Microwave-assisted synthesis of a MK2 inhibitor by Suzuki-Miyaura coupling for study in Werner syndrome cells

Microwave-assisted Suzuki-Miyaura cross-coupling reactions have been employed towards the synthesis of three different MAPKAPK2 (MK2) inhibitors to study accelerated aging in Werner syndrome (WS) cells, including the cross-coupling of a 2-chloroquinoline with a 3-pyridinylboronic acid, the coupling of an aryl bromide with an indolylboronic acid and the reaction of a 3-amino-4-bromopyrazole with 4-carbamoylphenylboronic acid. In all of these processes, the Suzuki-Miyaura reaction was fast and relatively efficient using a palladium catalyst under microwave irradiation. The process was incorporated into a rapid 3-step microwave-assisted method for the synthesis of a MK2 inhibitor involving 3-aminopyrazole formation, pyrazole C-4 bromination using N-bromosuccinimide (NBS), and Suzuki-Miyaura cross-coupling of the pyrazolyl bromide with 4-carbamoylphenylboronic acid to give the target 4-arylpyrazole in 35% overall yield, suitable for study in WS cells

Microwave-assisted synthesis of a MK2 inhibitor by Suzuki-Miyaura coupling for study in Werner syndrome cells

Microwave-assisted Suzuki-Miyaura cross-coupling reactions have been employed towards the synthesis of three different MAPKAPK2 (MK2) inhibitors to study accelerated aging in Werner syndrome (WS) cells, including the cross-coupling of a 2-chloroquinoline with a 3-pyridinylboronic acid, the coupling of an aryl bromide with an indolylboronic acid and the reaction of a 3-amino-4-bromopyrazole with 4-carbamoylphenylboronic acid. In all of these processes, the Suzuki-Miyaura reaction was fast and relatively efficient using a palladium catalyst under microwave irradiation. The process was incorporated into a rapid 3-step microwave-assisted method for the synthesis of a MK2 inhibitor involving 3-aminopyrazole formation, pyrazole C-4 bromination using N-bromosuccinimide (NBS), and Suzuki-Miyaura cross-coupling of the pyrazolyl bromide with 4-carbamoylphenylboronic acid to give the target 4-arylpyrazole in 35% overall yield, suitable for study in WS cells

Crystal structure of 3-amino-2-ethylquinazolin-4(3H)-one

The mol­ecule of the title compound, C10H11N3O, is planar, including the ethyl group, as indicated by the N-C-C-C torsion angle of 1.5 (2)°. In the crystal, inversion-related mol­ecules are stacked along the a axis. Mol­ecules are oriented head-to-tail and display [pi]-[pi] inter­actions with a centroid-to-centroid distance of 3.6664 (8) Å. N-H...O hydrogen bonds between mol­ecules generate a `step' structure through formation of an R22(10) ring

The effect of RO3201195 and a pyrazolyl ketone P38 MAPK inhibitor library on the proliferation of Werner syndrome cells

No description supplie

Crystal structure of (E)-5-((4-chlorophenyl)diazenyl)-2-(5-(4-fluorophenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-methylthiazole, C23H17ClFN5S2

Abstract C23H17ClFN5S2, monoclinic, P21/c (no. 14), a = 20.9691(12) Å, b = 11.5316(6) Å, c = 9.2546(4) Å, β = 95.484(4)°, V = 2227.6(2) Å3, Z = 4, R gt(F) = 0.0468, wR ref(F 2) = 0.1126, T = 296 K.</jats:p

Crystal structure of 1-phenyl-N′-(1-phenyl-5-(thiophen-2-yl)-1H-pyrazole-3-carbonyl)-5-(thiophen-2-yl)-1H-pyrazole-3-carbohydrazide, C28H20N6O2S2

C28H20N6O2S2, triclinic, P1̅ (no. 2), a = 10.6738(6) Å, b = 11.7869(7) Å, c = 12.5381(7) Å, α = 112.842(6)°, β = 91.963(4)°, γ = 116.129(6)°, V = 1264.38(15) Å3, Z = 2, Rgt(F) = 0.0523, wRref(F2) = 0.1390, T = 296(2) K

