Metal-Free, Mild, Nonepimerizing, Chemo- and Enantio- or Diastereoselective N‑Alkylation of Amines by Alcohols via Oxidation/Imine–Iminium Formation/Reductive Amination: A Pragmatic Synthesis of Octahydropyrazinopyridoindoles and Higher Ring Analogues

A mild step and atom-economical nonepimerizing chemo- and enantioselective N-alkylating procedure has been developed via oxidation/imine–iminium formation/reduction cascade using TEMPO–BAIB–HEH–Brønsted acid catalysis in DMPU as solvent and a stoichiometric amount of amine. The optimized conditions were further extended for the nonenzymatic kinetic resolution of the chiral amine thus formed under nonenzymatic in situ hydrogen-transfer conditions using VAPOL-derived phosphoric acid (VAPOL-PA) as the Brønsted acid catalyst. The enantioselective cascade of the presented reaction was successfully utilized in the synthesis of octahydropyrazinopyridoindole and its higher ring analogues

Metal-Free, Mild, Nonepimerizing, Chemo- and Enantio- or Diastereoselective N‑Alkylation of Amines by Alcohols via Oxidation/Imine–Iminium Formation/Reductive Amination: A Pragmatic Synthesis of Octahydropyrazinopyridoindoles and Higher Ring Analogues

A mild step and atom-economical nonepimerizing chemo- and enantioselective N-alkylating procedure has been developed via oxidation/imine–iminium formation/reduction cascade using TEMPO–BAIB–HEH–Brønsted acid catalysis in DMPU as solvent and a stoichiometric amount of amine. The optimized conditions were further extended for the nonenzymatic kinetic resolution of the chiral amine thus formed under nonenzymatic in situ hydrogen-transfer conditions using VAPOL-derived phosphoric acid (VAPOL-PA) as the Brønsted acid catalyst. The enantioselective cascade of the presented reaction was successfully utilized in the synthesis of octahydropyrazinopyridoindole and its higher ring analogues

Metal-Free, Mild, Nonepimerizing, Chemo- and Enantio- or Diastereoselective N‑Alkylation of Amines by Alcohols via Oxidation/Imine–Iminium Formation/Reductive Amination: A Pragmatic Synthesis of Octahydropyrazinopyridoindoles and Higher Ring Analogues

A mild step and atom-economical nonepimerizing chemo- and enantioselective N-alkylating procedure has been developed via oxidation/imine–iminium formation/reduction cascade using TEMPO–BAIB–HEH–Brønsted acid catalysis in DMPU as solvent and a stoichiometric amount of amine. The optimized conditions were further extended for the nonenzymatic kinetic resolution of the chiral amine thus formed under nonenzymatic in situ hydrogen-transfer conditions using VAPOL-derived phosphoric acid (VAPOL-PA) as the Brønsted acid catalyst. The enantioselective cascade of the presented reaction was successfully utilized in the synthesis of octahydropyrazinopyridoindole and its higher ring analogues

Toward the Identification of a Reliable 3D QSAR Pharmacophore Model for the CCK2 Receptor Antagonism

The present study describes application of computational approaches to identify a validated and reliable 3D QSAR pharmacophore model for the CCK-2R antagonism through integrated ligand and structure based studies using anthranilic sulfonamide and 1,3,4-benzotriazepine based CCK-2R antagonists. The best hypothesis consisted five features viz. two aliphatic hydrophobic, one aromatic hydrophobic, one H-bond acceptor, and one ring aromatic feature with an excellent correlation for 34 training set (r²_training = 0.83) and 58 test set compounds (r²_test = 0.74). This model was validated through F-test and docking studies at the active site of the plausible CCK-2R where the 99% significance and well corroboration with the pharmacophore model respectively describes the model’s reliability. The model also predicts well to other known clinically effective CCK-2R antagonists. Therefore, the developed model may useful in finding new scaffolds that may aid in design and develop new chemical entities (NCEs) as potent CCK-2R antagonists before their synthesis

Identification of Novel Amino Acid Derived CCK-2R Antagonists As Potential Antiulcer Agent: Homology Modeling, Design, Synthesis, and Pharmacology

