New Multifunctional Agents Based on Conjugates of 4-Amino-2,3-polymethylenequinoline and Butylated Hydroxytoluene for Alzheimer’s Disease Treatment

New hybrids of 4-amino-2,3-polymethylenequinoline with different sizes of the aliphatic ring linked to butylated hydroxytoluene (BHT) by enaminoalkyl (7) or aminoalkyl (8) spacers were synthesized as potential multifunctional agents for Alzheimer’s disease (AD) treatment. All compounds were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. Lead compound 8c, 2,6-di-tert-butyl-4-{[2-(7,8,9,10- tetrahydro-6H-cyclohepta[b]quinolin-11-ylamino)-ethylimino]-methyl}-phenol exhibited an IC₅₀(AChE) = 1.90 ± 0.16 µM, IC₅₀(BChE) = 0.084 ± 0.008 µM, and 13.6 ± 1.2% propidium displacement at 20 μM. Compounds possessed low activity against carboxylesterase, indicating likely absence of clinically unwanted drug-drug interactions. Kinetics were consistent with mixed-type reversible inhibition of both cholinesterases. Docking indicated binding to catalytic and peripheral AChE sites; peripheral site binding along with propidium displacement suggest the potential of the hybrids to block AChE-induced β-amyloid aggregation, a disease-modifying effect. Compounds demonstrated high antioxidant activity in ABTS and FRAP assays as well as inhibition of luminol chemiluminescence and lipid peroxidation in mouse brain homogenates. Conjugates 8 with amine-containing spacers were better antioxidants than those with enamine spacers 7. Computational ADMET profiles for all compounds predicted good blood-brain barrier distribution (permeability), good intestinal absorption, and medium cardiac toxicity risk. Overall, based on their favorable pharmacological and ADMET profiles, conjugates 8 appear promising as candidates for AD therapeutics.     

Bis-Amiridines as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: N-Functionalization Determines the Multitarget Anti-Alzheimer’s Activity Profile

Using two ways of functionalizing amiridine—acylation with chloroacetic acid chloride and reaction with thiophosgene—we have synthesized new homobivalent bis-amiridines joined by two different spacers—bis-N-acyl-alkylene (3) and bis-N-thiourea-alkylene (5) —as potential multifunctional agents for the treatment of Alzheimer’s disease (AD). All compounds exhibited high inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity for BChE. These new agents displayed negligible carboxylesterase inhibition, suggesting a probable lack of untoward drug–drug interactions arising from hydrolytic biotransformation. Compounds 3 with bis-N-acyl-alkylene spacers were more potent inhibitors of both cholinesterases compared to compounds 5 and the parent amiridine. The lead compounds 3a–c exhibited an IC₅₀(AChE) = 2.9–1.4 µM, IC₅₀(BChE) = 0.13–0.067 µM, and 14–18% propidium displacement at 20 μM. Kinetic studies of compounds 3a and 5d indicated mixed-type reversible inhibition. Molecular docking revealed favorable poses in both catalytic and peripheral AChE sites. Propidium displacement from the peripheral site by the hybrids suggests their potential to hinder AChE-assisted Aβ₄₂ aggregation. Conjugates 3 had no effect on Aβ₄₂ self-aggregation, whereas compounds 5c–e (m = 4, 5, 6) showed mild (13–17%) inhibition. The greatest difference between conjugates 3 and 5 was their antioxidant activity. Bis-amiridines 3 with N-acylalkylene spacers were nearly inactive in ABTS and FRAP tests, whereas compounds 5 with thiourea in the spacers demonstrated high antioxidant activity, especially in the ABTS test (TEAC = 1.2–2.1), in agreement with their significantly lower HOMO-LUMO gap values. Calculated ADMET parameters for all conjugates predicted favorable blood–brain barrier permeability and intestinal absorption, as well as a low propensity for cardiac toxicity. Thus, it was possible to obtain amiridine derivatives whose potencies against AChE and BChE equaled (5) or exceeded (3) that of the parent compound, amiridine. Overall, based on their expanded and balanced pharmacological profiles, conjugates 5c–e appear promising for future optimization and development as multitarget anti-AD agents.     

Nuclear level densities in <Superscript>47</Superscript>V, <Superscript>48</Superscript>V, <Superscript>49</Superscript>V, <Superscript>53</Superscript>Mn,and <Superscript>54</Superscript>Mn from neutron evaporation spectra

The spectra of neutrons from the (p, n) reactions on ⁴⁷Ti, ⁴⁸Ti, ⁴⁹Ti, ⁵³Cr, and ⁵⁴Cr nuclei were measured in the proton-energy range 7–11 MeV. The measurements were performed with the aid of a fast-neutron spectrometer by the time-of-flight method over the base of the EGP-15 tandem accelerator of the Institute for Physics and Power Engineering (IPPE, Obninsk). Owing to a high resolution and a high stability of the time-of-flight spectrometer used, low-lying discrete levels could be identified reliably along with a continuum section of neutron spectra. An analysis of measured data was performed within the statistical equilibrium and preequilibrium models of nuclear reactions. The relevant calculations were performed by using the exact formalism of Hauser-Feshbach statistical theory supplemented with the generalized model of a superfluid nucleus, the back-shifted Fermi gas model, and the Gilbert-Cameron composite formula for the nuclear level density. The nuclear level densities for ⁴⁷V, ⁴⁸V, ⁴⁹V, ⁵³Mn, and ⁵⁴Mn were determined along with their energy dependences and model parameters. The results are discussed together with available experimental data and recommendations of model systematics.     

