80809-38-7Relevant articles and documents
Discovery of Novel Triazolothiadiazines as Fungicidal Leads Targeting Pyruvate Kinase
Chen, Hongyu,Chen, Lai,Chen, Lei,Fan, Zhijin,Gao, Wei,Liu, Xiaoyu,Qi, Xin,Tang, Liangfu,Ye, Rong,Zhang, Yue
, p. 1047 - 1057 (2022/02/14)
Pyruvate kinase (PK) was discovered as a potent new target for novel fungicide development. A series of novel triazolothiadiazine derivatives were rationally designed and synthesized by a ring expansion strategy and computer-aided pesticide design using the 3D structure of Rhizoctonia solani PK (RsPK) obtained by homology modeling as a receptor and our previously discovered lead YZK-C22 as a ligand. The in vitro bioassay results indicated that compounds 4g, 6h, 6m, 6n, 6o, and 6p exhibited good activity against R. solani with the EC50 values falling between 10.99 and 72.76 μM. Especially, 6m showed similar potency to YZK-C22 (10.99 vs 11.97 μM of the EC50 value, respectively). The in vivo bioassay results suggested that 6m against R. solani at a concentration of 200 μg/mL displayed a numerically higher inhibition than YZK-C22 (70 vs 60%, respectively). A field experiment validated that 6m at an application rate of 120 g ai/ha showed comparable efficacy against R. solani to thifluzamide at an application rate of 80 g ai/ha (77.80 vs 84.5%, respectively). Enzymatic inhibition suggested that the potency of 6m was about twofold lower than that of YZK-C22 (67.30 vs 32.64 μM of IC50, respectively). Fluorescence quenching studies validated that RsPK was quenched by both 6m and YZK-C22, implying that they both might act at the same target site of PK. A possible binding conformation of 6m in the RsPK active site was depicted by molecular docking. Our studies suggest that 6m could be a fungicidal lead targeting PK.
New fluorescence-based high-throughput screening assay for small molecule inhibitors of tyrosyl-DNA phosphodiesterase 2 (TDP2)
Ribeiro, Carlos J.A.,Kankanala, Jayakanth,Shi, Ke,Kurahashi, Kayo,Kiselev, Evgeny,Ravji, Azhar,Pommier, Yves,Aihara, Hideki,Wang, Zhengqiang
, p. 67 - 79 (2018/04/02)
Tyrosyl-DNA phosphodiesterase 2 (TDP2) repairs topoisomerase II (TOP2) mediated DNA damages and causes resistance to TOP2-targeted cancer therapy. Inhibiting TDP2 could sensitize cancer cells toward TOP2 inhibitors. However, potent TDP2 inhibitors with favorable physicochemical properties are not yet reported. Therefore, there is a need to search for novel molecular scaffolds capable of inhibiting TDP2. We report herein a new simple, robust, homogenous mix-and-read fluorescence biochemical assay based using humanized zebrafish TDP2 (14M_zTDP2), which provides biochemical and molecular structure basis for TDP2 inhibitor discovery. The assay was validated by screening a preselected library of 1600 compounds (Z′ ≥ 0.72) in a 384-well format, and by running in parallel gel-based assays with fluorescent DNA substrates. This library was curated via virtual high throughput screening (vHTS) of 460,000 compounds from Chembridge Library, using the crystal structure of the novel surrogate protein 14M_zTDP2. From this primary screening, we selected the best 32 compounds (2% of the library) to further assess their TDP2 inhibition potential, leading to the IC50 determination of 10 compounds. Based on the dose-response curve profile, pan-assay interference compounds (PAINS) structure identification, physicochemical properties and efficiency parameters, two hit compounds, 11a and 19a, were tested using a novel secondary fluorescence gel-based assay. Preliminary structure-activity relationship (SAR) studies identified guanidine derivative 12a as an improved hit with a 6.4-fold increase in potency over the original HTS hit 11a. This study highlights the importance of the development of combination approaches (biochemistry, crystallography and high throughput screening) for the discovery of TDP2 inhibitors.
Exploiting the Role of Molecular Electrostatic Potential, Deformation Density, Topology, and Energetics in the Characterization of S?N and Cl?N Supramolecular Motifs in Crystalline Triazolothiadiazoles
Khan, Imtiaz,Panini, Piyush,Khan, Salah Ud-Din,Rana, Usman Ali,Andleeb, Hina,Chopra, Deepak,Hameed, Shahid,Simpson, Jim
, p. 1371 - 1386 (2016/03/12)
A detailed analysis of the molecular and crystal packing of a series of pharmaceutically active triazolothiadiazole derivatives is reported. The most notable feature from the analysis of the supramolecular motifs is the presence of inversion dimers due to the formation of strong S?N chalcogen bonds. This has been unequivocally established via inputs from energy calculations from PIXEL, the topological analysis using the approach of QTAIM from AIMALL, an analysis of the molecular electrostatic potentials plotted on Hirshfeld surfaces, and the analysis of the 3D-deformation densities obtained using Crystal Explorer. The total interaction energy for this contact is in the range of 28-33 kJ/mol in the molecules under investigation, and the electrostatic (Coulombic + polarization) contribution toward the total stabilization energy is more than 70%, indicating that such interactions are principally electrostatic in origin. The results from the analysis of the molecular ESP depict that this interaction exists between a strongly electropositive σ-hole on the sulfur atom and an electronegative region on the nitrogen. 3D-deformation density (DD) maps reveal the presence of a charge depletion (CD) region on the sulfur atom which is directed toward the charge concentration (CC) region on the nitrogen atom facilitating formation of such contacts in the crystal. These are further invesigated by QTAIM based calculations which establish the closed-shell nature of these contacts. The crystal packing is further stabilized by the presence of significantly important π?π stacking interactions, wherein the interaction energies, calculated by the PIXEL method, reveal that some of these interactions in crystals have significant contributions from electrostatic components, with a lesser contribution from dispersion forces that normally dominate such interactions. The existence of a contribution of ～48% from electrostatics between stacked rings owing to their unique electrostatic complementarity is a rare supramolecular feature observed in crystal packing in these solids. In addition, the existence of C-H?O, C-H?N, C-H?F, and Cl?N interactions is also characterized by a significant electrostatic component in their formation in crystals of these compounds.
