Design, synthesis, molecular dynamics simulation, MM/GBSA studies and kinesin spindle protein inhibitory evaluation of some 4-aminoquinoline hybrids.

The discovery of novel chemotherapeutic agents is always challenging for researchers in industry and academia. Among the recent promising anticancer therapeutic targets, an important modulatory factor in mitosis is the expression of the kinesin family motor protein (Eg5). In terms of chemotherapy treatment, mitosis has gained significant attention due to its role as one of the biological processes that can be intervened in it. This study was undertaken to design, synthesise and evaluation of 4-aminoquinoline hybrid compounds as potential Eg5 inhibitors. Based on data collected from Malachite green and steady state ATPase assays, it has been determined that compounds such as 6c, 6d, 6g, and 6h are sensitive to Eg5 inhibition. In special mention, compounds 4 and 6c showed promising inhibitory activity in Malachite green assay with IC50 values of 2.32 ± 0.23 µM and 1.97 ± 0.23 µM respectively. Compound 4 showed favourable inhibitory potential Steady state ATPase Assay with IC50 value of 5.39 ± 1.39 µM. We performed molecular docking, MM/GBSA calculations, and molecular dynamic simulations to evaluate the interactions between ligands and the binding site of the kinesin spindle protein to evaluate the functional consequences of these interactions. As a result of these findings, it can be concluded that these 4-amioquinoline Schiff's base hybrids may prove to be promising candidates for development as novel inhibitors of Eg5. Further in-vivo research in this area is required.

Design, synthesis, and molecular docking study of some 2-((7-chloroquinolin-4-yl) amino) benzohydrazide Schiff bases as potential Eg5 inhibitory agents.

In Search of new microtubule-targeting compounds and to identify a promising Eg5 inhibitory agents, a series of 2-((7-chloroquinolin-4-yl) amino) benzohydrazide Schiff bases molecules (6 a-r) were synthesized using appropriate synthetic method. The synthesized compounds were characterized by using FTIR, Proton NMR, Carbon NMR and mass spectral analysis. All eighteen compounds were evaluated for their Eg5 inhibitory activity. Among the evaluated compounds, only seven compounds are shown inhibitory activity. The results of Steady state ATPase reveled that compounds 6b, 6l and 6p exhibited promising inhibitory activity with IC50 Values of 2.720 ± 0.69, 2.676 ± 0.53 and 2.408 ± 0.46 respectively. Malachite Green Assay results reveled that 6q compound showed better inhibitory activity with IC50 Value of 0.095 ± 0.27. In vitro antioxidant capacity of the synthesized compounds was investigated. A molecular docking studies were performed to evaluate interaction in to binding site of kinesin spindle protein, these interaction influencing may support Eg5 inhibitory activity. The drug like parameters of the eighteen synthesized compounds were also computed using Qikprop software. In conclusion, some of 2-((7-chloroquinolin-4-yl) amino) benzohydrazide Schiff base compounds represent promising drug like agents for discovery of effective anticancer molecules.

Structure-activity relationship of pyrazolo pyrimidine derivatives as inhibitors of mitotic kinesin Eg5 and anticancer agents.

Human kinesin Eg5 is a potential inhibiting site for cancer chemotherapy. Blocking metaphase by binding foreign inhibitors with Eg5 eventually leads to apoptotic cell death. Here, we report the pyrazolopyrimidine derivates as potent inhibitors of Eg5 that prevents mitotic kinesin progression. IC50 values were evaluated against the motor domain of Eg5 using steady-state ATPase assay. To better understanding, we have performed molecular docking simulation. It reveals that the interactions of the proposed inhibitors with both the allosteric sites (helices α2, α3 and loopL5, and helices α4 & α6). Out of fifteen pyrazolopyrimidine derivates, three compounds (12, 25, and 27) have shown significant inhibition of Eg5. The synthesized compounds (12, 25, and 27) were tested for their in-vitro anticancer activity against cervical cancer cell line (HeLa).

Synthesis of N-(1-(6-acetamido-5-phenylpyrimidin-4-yl) piperidin-3-yl) amide derivatives as potential inhibitors for mitotic kinesin spindle protein.

Kinesin Spindle Protein (KSP) or Eg5 is an essential kinesin that is involved in spindle separation process during mitosis and also unregulated in certain cancer cells. Inhibitors of this enzyme have proved to be effective to block spindle separation followed by mitotic arrest and apoptosis of the cancer cells. Since this enzyme has two allosteric inhibitor binding sites, it's an excellent target for developing drugs for cancer chemotherapy. Many pyrimidine derivatives have been proved to be active against cancer and other enzymes. In this report, we have synthesized a set ten novel N-(1-(6-acetamido-5-phenylpyrimidin-4-yl)piperidin-3-yl)amide derivatives and have evaluated their activity against the KSP. The SAR of these active compounds was further analyzed using in silico molecular docking studies using GOLD and AutoDock softwares. All these compounds form hydrophobic interaction, aromatic π-π stacking and hydrogen bond efficiently with the Eg5.

Crystal engineering with heteroboranes. I. 1-Carboxy-1,2-dicarba-closo-dodecaborane(11).

The title compound, C(3)H(12)B(10)O(2) or 1-COOH-1,2-closo-C(2)B(10)H(11), forms centrosymmetric dimers through intermolecular hydrogen bonding between the carboxylic acid groups, resulting in the formation of an eight-membered ring [R(2)(2)(8)]. The C==O bond of the carboxylic acid group almost eclipses the unsubstituted cage C atom, with a C-C-C-O torsion angle of 2.6 (2) degrees.

Subtlety in the reactivity of a diketo phosphorus ylide towards mercuric halides: the unprecedented O-coordination of alpha-acetyl-alpha-benzoylmethylenetriphenylphosphorane to Hg(II).

The reactions of the title ylide with HgX2 (X = Cl, Br or I) lead to the regiospecific binding of the acetyl oxygen to soft Hg(II), producing a chloro complex with (2 + 2) coordination and isostructural dimeric bromo and iodo complexes containing halogen bridges with tetrahedral configurations around the metal centres.