The present study revisited the three-dimensional (3D) homology model of CCK-2R using human A_2a adenosine receptor and the resolved NMR based structure of the third extracellular loop of the CCK-2R as templates. Further in order to identify novel antiulcer agents, rational designing have been performed utilizing the substructure of a well-known CCK-2R antagonist benzotript as a lead molecule and submitted to the combined docking and simulation studies. This led to the understanding of the essential structure requirement as well as variation of binding mode among conformational isomers of small molecule CCK-2R antagonists. In the next step, preparation of each configurational isomer of these molecules was carried out and submitted for their in vitro activity followed by in vivo screening into antiulcer rat model. The biological screening of these compounds has not only validated the developed homology model of CCK-2R but also led to the identification of highly potent CCK-2R antagonist <b>6a</b> as an orally active and safe candidate molecule having better antiulcer properties than the well-known drug benzotript

Identification of Novel <i>S-</i>Adenosyl-l-Homocysteine Hydrolase Inhibitors through Homology-Model-Based Virtual Screening, Synthesis, and Biological Evaluation

The present study describes a successful application of computational approaches to identify novel Leishmania donovani (<i>Ld)</i> AdoHcyase inhibitors utilizing the differences for <i>Ld</i> AdoHcyase NAD⁺ binding between human and <i>Ld</i> parasite. The development and validation of the three-dimensional (3D) structures of <i>Ld</i> AdoHcyase using the L. major AdoHcyase as template has been carried out. At the same time, cloning of the <i>Ld</i> AdoHcyase gene from clinical strains, its overexpression and purification have been performed. Further, the model was used in combined docking and molecular dynamics studies to validate the binding site of NAD in <i>Ld</i>. The hierarchical structure based virtual screening followed by the synthesis of five active hits and enzyme inhibition assay has resulted in the identification of novel <i>Ld</i> AdoHcyase inhibitors. The most potent inhibitor, compound <b>5</b>, may serve as a “lead” for developing more potent <i>Ld</i> AdoHcy hydrolase inhibitors as potential antileishmanial agents

Novel Glycoprotein VI Antagonists as Antithrombotics: Synthesis, Biological Evaluation, and Molecular Modeling Studies on 2,3-Disubstituted Tetrahydropyrido(3,4‑<i>b</i>)indoles

The development of small molecule inhibitors targeting GPVI has promising therapeutic role, as they inhibit arterial thrombosis with limited risk of bleeding. Among the compounds showing in vivo antithrombotic activity, the most active compound <b>6b</b> (ED₅₀ = 28.36 μmol/kg po in mice) showed improved inhibition for collagen (IC₅₀ = 6.7 μM), CRP-XL (IC₅₀ = 53.5 μM), and convulxin (CVX) (IC₅₀ = 5.7 μM) mediated platelet aggregation as compared to losartan (LOS) (collagen, IC₅₀ = 10.4 μM; CRP-XL, IC₅₀ = 158 μM; CVX, IC₅₀ = 11 μM) than any of its enantiomers <i>S</i> (<b>6c</b>) (collagen, IC₅₀ = 25.3 μM; CRP-XL, IC₅₀ = 181.4 μM; CVX, IC₅₀ = 9 μM) and <i>R</i> (<b>6d</b>) (collagen, IC₅₀ = 126.3 μM; CRP-XL, IC₅₀ > 500 μM; CVX, IC₅₀ = 86.8 μM). Compound <b>6b</b> also inhibited platelet P-selectin expression and thus may diminish atherosclerosis. The molecular interactions of both enantiomers <b>6c</b> and <b>6d</b> at the GPVI receptor have been explained through docking studies

Novel Glycoprotein VI Antagonists as Antithrombotics: Synthesis, Biological Evaluation, and Molecular Modeling Studies on 2,3-Disubstituted Tetrahydropyrido(3,4‑<i>b</i>)indoles