Synthesis, analysis and biological evaluation of heterocyclic drugs

Chapter 1: Chapter One provides an overview on the Bohlmann-Rahtz pyridine synthesis. New procedures, implementing metal based Lewis acids, Brønsted acids and metal-free Lewis acid catalysts have been used in this process. Also, new one-pot two- and three-component methodologies have been developed for the synthesis of various natural products containing the pyridine motif and these have been compared and contrasted. This chapter also discusses signalling pathways in Werner syndrome cells. The inhibitor SB203580 has been shown to prevent the phosphorylation of the p38α kinase in a ATP competitive manner and this implicates this mechanism in accelerated ageing and gives potential to the prospect of targeting this pathway in a drug discovery programme, if better mechanistic understanding can be garnered. Chapter 2: Chapter Two discusses the Bohlman–Rahtz synthesis of various substituted pyridines. The process has been modified to be simple, involves mild conditions and provides the heterocyclic targets in high yield. We have shown that substituted pyridines could be synthesised efficiently under microwave conditions using a relatively short reaction time. The process was also successful for the production of a range of fused heterocycles containing the pyridine moiety in high yield, including pyrido[2,3-d]pyrimidin-4(3H)-ones and pyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones. Chapter 3: Chapter Three describes the efficient synthesis of the p38 MAPK inhibitor UR-13756 using a Hantzsch-type three component cyclocondensation. Microwave irradiation of a mixture of 3-amino-1-methylpyrazole hydrochloride, 1-(4-fluorophenyl)-2-(pyridine-4-yl)ethanone and 4-fluorobenzaldhyde for 4 hours in ethanol under acidic catalytic conditions provided UR-13756 in high yield (71%) after purification by column chromatography. Chapter 4: Chapter Four shows the synthesis of 4-(3-amino-1-(4-methoxyphenyl)-1H-pyrazol-4-yl)benzamide in three steps by the use of rigorous experimental procedures under microwave conditions. This technique led to faster heating rates and allowed the rapid optimization of yields. These advantages were observed in all steps and allow formation of products in high yields. Biological study of the inhibitor 4-(3-amino-1-(4-methoxyphenyl)-1H-pyrazol-4-yl)benzamide showed, by ELISA analysis, that p38 signalling was inhibited in control dermal cells. Some progress was made towards the synthesis of 3-amino-4-[1-(3-1H-pyrazol-4-yl)]benzamide. Chapter 5: Chapter Five investigates the synthesis of the chemotherapeutic agent RO3201195, a highly selective inhibitor of p38α, in seven steps under microwave conditions. The procedure provides a relatively high overall yield of the desired product and all other intermediates involved in individual steps compared with conventional heating methods. Chapter 6: Chapter Six provides the experimental procedures and various spectroscopic data for the synthesized compounds

A New Zn(II) Metal Hybrid Material of 5-Nitrobenzimidazolium Organic Cation (C7H6N3O2)2[ZnCl4]: Elaboration, Structure, Hirshfeld Surface, Spectroscopic, Molecular Docking Analysis, Electric and Dielectric Properties

The slow solvent evaporation approach was used to create a single crystal of (CHNO)[ZnCl] at room temperature. Our compound has been investigated by single-crystal XRD which declares that the complex crystallizes in the monoclinic crystallographic system with the P2/c as a space group. The molecular arrangement of the compound can be described by slightly distorted tetrahedral ZnCl anionic entities and 5-nitrobenzimidazolium as cations, linked together by different non-covalent interaction types (H-bonds, Cl…Cl, π…π and C–H…π). Hirshfeld’s surface study allows us to identify that the dominant contacts in the crystal building are H…Cl/Cl…H contacts (37.3%). FT-IR method was used to identify the different groups in (CHNO)[ZnCl]. Furthermore, impedance spectroscopy analysis in 393 ≤ T ≤ 438 K shows that the temperature dependence of DC conductivity follows Arrhenius’ law. The frequency–temperature dependence of AC conductivity for the studied sample shows one region (E = 2.75 eV). In order to determine modes of interactions of compound with double stranded DNA, molecular docking simulations were performed at molecular level

Crystal structure of 3-(5-methyl-1-p-tolyl-1H-1,2,3-triazol-4-yl)-1-phenyl-1H-pyrazole-4-carbaldehyde, a rare Z' = 3 structure, C20H17N5O

Abstract C20H17N5O, triclinic, P1̅ (no. 2), a = 11.5358(7) Å, b = 13.8746(9) Å, c = 16.3942(10) Å, α = 85.958(5)°, β = 87.407(5)°, γ = 87.619(5)°, V = 2612.8(3)Å3, Z = 6, R gt(F) = 0.0607, wR ref(F 2) = 0.1510, T = 293(2) K.</jats:p