azide was reacted with the same 56 mono-and diynes that were used in the first generation library. After screening the crude inhibitors against the Yersinia PTP and PTP1B, four compounds were selected and evaluated in pure form against the Yersinia PTP, PTP1B, TCPTP, LAR and CD45. The best bis(α-ketocarboxylic acid) inhibitor 34 had an IC 50 value of 550 nM against the Yersinia PTP, and an IC 50 value of 710 nM against TCPTP. The most potent inhibitor containing a single α-ketocarboxylic acid group 32 had IC 50 values of 2.1, 5.7 and 2.6 μM against the Yersinia PTP, PTP1B and TCPTP, respectively.

Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents

“…More importantly, the cycloaddition reaction can be conducted in aqueous solution in the absence of deleterious reagents, thus allowing direct screening and identification of hits from the library. In fact, click chemistry has found increasing applications in lead discovery and optimization for a number of enzymes including the PTPs (27)(28)(29)(30)(31). The azide-containing building blocks were synthesized in a one-pot procedure, in which alkyl or aryl amines were reacted with the acyl chloride linkers in N,N-Dimethylformamide (DMF), followed by S N 2 reaction with sodium azide to generate the corresponding azides.…”

Synthesis and SAR Study of Novel Amidino 2-substituted Benzimidazoles as Potential Antibacterial Agents

“…A convenient and efficient synthetic route was applied starting from commercially available different heterocyclic aldehydes and all new compounds were characterized by 1 H NMR, 13 C NMR and elemental analysis. The in vitro antimicrobial activities of newly prepared benzimidazole derivatives were evaluated against four bacterial strains.…”

“…All compounds were routinely checked by TLC with Merck silica gel 60F-254 glass plates. The spectroscopic data regarding 13 C NMR spectra and elemental analysis are reported in the Supporting Materials.…”

“…[10] In addition, there is a trend in the design of novel hybrid antibacterial compounds by combining two or more biologically active heterocyclic pharmacophores in a single molecule. [11][12][13] The most used heterocycles containing one or two nitrogen atoms have been imidazole, pyridine and pyrrole, and fused scaffolds like benzothiophens, indols, benzothiazoles and quinolines. [14] Furthermore, the amidine moiety is found in a variety of biologically active molecules.…”

Smectic liquid crystals comprising triazole banana shaped achiral molecules: Synthesis and characterization

“…They are generally used in medicinal chemistry [15][16], organic chemistry, materials chemistry [17] and other fields, but they are rarely used in liquid crystal. In the linear molecule, a negative dielectric anisotropy can be obtained by introducing substituent group, such as cyanogroup [18], nitro [19], fluorine [20] and chlorine [21] to the side of the molecule.…”