The development of small molecule inhibitors targeting GPVI has promising therapeutic role, as they inhibit arterial thrombosis with limited risk of bleeding. Among the compounds showing in vivo antithrombotic activity, the most active compound <b>6b</b> (ED₅₀ = 28.36 μmol/kg po in mice) showed improved inhibition for collagen (IC₅₀ = 6.7 μM), CRP-XL (IC₅₀ = 53.5 μM), and convulxin (CVX) (IC₅₀ = 5.7 μM) mediated platelet aggregation as compared to losartan (LOS) (collagen, IC₅₀ = 10.4 μM; CRP-XL, IC₅₀ = 158 μM; CVX, IC₅₀ = 11 μM) than any of its enantiomers <i>S</i> (<b>6c</b>) (collagen, IC₅₀ = 25.3 μM; CRP-XL, IC₅₀ = 181.4 μM; CVX, IC₅₀ = 9 μM) and <i>R</i> (<b>6d</b>) (collagen, IC₅₀ = 126.3 μM; CRP-XL, IC₅₀ > 500 μM; CVX, IC₅₀ = 86.8 μM). Compound <b>6b</b> also inhibited platelet P-selectin expression and thus may diminish atherosclerosis. The molecular interactions of both enantiomers <b>6c</b> and <b>6d</b> at the GPVI receptor have been explained through docking studies

Novel Glycoprotein VI Antagonists as Antithrombotics: Synthesis, Biological Evaluation, and Molecular Modeling Studies on 2,3-Disubstituted Tetrahydropyrido(3,4‑<i>b</i>)indoles

The development of small molecule inhibitors targeting GPVI has promising therapeutic role, as they inhibit arterial thrombosis with limited risk of bleeding. Among the compounds showing in vivo antithrombotic activity, the most active compound <b>6b</b> (ED₅₀ = 28.36 μmol/kg po in mice) showed improved inhibition for collagen (IC₅₀ = 6.7 μM), CRP-XL (IC₅₀ = 53.5 μM), and convulxin (CVX) (IC₅₀ = 5.7 μM) mediated platelet aggregation as compared to losartan (LOS) (collagen, IC₅₀ = 10.4 μM; CRP-XL, IC₅₀ = 158 μM; CVX, IC₅₀ = 11 μM) than any of its enantiomers <i>S</i> (<b>6c</b>) (collagen, IC₅₀ = 25.3 μM; CRP-XL, IC₅₀ = 181.4 μM; CVX, IC₅₀ = 9 μM) and <i>R</i> (<b>6d</b>) (collagen, IC₅₀ = 126.3 μM; CRP-XL, IC₅₀ > 500 μM; CVX, IC₅₀ = 86.8 μM). Compound <b>6b</b> also inhibited platelet P-selectin expression and thus may diminish atherosclerosis. The molecular interactions of both enantiomers <b>6c</b> and <b>6d</b> at the GPVI receptor have been explained through docking studies

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<p>Salinity stress is one of the serious factors, limiting production of major agricultural crops; especially, in sodic soils. A number of approaches are being applied to mitigate the salt-induced adverse effects in agricultural crops through implying different halotolerant microbes. In this aspect, a halotolerant, Exiguobacterium profundum PHM11 was evaluated under eight different salinity regimes; 100, 250, 500, 1000, 1500, 2000, 2500, and 3000 mM to know its inherent salt tolerance limits and salt-induced consequences affecting its natural metabolism. Based on the stoichiometric growth kinetics; 100 and 1500 mM concentrations were selected as optimal and minimal performance limits for PHM11. To know, how salt stress affects the expression profiles of regulatory genes of its key metabolic pathways, and total production of important metabolites; biomass, carotenoids, beta-carotene production, IAA and proline contents, and expression profiles of key genes affecting the protein folding, structural adaptations, transportation across the cell membrane, stress tolerance, carotenoids, IAA and mannitol production in PHM11 were studied under 100 and 1500 mM salinity. E. profundum PHM11 showed maximum and minimum growth, biomass and metabolite production at 100 and 1500 mM salinity respectively. Salt-induced fine-tuning of expression profiles of key genes of stress pathways was determined in halotolerant bacterium PHM11.</p