Exploring the Coordination Potential of Monodentate and Bidentate Bicyclic Guanidine Ligands

<p>This thesis reports investigations of the interaction of arene-bicyclic guanidine ligands, using the 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (hppH) guandine (Figure i) as a foundation, with a variety of metal centres. Beginning with 1-benzyl-1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (Ph(CH2hpp)), attempts were made to coordinate this ligand to group 1 metal N{SiMe3}2- salts, which resulted in a novel NaN{SiMe3}2 crystal structure. Ligands comprised of a phenyl group with multiple hpp units in varying substitution patterns were also synthesised and reacted with group 1 metal N{SiMe3}2- salts to investigate the possibility of bidentate and tridentate arene-hpp coordination. This resulted in the synthesis of two novel compounds containing KN{SiMe3}2. Both sigma and pi-interactions with potassium were observed in the crystal structure of one of these compounds. NMR data that support analogous coordination to lithium and sodium analogues were also obtained. The ligands with multiple hpp units were introduced to highly reactive main group antinomy and bismuth species in an attempt to achieve a coordination with increased hapticity of the pi-interaction. A novel antimony structure was obtained with asymmetric coordination of an arene-hpp ligand in which an intramolecular C-H activation was achieved. An N-phosphino guaninde was synthesised and employed in this research due its potential to coordinate through both its available nitrogen and phosphorus atoms. This ligand was reacted with a variety of metal centres which revealed information about the strength of the N-P bond in the ligand. Two novel crystal structures were obtained which both contained novel group 1 clusters with coordinating hpp units. Finally, attempts were made to coordinate Ph(CH2hpp) to transition metal halides and N{SiMe3}2- salts. These attempts resulted in one novel crystal structure.</p>

Exploring the Coordination Potential of Monodentate and Bidentate Bicyclic Guanidine Ligands

<p>This thesis reports investigations of the interaction of arene-bicyclic guanidine ligands, using the 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (hppH) guandine (Figure i) as a foundation, with a variety of metal centres. Beginning with 1-benzyl-1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (Ph(CH2hpp)), attempts were made to coordinate this ligand to group 1 metal N{SiMe3}2- salts, which resulted in a novel NaN{SiMe3}2 crystal structure. Ligands comprised of a phenyl group with multiple hpp units in varying substitution patterns were also synthesised and reacted with group 1 metal N{SiMe3}2- salts to investigate the possibility of bidentate and tridentate arene-hpp coordination. This resulted in the synthesis of two novel compounds containing KN{SiMe3}2. Both sigma and pi-interactions with potassium were observed in the crystal structure of one of these compounds. NMR data that support analogous coordination to lithium and sodium analogues were also obtained. The ligands with multiple hpp units were introduced to highly reactive main group antinomy and bismuth species in an attempt to achieve a coordination with increased hapticity of the pi-interaction. A novel antimony structure was obtained with asymmetric coordination of an arene-hpp ligand in which an intramolecular C-H activation was achieved. An N-phosphino guaninde was synthesised and employed in this research due its potential to coordinate through both its available nitrogen and phosphorus atoms. This ligand was reacted with a variety of metal centres which revealed information about the strength of the N-P bond in the ligand. Two novel crystal structures were obtained which both contained novel group 1 clusters with coordinating hpp units. Finally, attempts were made to coordinate Ph(CH2hpp) to transition metal halides and N{SiMe3}2- salts. These attempts resulted in one novel crystal structure.</p>

Sulfonium Ligands of the α7 nAChR

The α7 nicotinic acetylcholine receptor (nAChR) is an important target given its role in cognitive function as well as in the cholinergic anti-inflammatory pathway, where ligands that are effective at stabilizing desensitized states of the receptor are of particular interest. The typical structural element associated with a good desensitizer is the ammonium pharmacophore, but recent work has identified that a trivalent sulfur, in the positively charged sulfonium form, can substitute for the nitrogen in the ammonium pharmacophore. However, the breadth and scope of employing the sulfonium group is largely unexplored. In this work, we have surveyed a disparate group of sulfonium compounds for their functional activity with α7 as well as other nAChR subtypes. Amongst them, we found that there is a wide range of ability to induce α7 desensitization, with 4-hydroxyphenyldimethylsulfonium and suplatast sulfonium salts being the most desensitizing. The smallest sulfonium compound, trimethylsulfonium, was a partial agonist for α7 and other neuronal nAChR. Molecular docking into the α7 receptor extracellular domain revealed preferred poses in the orthosteric binding site for all but one compound, with typical cation–pi interactions as seen with traditional ammonium compounds. A number of the compounds tested may serve as useful platforms for further development of α7 desensitizing ability and for receptor subtype selectivity.