Nuclear-level densities around Z = 50 from neutron evaporation spectra in (p, n) reactions

Neutron excitation functions, spectra, and angular distributions in the (p, n) reactions on the isotopes ¹¹⁶Sn, ¹¹⁸Sn, ¹²²Sn, and ¹²⁴Sn were measured in the proton-energy range 7–11 MeV. The measurements were performed by the time-of-flight method with the aid of a fast-neutron spectrometer at the EGP-15 pulsed tandem accelerator of the Institute of Physics and Power Engineering (Obninsk). A high resolution (about 0.6 ns/m) and a high stability of the time-of-flight spectrometer made it possible to identify reliably low-lying levels along with the continuous section of the neutron spectra. The data obtained in this way were analyzed on the basis of the statistical equilibrium and preequilibrium models of nuclear reactions. The respective calculations were performed with the aid of the precise Hauser-Feshbach formalism of statistical theory. The nuclear-level densities in the isotopes ¹¹⁶Sb, ¹¹⁸Sb, ¹²²Sb, and ¹²⁴Sb were determined, along with their energy dependences and model parameters. In the excitation-energy range 0–2 MeV, the energy dependence of the nuclear-level densities exhibits a structure that is associated with the shell inhomogeneities of the spectrum of single-particle states near filled shells. The isotopic dependence of the nuclear-level density is discovered and explained. It is also shown that the data obtained here for the nuclear-level density differ markedly from the predictions of model systematics of nuclear-level densities.     

Level densities for nuclei with 47 ≤ A ≤ 59

Nuclear level densities of ⁴⁷V, ⁴⁸V, ⁴⁹V, ⁵³Mn, ⁵⁴Mn, ⁵⁷Co, ⁵⁹Ni and their energy dependences are determined from measurements of the neutron evaporation spectra in the (p, n) reaction. Neutron spectra from the (p, n) reaction on nuclei of ⁴⁷Ti, ⁴⁸Ti, ⁴⁹Ti, ⁵³Cr, ⁵⁴Cr, ⁵⁷Fe, and ⁵⁹Co are measured at proton energies between 7 and 11 MeV. The data are analyzed in terms of statistical equilibrium and pre-equilibrium models of nuclear reactions.     

Production of residual radioactive nuclei in thin <Superscript>209</Superscript>Bi, <Superscript>nat</Superscript>Pb, <Superscript>206</Superscript>Pb, <Superscript>207</Superscript>Pb,and <Superscript>208</Superscript>Pb targets bombarded with 0.04–2.6 GeV protons

The results of the experimental measurement and numerical simulation of the cross sections for residual radioactive nuclei production in thin ²⁰⁹Bi, ^natPb, ²⁰⁶Pb, ²⁰⁷Pb, and ²⁰⁸Pb targets bombarded with protons in the energy range from 0.04 to 2.6 GeV are reported. The nuclide production cross sections were measured using γ spectrometry with a high-resolution Ge detector. The experimental data include a total of 5972 reaction cross sections at 11 proton energy values. The results are compared to the data from other laboratories reported in 80 papers. The model calculations were carried out using eight simulation code packages: LAHET, INCL4 + ABLA, CEM03, LAQGSM + GEM2, CASCADE, CASCADE-2004, CASCADO, and LAHETO. A detailed analysis of discrepancies between the measured and calculated data is presented.     

Conjugation of Aminoadamantane and γ-Carboline Pharmacophores Gives Rise to Unexpected Properties of Multifunctional Ligands

A new series of conjugates of aminoadamantane and γ-carboline, which are basic scaffolds of the known neuroactive agents, memantine and dimebon (Latrepirdine) was synthesized and characterized. Conjugates act simultaneously on several biological structures and processes involved in the pathogenesis of Alzheimer’s disease and some other neurodegenerative disorders. In particular, these compounds inhibit enzymes of the cholinesterase family, exhibiting higher inhibitory activity against butyrylcholinesterase (BChE), but having almost no effect on the activity of carboxylesterase (anti-target). The compounds serve as NMDA-subtype glutamate receptor ligands, show mitoprotective properties by preventing opening of the mitochondrial permeability transition (MPT) pore, and act as microtubule stabilizers, stimulating the polymerization of tubulin and microtubule-associated proteins. Structure–activity relationships were studied, with particular attention to the effect of the spacer on biological activity. The synthesized conjugates showed new properties compared to their prototypes (memantine and dimebon), including the ability to bind to the ifenprodil-binding site of the NMDA receptor and to occupy the peripheral anionic site of acetylcholinesterase (AChE), which indicates that these compounds can act as blockers of AChE-induced β-amyloid aggregation. These new attributes of the conjugates represent improvements to the pharmacological profiles of the separate components by conferring the potential to act as neuroprotectants and cognition enhancers with a multifunctional mode of action.     

Excitation functions of residual nuclei production from 40-2600 MeV proton-irradiated <Superscript>206,207,208,nat</Superscript>Pb and <Superscript>209</Superscript>Bi

The work is aimed at experimental determination of the independent and cumulative yields of radioactive residual nuclei produced in intermediate-energy proton-irradiated thin targets made of highly isotopic enriched and natural lead (^{206,207,208,nat}Pb) and ²⁰⁹Bi. 5972 radioactive product nuclide yields have been measured in 55 thin targets induced by 0.04, 0.07, 0.10, 0.15, 0.25, 0.6, 0.8, 1.2, 1.4, 1.6 and 2.6 GeV protons extracted from the ITEP U-10 proton synchrotron. The measured data have been compared with data obtained at other laboratories as well as with theoretical simulations by seven codes. We found that the predictive power of the tested codes is different but is satisfactory for most of the nuclides in the spallation region, though none of the codes agree well with the data in the whole mass region of product nuclides and all should be improved further.