<span style="color:black;mso-bidi-language:HI">Pyrazolo-fused quinoline analogues: Synthesis of 1<i>H</i>-pyrazolo [3, 4-<i>b</i>] quinolines <span style="color:black;mso-bidi-language:HI">and 3-amino-1<i>H</i>-pyrazolo [3, <span style="mso-bidi-font-family:Arial;color:black;mso-bidi-language:HI">4<i>-b</i>]<i> </i><span style="color:black;mso-bidi-language:HI">quinolines from 3-formyl and 3-cyano-2- <span style="font-size:12.0pt;font-family:"Times New Roman";mso-fareast-font-family: "Times New Roman";mso-bidi-font-family:"Times New Roman";color:black; mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language:HI">chloroquinolines</span></span></span></span></span>

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mso-bidi-language:HI">l<span style="color:#131313;mso-bidi-language: HI">ysis <span style="color:#131313; mso-bidi-language:HI">wit<span style="color:black; mso-bidi-language:HI">h B<span style="color:#2C2C2C;mso-bidi-language: HI">iCI3. <span style="color:black; mso-bidi-language:HI">H<span style="color:#131313;mso-bidi-language: HI">owever<span style="color:#2C2C2C; mso-bidi-language:HI">, 3-amino<span style="color:black; mso-bidi-language:HI">-1H-p<span style="color:#131313;mso-bidi-language: HI">yra<span style="color:#2C2C2C; mso-bidi-language:HI">z<span style="color:#131313;mso-bidi-language: HI">olo<span style="color:black; mso-bidi-language:HI">[<span style="color:#131313;mso-bidi-language: HI">3, 4-b<span style="color:black; mso-bidi-language:HI">]quin<span style="color:#131313;mso-bidi-language: HI">olines <span style="color:black; mso-bidi-language:HI">7 h<span style="color:#131313;mso-bidi-language: HI">ave be<span style="color:#2C2C2C; mso-bidi-language:HI">en s<span style="color:#2C2C2C; mso-bidi-language:HI">ynt<span style="color:black; mso-bidi-language:HI">h<span style="color:#131313;mso-bidi-language: HI">esi<span style="color:#131313; mso-bidi-language:HI">z<span style="color:#2C2C2C;mso-bidi-language: HI">ed fr<span style="color:#131313; mso-bidi-language:HI">om 2<span style="color:black; mso-bidi-language:HI">-<span style="color:#131313;mso-bidi-language: HI">chlo<span style="color:black; mso-bidi-language:HI">r<span style="color:#2C2C2C;mso-bidi-language: HI">o-3<span style="color:black; mso-bidi-language:HI">-<span style="color:#131313;mso-bidi-language: HI">cya<span style="color:black; mso-bidi-language:HI">n<span style="color:#131313;mso-bidi-language: HI">oquino<span style="color:black; mso-bidi-language:HI">li<span style="color:#131313;mso-bidi-language: HI">nes <span style="color:black; mso-bidi-language:HI">2<span style="color:black;mso-bidi-language: HI"> wi<span style="color:#2C2C2C; mso-bidi-language:HI">t<span style="color:#131313;mso-bidi-language: HI">h ex<span style="color:#131313; mso-bidi-language:HI">cess <span style="color:#2C2C2C; mso-bidi-language:HI">of hydrazine hydrate in one step. The functional group manipulation of amino group in compounds 7 has also been studied. </span

Design and Synthesis of Amino Acid Derivatives of Substituted Benzimidazoles and Pyrazoles as Selective Sirt1 Inhibitors

