The self-assembly of [Cu2(dicarboxylate)2]4 nanoscale secondary building units (nSBUs) into coordination polymers can occur in such a way that a range of calix-like atropisomers can exist. Eight compounds have been prepared and crystallographically characterized via reaction between Cu(NO3)2 and angular dicarboxylate ligands:  {[Cu2(bdc)2(py)2]4•guest} n (1a), {[Cu2(bdc)2(py)2]4•4nitrobenzene•2EtOH} n (1b), {[Cu2(bdc)2(4-pic)2]4•4o-dichlorobenzene} n (2), {[Cu2(5-OEt-bdc)2(py)2]4•8H2O} n (3), {[Cu2(5-OPr-bdc)2(py)2]4•guest } n (4), {[Cu2(pdc)2(py)2]4•4MeOH} n (5), {[Cu2(pdc)2(4-pic)2]4•4H2O} n (6), and {[Cu2(tdc)2(MeOH)2]4•4naphthalene•8MeOH} n (7). The following atropisomers, all of which have also been observed in calixarenes, were observed:  (a) cone (1a, 3, and 4); (b) partial cone (1b); (c) 1,2-alternate (2 and 5−7); and (d) 1,3-alternate (1a, 3, and 4). The similarities and differences between the crystal structures of 1−7 are detailed herein.

A set of coumarin-fused electron-deficient 1,3-dienes was synthesized, which differ in the nature of the electron-withdrawing group (EWG) at the terminus of the diene unit and (when EWG = CO(2)Me) the nature and position of substituents. These dienes reacted with the enamine derived from cyclopentanone and pyrrolidine to afford the corresponding cyclopenteno-fused 6H-dibenzo[b,d]pyran-6-ones, most likely via a domino inverse electron demand Diels-Alder (IEDDA)/elimination/transfer hydrogenation sequence. The parent diene (EWG = CO(2)Me, no substituents) was reacted with a range of electron-rich dienophiles (mostly enamines) to afford the corresponding 6H-dibenzo[b,d]pyran-6-ones or their nondehydrogenated precursors, which were aromatized upon treatment with a suitable oxidant. The enamines could either be synthesized prior to the reaction or generated in situ. The syntheses of 30 dibenzopyranones are reported.

The disease, COVID-19, is caused by the severe acute respiratory coronavirus 2 (SARS-CoV-2) for which there is currently no treatment. The SARS-CoV-2 main protease (M pro ) is an important enzyme for viral replication. Small molecules that inhibit this protease could lead to an effective COVID-19 treatment. The 2-pyridone scaffold was previously identified as a possible key pharmacophore to inhibit SARS-CoV-2 M pro . A search for natural, antimicrobial products with the 2-pyridone moiety was undertaken herein, and their calculated potency as inhibitors of SARS-CoV-2 M pro was investigated. Thirty-three natural products containing the 2-pyridone scaffold were identified from the literature. An in silico methodology using AutoDock was employed to predict the binding energies and inhibition constants ( K i values) for each 2-pyridone-containing compound with SARS-CoV-2 M pro . This consisted of molecular optimization of the 2-pyridone compound, docking of the compound with a crystal structure of SARS-CoV-2 M pro , and evaluation of the predicted interactions and ligand-enzyme conformations. All compounds investigated bound to the active site of SARS-CoV-2 M pro , close to the catalytic dyad (His-41 and Cys-145). Thirteen molecules had predicted K i values < 1 μM. Glu-166 formed a key hydrogen bond in the majority of the predicted complexes, while Met-165 had some involvement in the complex binding as a close contact to the ligand. Prominent 2-pyridone compounds were further evaluated for their ADMET properties. This work has identified 2-pyridone natural products with calculated potent inhibitory activity against SARS-CoV-2 M pro and with desirable drug-like properties, which may lead to the rapid discovery of a treatment for COVID-19.

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A coumarin-fused electron deficient diene was prepared by the base-induced reaction of dimethyl glutaconate and salicaldehyde. Its inverse electron demand Diels-Alder reactions with enamines give, after in situ elimination and dehydrogenation, benzocoumarins.

IntroductionDiagnosis of Alzheimer's disease (AD) in vivo, by molecular imaging of amyloid or tau, is constrained because similar changes can be found in brains of cognitively normal individuals. Butyrylcholinesterase (BChE), which becomes associated with these structures in AD, could elevate the accuracy of AD diagnosis by focusing on BChE pathology in the cerebral cortex, a region of scant BChE activity in healthy brain.MethodsN-methylpiperidin-4-yl 4-[123I]iodobenzoate, a BChE radiotracer, was injected intravenously into B6SJL-Tg(APPSwFlLon, PSEN1∗M146 L∗L286 V) 6799Vas/Mmjax (5XFAD) mice and their wild-type (WT) counterparts for comparative single photon emission computed tomography (SPECT) studies. SPECT, computed tomography (CT), and magnetic resonance imaging (MRI) enabled comparison of whole brain and regional retention of the BChE radiotracer in both mouse strains.ResultsRetention of the BChE radiotracer was consistently higher in the 5XFAD mouse than in WT, and differences were particularly evident in the cerebral cortex.DiscussionCerebral cortical BChE imaging with SPECT can distinguish 5XFAD mouse model from the WT counterpart.

A series of novel bistriazenes, the 1,2-bis(1-aryl-3-methyltriazen-3-yl)ethanes, Ar-N T N-NMe-CH2CH2-NMe-N T N-Ar, have been synthesized by diazonium coupling with N,N'-dimethylethylenediamine. These bistriazenes are stable crystalline compounds and have been unequivocally characterized by IR and NMR spectroscopy (1H and 13C), and elemental analysis. The structures of two compounds in the series have been confirmed by X-ray crystallography. The 1H NMR spectra show significant line broadening of the N-methyl resonances arising from the restricted rotation around the N2-N3 bond of the triazene units. The presence of strongly electron-withdrawing groups on the aryl ring restricts the rotation to the point where the N-methyl signals of the rotamers are distinct even at room temperature; four resonances of the N-methyl signal are clearly evident and these can be assigned to the anti-anti, syn-syn, and syn-anti conformations of the bistriazene. Diazonium coupling with N,N'-diethylethylenediamine affords the N,N'-diethyl homologues of the bistriazenes, which have been similarly characterized. As model compounds to assist in spectroscopic analysis, a series of related triazenes, the 1-(1-aryl-3-methyltriazen-3-yl)-N,N-dimethyl-2-ethanamines, were prepared by diazonium coupling with N,N,N'-trimethylethylenediamine. These dialkyltriazenes exist mainly as oils, but characterization was achieved by IR, 1H NMR, and 13C NMR spectroscopy, also showing the presence of two rotamers in solution when strongly electron-withdrawing substituents are bonded to the aryl moiety.Key words: triazene, bistriazene, diazonium, ethylenediamine, molecular dynamics, NMR.

BuChE-specific radiolabeled iodobenzoates enter the brain and, in general, label areas known to exhibit BuChE activity in histochemical studies. Such molecules may represent a new direction for the development of agents for the molecular imaging of BuChE in the living brain, especially in regions where BuChE-containing neuropathological structures appear in AD.