Benchmarking London dispersion corrected density functional theory for noncovalent ion-pi interactions

<p>The strongly attractive noncovalent interactions of charged atoms or molecules with p-systems are important binding motifs in many chemical and biological systems. These so-called ion-pi interactions play a major role in enzymes, molecular recognition, and for the structure of proteins. In this work, a molecular test set termed IONPI19 is compiled for inter- and intramolecular ion-pi interactions, which is well balanced between anionic and cationic systems. The IONPI19 set includes interaction energies of significantly larger molecules (up to 133 atoms) than in other ion-pi test sets and covers a broad range of binding motifs. Accurate (local) coupled cluster values are provided as reference. Overall, 18 density functional approximations, including seven (meta-)GGAs, seven hybrid functionals, and four double hybrid functionals combined with three different London dispersion corrections, are benchmarked for interaction energies. DFT results are further compared to wave function based methods such as MP2 and dispersion corrected Hartree-Fock. Also the performance</p><p>of semiempirical QM methods such as the GFNn-xTB and PMx family of methods is tested. It is shown that dispersion-uncorrected DFT underestimates ion-pi interactions significantly, even though electrostatic interactions dominate the overall binding. Accordingly, the new charge dependent D4 dispersion model is found to be consistently better than the standard D3 correction. Furthermore, the functional performance trend along Jacob’s ladder is generally obeyed and the reduction of the self-interaction error leads to an improvement of (double) hybrid functionals over (meta-)GGAs, even though the effect of the SIE is smaller than expected. Overall, the double hybrids PWPB95-D4/QZ and revDSD-PBEP86-D4/QZ turned out to be the most reliable among all assessed methods in predicting ion-pi interactions, which opens up new perspectives for systems where coupled cluster calculations are no longer computationally feasible.</p>

Coordination Chemistry of a bis(tetrazine) tweezer: A Case of Host-guest Behavior With Silver Salts

The carbon-carbon cross-coupling of phenyl s-tetrazine (Tz) units at their ortho-phenyl positions allows to form constrained bis(tetrazines) with original tweezer structures. In these compounds, the face-to-face positioning of the central tetrazine cores is endorsed by pi-staking of the electron-poor nitrogen-containing heteroaromatic moieties. The resulting tetra-aromatic structure can be used as a weak coordinating ligand with cationic silver. This coordination generates a set of bis(tetrazine)‐silver(I) coordination complexes tolerating a large variety of counter anions of various geometries, namely, PF6&ndash;, BF4&ndash;, SbF6&ndash;, ClO4&ndash;, NTf2&ndash;, OTf2&ndash;. These compounds were characterized in the solid-state by single crystal XRD and reflectance spectra, and in solution by 1H NMR, mass spectrometry, electroanalysis and UV-visible absorption spectroscopy. The X-ray diffraction (XRD) structure of complexes {[Ag(3)][PF6]}&infin; (4) and {[Ag(3)][SbF6]&infin; (6), where 3 is 3,3'-[(1,1'-biphenyl)-2,2'-diyl]-6,6'-bis[phenyl]-1,2,4,5-tetrazine, revealed the formation of 1D polymeric chains, characterized by an evolution to a large opening of the original tweezer and a coordination of silver(I) via two chelating nitrogen atom and some C=C pi-interactions. Electrochemical and UV spectroscopic properties of the original tweezer and of the corresponding silver complex are reported and compared. 1H NMR titrations with AgNTf2 allowed to determine the stoichiometry, and apparent stability of two solution species, namely [Ag(3)]+ and [Ag(3)2]2+, that formed in CDCl3/CD3OD 2:1 v/v mixtures.