Owing to its presence in several biological processes Sirt1 served as a potential therapeutic target for many diseases. Here we report the synthesis of two distinct series of novel Sirt1 selective inhibitors, benzimidazole monopeptides and 5-pyrazolyl methylidene rhodanine carboxylic acid derived amino acids, constructed using structure-guided computational approaches. Furthermore, compounds were evaluated, against human Sirt1-3 for in-vitro inhibitory activity compared to Ex527 (reported Sirt1-selective inhibitor), in liver and breast cancer cell lines for cytotoxicity. The tryptophan conjugates 13h (IC50 = 0.66 µM) and 7d (IC50 = 0.77 µM) demonstrated maximum efficacy to inhibit Sirt1. Molecular dynamics simulations unveil the interaction map and electrostatic complementarity at substrate binding site, could be a cause of selective Sirt1 inhibition. Furthermore, the Sirt1 inhibition was monitored via increased p53 acetylation status checked in HepG2 cells. These findings will pave the pathway for developing novel selective Sirt1-inhibitors in cancer therapeutics

Mechanism of Oxygen Atom Transfer from Fe^V(O) to Olefins at Room Temperature

In biological oxidations, the intermediate Fe^V(O)­(OH) has been proposed to be the active species for catalyzing the epoxidation of alkenes by nonheme iron complexes. However, no study has been reported yet that elucidates the mechanism of direct O-atom transfer during the reaction of Fe^V(O) with alkenes to form the corresponding epoxide. For the first time, we study the mechanism of O-atom transfer to alkenes using the Fe^V(O) complex of biuret-modified Fe–TAML at room temperature. The second-order rate constant (<i>k</i>₂) for the reaction of different alkenes with Fe^V(O) was determined under single-turnover conditions. An 8000-fold rate difference was found between electron-rich (4-methoxystyrene; <i>k</i>₂ = 216 M^–1 s^–1) and electron-deficient (methyl <i>trans</i>-cinnamate; <i>k</i>₂ = 0.03 M^–1 s^–1) substrates. This rate difference indicates the electrophilic character of Fe^V(O). The use of <i>cis</i>-stilbene as a mechanistic probe leads to the formation of both <i>cis</i>- and <i>trans</i>-stilbene epoxides (73:27). This suggests the formation of a radical intermediate, which would allow C–C bond rotation to yield both stereoisomers of stilbene–epoxide. Additionally, a Hammett ρ value of −0.56 was obtained for the para-substituted styrene derivatives. Detailed DFT calculations show that the reaction proceeds via a two-step process through a doublet spin surface. Finally, using biuret-modified Fe–TAML as the catalyst and NaOCl as the oxidant under catalytic conditions epoxide was formed with modest yields and turnover numbers

Tuning the Reactivity of Fe^V(O) toward C–H Bonds at Room Temperature: Effect of Water

The presence of an Fe^V(O) species has been postulated as the active intermediate for the oxidation of both C–H and CC bonds in the Rieske dioxygenase family of enzymes. Understanding the reactivity of these high valent iron–oxo intermediates, especially in an aqueous medium, would provide a better understanding of these enzymatic reaction mechanisms. The formation of an Fe^V(O) complex at room temperature in an aqueous CH₃CN mixture that contains up to 90% water using NaOCl as the oxidant is reported here. The stability of Fe^V(O) decreases with increasing water concentration. We show that the reactivity of Fe^V(O) toward the oxidation of C–H bonds, such as those in toluene, can be tuned by varying the amount of water in the H₂O/CH₃CN mixture. Rate acceleration of up to 60 times is observed for the oxidation of toluene upon increasing the water concentration. The role of water in accelerating the rate of the reaction has been studied using kinetic measurements, isotope labeling experiments, and density functional theory (DFT) calculations. A kinetic isotope effect of ∼13 was observed for the oxidation of toluene and <i>d</i>₈-toluene showing that C–H abstraction was involved in the rate-determining step. Activation parameters determined for toluene oxidation in H₂O/CH₃CN mixtures on the basis of Eyring plots for the rate constants show a gain in enthalpy with a concomitant loss in entropy. This points to the formation of a more-ordered transition state involving water molecules. To further understand the role of water, we performed a careful DFT study, concentrating mostly on the rate-determining hydrogen abstraction step. The DFT-optimized structure of the starting Fe^V(O) and the transition state indicates that the rate enhancement is due to the transition state’s favored stabilization over the reactant due to enhanced hydrogen bonding with water