Benchmarking London dispersion corrected density functional theory for noncovalent ion-pi interactions

<p>The strongly attractive noncovalent interactions of charged atoms or molecules with p-systems are important binding motifs in many chemical and biological systems. These so-called ion-pi interactions play a major role in enzymes, molecular recognition, and for the structure of proteins. In this work, a molecular test set termed IONPI19 is compiled for inter- and intramolecular ion-pi interactions, which is well balanced between anionic and cationic systems. The IONPI19 set includes interaction energies of significantly larger molecules (up to 133 atoms) than in other ion-pi test sets and covers a broad range of binding motifs. Accurate (local) coupled cluster values are provided as reference. Overall, 18 density functional approximations, including seven (meta-)GGAs, seven hybrid functionals, and four double hybrid functionals combined with three different London dispersion corrections, are benchmarked for interaction energies. DFT results are further compared to wave function based methods such as MP2 and dispersion corrected Hartree-Fock. Also the performance</p><p>of semiempirical QM methods such as the GFNn-xTB and PMx family of methods is tested. It is shown that dispersion-uncorrected DFT underestimates ion-pi interactions significantly, even though electrostatic interactions dominate the overall binding. Accordingly, the new charge dependent D4 dispersion model is found to be consistently better than the standard D3 correction. Furthermore, the functional performance trend along Jacob’s ladder is generally obeyed and the reduction of the self-interaction error leads to an improvement of (double) hybrid functionals over (meta-)GGAs, even though the effect of the SIE is smaller than expected. Overall, the double hybrids PWPB95-D4/QZ and revDSD-PBEP86-D4/QZ turned out to be the most reliable among all assessed methods in predicting ion-pi interactions, which opens up new perspectives for systems where coupled cluster calculations are no longer computationally feasible.</p>

Reducing hERG Toxicity Using hERG Classification Model and Fragment-growing Network

Drug-induced cardiotoxicity has become one of the major reasons leading to drug withdrawal in past decades, which is closely related to the blockade of human Ether-a-go-go-related gene (hERG) potassium channel. Developing reliable hERG predicting model and optimizing model can greatly reduce the risk faced in drug discovery. In this study, we constructed eight hERG classification models, the best of which shows desirable generalization ability on low-similarity clinical compounds, as well as advantages in perceiving activity gap caused by small structural changes. Furthermore, we developed a hERG optimizer based on fragment grow strategy and explored its usage in four cases. After reinforcement learning, our model successfully suggests same or similar compounds as chemists’ optimization. Results suggest that our model can provide reasonable optimizing direction to reduce hERG toxicity when hERG risk is corresponding to lipophilicity, basicity, the number of rotatable bonds and pi-pi interactions. Overall, we demonstrate our model as a promising tool for medicinal chemists in hERG optimization attempts.

The modulation effect of pi–pi interactions on the electronic and photochromic properties of viologen complexes containing N,N′-bis(carboxyethyl)-4,4′-bipyridinium

Two viologen complexes containing BCEbpy were prepared and displayed excellent photo-response properties by the modulation effect of pi–pi interactions.

Docking Study of Naringin Binding with COVID-19 Main Protease Enzyme

The Coronavirus Disease (COVID-19) has recently emerged as a human pathogen caused by SARS-CoV-2 virus was first reported from Wuhan, China, on 31 December 2019. Upon study, it has been used molecular docking to binding affinity between COVID-19 protease enzyme and flavonoids with evaluations based on docking scores calculated by AutoDock Vina. Results showed that naringin suppressed COVID-19 protease, as it has the highest binding value than other flavonoids including quercetin, hesperetin, garcina and naringenin. An important finding in this study is that naringin with neighboring poly hydroxyl groups can serve as inhibitors of COVID-19 protease bind to the S pocket of protein, it is shown that residues His163, Glu166, Asn142, His41and PHe181 participate in the hydrogen bonding and pi-pi interactions, the same as happened with decahydroisoquinolin as a novel scaffold for SARS 3CL protease inhibitors.In other hand, some of the known protease inhibitors and anti-influenza drugs docked with COVID-19 protease, it has low binding value than naringin